Professor Emeritus-Hourly, Psychiatry and Behavioral Sciences
Psychopharmacology of dementia and Alzheimer's disease;, biological correlates of Alzheimer's disease; sexual dysfunction in, Alzheimer's disease; memory disorders.
Modafinil, trade named Provigil, is a medication approved by the Food and Drug Administration for the treatment of narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder. Each of these problems is characterized by difficulty sleeping at night and excessive daytime sleepiness. Modafinil is prescribed during the day to counteract this sleepiness. The idea behind this treatment is that sleepiness that leads to napping during the day prevents a patient from being tired or sleepy enough to get good sleep at night. This study is designed to determine if the medication can "reset" participants' sleep/wake rhythm to a more normal rhythm.
Stanford is currently not accepting patients for this trial. For more information, please contact Ban Ku, (650) 849 - 1971.
Alzheimer's disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy. Here, we report FAM222A as a putative brain atrophy susceptibility gene. Our cross-phenotype association analysis of imaging genetics indicates a potential link between FAM222A and AD-related regional brain atrophy. The protein encoded by FAM222A is predominantly expressed in the CNS and is increased in brains of patients with AD and in an AD mouse model. It accumulates within amyloid deposits, physically interacts with amyloid-? (A?) via its N-terminal A? binding domain, and facilitates A? aggregation. Intracerebroventricular infusion or forced expression of this protein exacerbates neuroinflammation and cognitive dysfunction in an AD mouse model whereas ablation of this protein suppresses the formation of amyloid deposits, neuroinflammation and cognitive deficits in the AD mouse model. Our data support the pathological relevance of protein encoded by FAM222A in AD.
View details for DOI 10.1038/s41467-019-13962-0
View details for Web of Science ID 000511941200001
View details for PubMedID 31964863
View details for PubMedCentralID PMC6972869
There is well-documented evidence of brain network differences between individuals with Alzheimer's disease (AD) and healthy controls (HC). To date, imaging studies investigating brain networks in these populations have typically been cross-sectional, and the reproducibility of such findings is somewhat unclear. In a novel study, we use the longitudinal ADNI data on the whole brain to jointly compute the brain network at baseline and one-year using a state of the art approach that pools information across both time points to yield distinct visit-specific networks for the AD and HC cohorts, resulting in more accurate inferences. We perform a multiscale comparison of the AD and HC networks in terms of global network metrics as well as at the more granular level of resting state networks defined under a whole brain parcellation. Our analysis illustrates a decrease in small-worldedness in the AD group at both the time points and also identifies more local network features and hub nodes that are disrupted due to the progression of AD. We also obtain high reproducibility of the HC network across visits. On the other hand, a separate estimation of the networks at each visit using standard graphical approaches reveals fewer meaningful differences and lower reproducibility.
View details for DOI 10.1038/s41598-019-55818-z
View details for Web of Science ID 000508872700035
View details for PubMedID 31863067
View details for PubMedCentralID PMC6925181
Numerous studies have proposed biomarkers based on magnetic resonance imaging (MRI) to detect and predict the risk of evolution toward Alzheimer's disease (AD). Most of these methods have focused on the hippocampus, which is known to be one of the earliest structures impacted by the disease. To date, patch-based grading approaches provide among the best biomarkers based on the hippocampus. However, this structure is complex and is divided into different subfields, not equally impacted by AD. Former in-vivo imaging studies mainly investigated structural alterations of these subfields using volumetric measurements and microstructural modifications with mean diffusivity measurements. The aim of our work is to improve the current classification performances based on the hippocampus with a new multimodal patch-based framework combining structural and diffusivity MRI. The combination of these two MRI modalities enables the capture of subtle structural and microstructural alterations. Moreover, we propose to study the efficiency of this new framework applied to the hippocampal subfields. To this end, we compare the classification accuracy provided by the different hippocampal subfields using volume, mean diffusivity, and our novel multimodal patch-based grading framework combining structural and diffusion MRI. The experiments conducted in this work show that our new multimodal patch-based method applied to the whole hippocampus provides the most discriminating biomarker for advanced AD detection while our new framework applied into subiculum obtains the best results for AD prediction, improving by two percentage points the accuracy compared to the whole hippocampus.
View details for DOI 10.1038/s41598-019-49970-9
View details for Web of Science ID 000487586600036
View details for PubMedID 31554909
Non-invasive brain stimulation (NIBS) has been widely used to treat mild cognitive impairment (MCI). However, there exists no consensus on the best stimulation sites.To explore potential stimulation locations for NIBS treatment in patients with MCI, combining meta- and resting state functional connectivity (rsFC) analyses.The meta-analysis was conducted to identify brain regions associated with MCI. Regions of interest (ROIs) were extracted based on this meta-analysis. The rsFC analysis was applied to 45 MCI patients to determine brain surface regions that are functionally connected with the above ROIs.We found that the dorsolateral prefrontal cortex (DLPFC) and inferior frontal gyrus (IFG) were the overlapping brain regions between our results and those of previous studies. In addition, we recommend that the temporoparietal junction (including the angular gyrus), which was found in both the meta- and rsFC analysis, should be considered in NIBS treatment of MCI. Furthermore, the bilateral orbital prefrontal gyrus, inferior temporal gyrus, medial superior frontal gyrus, and right inferior occipital gyrus may be potential brain stimulation sites for NIBS treatment of MCI.Our results provide several potential sites for NIBS, such as the DLFPC and IFG, and may shed light on the locations of NIBS sites in the treatment of patients with MCI.
View details for DOI 10.3389/fnagi.2019.00228
View details for Web of Science ID 000482809900001
View details for PubMedID 31551754
View details for PubMedCentralID PMC6736566
Alzheimer's disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-?4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-?4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
View details for DOI 10.1038/s41467-019-10945-z
View details for Web of Science ID 000477017000003
View details for PubMedID 31346172
View details for PubMedCentralID PMC6658518
We investigated the association between amyloid-? deposition and white matter (WM) integrity as a determinant of brain glucose hypometabolism across the Alzheimer's disease (AD) spectrum. We assessed ninety-six subjects (27 cognitively normal, 49 mild cognitive impairment, and 20 AD dementia) who underwent [18F]FDG and [18F]Florbetapir positron emission tomography (PET) as well as magnetic resonance imaging (MRI) with diffusion tensor imaging. Among the regions with reduced fractional anisotropy (FA) in the AD group, we selected a voxel of interest in the angular bundle bilaterally for subsequent analyses. Using voxel-based interaction models at voxel level, we tested whether the regional hypometabolism is associated with FA in the angular bundle and regional amyloid-? deposition. In the AD patients, [18F]FDG hypometabolism in the striatum, mesiobasal temporal, orbitofrontal, precuneus, and cingulate cortices were associated with the interaction between high levels of [18F]Florbetapir standard uptake value ratios (SUVR) in these regions and low FA in the angular bundle. We found that the interaction between, rather than the independent effects of, high levels of amyloid-? deposition and WM integrity disruption determined limbic hypometabolism in patients with AD. This finding highlights a more integrative model for AD, where the interaction between partially independent processes determines the glucose hypometabolism.
View details for DOI 10.1007/s12035-018-1405-1
View details for Web of Science ID 000483159700024
View details for PubMedID 30414086
The single nucleotide polymorphism (SNP) rs744373 in the bridging integrator-1 gene (BIN1) is a risk factor for Alzheimer's disease (AD). In the brain, BIN1 is involved in endocytosis and sustaining cytoskeleton integrity. Post-mortem and in vitro studies suggest that BIN1-associated AD risk is mediated by increased tau pathology but whether rs744373 is associated with increased tau pathology in vivo is unknown. Here we find in 89 older individuals without dementia, that BIN1 rs744373 risk-allele carriers show higher AV1451 tau-PET across brain regions corresponding to Braak stages II-VI. In contrast, the BIN1 rs744373 SNP was not associated with AV45 amyloid-PET uptake. Furthermore, the rs744373 risk-allele was associated with worse memory performance, mediated by increased global tau levels. Together, our findings suggest that the BIN1 rs744373 SNP is associated with increased tau but not beta-amyloid pathology, suggesting that alterations in BIN1 may contribute to memory deficits via increased tau pathology.
View details for DOI 10.1038/s41467-019-09564-5
View details for Web of Science ID 000464654700005
View details for PubMedID 30992433
View details for PubMedCentralID PMC6467911
White matter hyperintensities (WMHs) are common in individuals with mild cognitive impairment (MCI) and Alzheimer's disease. Patients with MCI with high WMH volumes are known to have an increased chance of conversion to Alzheimer's disease compared with those without WMHs. In this article, we assess the differences between patients with MCI that remain stable (N = 413) and those that progress to dementia (N = 178) in terms of WMH volume (as a surrogate of amount of tissue damage) and T1-weighted (T1w) image hypointensity (as a surrogate of severity of tissue damage) in periventricular, deep, and juxtacortical brain regions. Together, lesion volume and T1w hypointensity are used as a surrogate of vascular disease burden. Our results show a significantly greater increase of all regional WMH volumes in the MCI population that converts to dementia (p < 0.001). T1w hypointensity for the juxtacortical WMHs was significantly lower in the converter group (p < 0.0001) and was not affected by age. Conversely, T1w hypointensity in other regions showed a significant decrease with age (p < 0.0001). Within the converters, Time2Conversion was associated with both WMH volume and T1w hypointensity (p < 0.0001), and conversion to dementia was significantly associated with decreased intensity (and not volume) of periventricular and juxtacortical WMHs (p < 0.001). These changes differ according to the WM region, suggesting that different mechanisms affect the juxtacortical area in comparison to deep and periventricular regions in the process of conversion to dementia.
View details for DOI 10.1016/j.neurobiolaging.2018.12.004
View details for Web of Science ID 000459500800009
View details for PubMedID 30703628
It is increasingly recognized that Alzheimer's disease (AD) exists before dementia is present and that shifts in amyloid beta occur long before clinical symptoms can be detected. Early detection of these molecular changes is a key aspect for the success of interventions aimed at slowing down rates of cognitive decline. Recent evidence indicates that of the two established methods for measuring amyloid, a decrease in cerebrospinal fluid (CSF) amyloid ?1-42 (A?1-42) may be an earlier indicator of Alzheimer's disease risk than measures of amyloid obtained from Positron Emission Tomography (PET). However, CSF collection is highly invasive and expensive. In contrast, blood collection is routinely performed, minimally invasive and cheap. In this work, we develop a blood-based signature that can provide a cheap and minimally invasive estimation of an individual's CSF amyloid status using a machine learning approach. We show that a Random Forest model derived from plasma analytes can accurately predict subjects as having abnormal (low) CSF A?1-42 levels indicative of AD risk (0.84 AUC, 0.78 sensitivity, and 0.73 specificity). Refinement of the modeling indicates that only APOE?4 carrier status and four plasma analytes (CGA, A?1-42, Eotaxin 3, APOE) are required to achieve a high level of accuracy. Furthermore, we show across an independent validation cohort that individuals with predicted abnormal CSF A?1-42 levels transitioned to an AD diagnosis over 120 months significantly faster than those with predicted normal CSF A?1-42 levels and that the resulting model also validates reasonably across PET A?1-42 status (0.78 AUC). This is the first study to show that a machine learning approach, using plasma protein levels, age and APOE?4 carrier status, is able to predict CSF A?1-42 status, the earliest risk indicator for AD, with high accuracy.
View details for DOI 10.1038/s41598-018-37149-7
View details for Web of Science ID 000460755200011
View details for PubMedID 30853713
Alzheimer's disease (AD) is the most common type of dementia in the elderly with no effective treatment currently. Recent studies of noninvasive neuroimaging, resting-state functional magnetic resonance imaging (rs-fMRI) with graph theoretical analysis have shown that patients with AD and mild cognitive impairment (MCI) exhibit disrupted topological organization in large-scale brain networks. In previous work, it is a common practice to threshold such networks. However, it is not only difficult to make a principled choice of threshold values, but also worse is the discard of potential important information. To address this issue, we propose a threshold-free feature by integrating a prior persistent homology-based topological feature (the zeroth Betti number) and a newly defined connected component aggregation cost feature to model brain networks over all possible scales. We show that the induced topological feature (Integrated Persistent Feature) follows a monotonically decreasing convergence function and further propose to use its slope as a concise and persistent brain network topological measure. We apply this measure to study rs-fMRI data from the Alzheimer's Disease Neuroimaging Initiative and compare our approach with five other widely used graph measures across five parcellation schemes ranging from 90 to 1,024 region-of-interests. The experimental results demonstrate that the proposed network measure shows more statistical power and stronger robustness in group difference studies in that the absolute values of the proposed measure of AD are lower than MCI and much lower than normal controls, providing empirical evidence for decreased functional integration in AD dementia and MCI.
View details for DOI 10.1002/hbm.24383
View details for Web of Science ID 000459470400002
View details for PubMedID 30569583
Memory assessment is a key factor for the diagnosis of cognitive impairment. However, memory performance over time may be quite heterogeneous within diagnostic groups.To identify latent trajectories in memory performance and their associated risk factors, we analyzed data from Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who were classified either as cognitively normal or as Mild Cognitive Impairment (MCI) at baseline and were administered the Rey Auditory Verbal Learning test (RAVLT) for up to 9 years. Group-based trajectory modeling on the 30-minute RAVLT delayed recall score was applied separately to the two baseline diagnostic groups.There were 219 normal subjects with mean age 75.9 (range from 59.9 to 89.6) and 52.5% male participants, and 372 MCI subjects with mean age 74.8 (range from 55.1 to 89.3) and 63.7% male participants included in the analysis. For normal subjects, six trajectories were identified. Trajectories were classified into three types, determined by the shape, each of which may comprise more than one trajectory: stable (~30% of subjects), curvilinear decline (~ 28%), and linear decline (~ 42%). Notably, none of the normal subjects assigned to the stable stratum progressed to dementia during the study period. In contrast, all trajectories identified for the MCI group tended to decline, although some participants were later re-diagnosed with normal cognition. Age, sex, and education were significantly associated with trajectory membership for both diagnostic groups, while APOE ?4 was only significantly associated with trajectories among MCI participants.Memory trajectory is a strong indicator of dementia risk. If likely trajectory of memory performance can be identified early, such work may allow clinicians to monitor or predict progression of individual patient cognition. This work also shows the importance of longitudinal cognitive testing and monitoring.
View details for DOI 10.1371/journal.pone.0212435
View details for Web of Science ID 000459710700013
View details for PubMedID 30802256
View details for PubMedCentralID PMC6389289
In the Alzheimer's disease (AD) continuum, the prodromal state of mild cognitive impairment (MCI) precedes AD dementia and identifying MCI individuals at risk of progression is important for clinical management. Our goal was to develop generalizable multivariate models that integrate high-dimensional data (multimodal neuroimaging and cerebrospinal fluid biomarkers, genetic factors, and measures of cognitive resilience) for identification of MCI individuals who progress to AD within 3 years. Our main findings were i) we were able to build generalizable models with clinically relevant accuracy (~93%) for identifying MCI individuals who progress to AD within 3 years; ii) markers of AD pathophysiology (amyloid, tau, neuronal injury) accounted for large shares of the variance in predicting progression; iii) our methodology allowed us to discover that expression of CR1 (complement receptor 1), an AD susceptibility gene involved in immune pathways, uniquely added independent predictive value. This work highlights the value of optimized machine learning approaches for analyzing multimodal patient information for making predictive assessments.
View details for DOI 10.1038/s41598-019-38793-3
View details for Web of Science ID 000459092800005
View details for PubMedID 30783207
View details for PubMedCentralID PMC6381141
The CD40 pathway has been implicated in microglial activation, which is considered as a key factor in the pathogenesis of Alzheimer's disease (AD). However, the association of CSF CD40 and synaptic degeneration in living human is not clear. A total of 294 subjects with different severities of cognitive impairments were included in this study: 84 participants with normal cognition, 143 patients with mild cognitive impairment (MCI) and 67 patients with mild AD. Levels of CD40 in CSF were compared among the three groups. Further, several linear regression models were conducted to explore the associations of CSF CD40 and neurogranin levels (reflecting synaptic degeneration) when controlling for age, gender, educational attainment, APOE4 genotype, clinical diagnosis, CSF A?42 and tau proteins. We found that CSF CD40 levels were significantly decreased in patients with mild AD compared with healthy controls and MCI patients (control vs. AD, p?=?0.0026; MCI vs. AD, p?=?0.0268). However, there were no significant differences in CSF CD40 levels between controls and patients with MCI (p?=?0.37). In addition, CSF CD40 levels were associated with neurogranin in the pooled sample when controlling for age, gender, educational attainment, APOE4 genotype and diagnosis. In summary, our findings support the notion that the CD40 pathway may contribute to an important mechanism underlying synaptic degeneration in AD.
View details for DOI 10.1016/j.neulet.2018.11.019
View details for Web of Science ID 000459643800007
View details for PubMedID 30447377
The microtubule-associated protein tau gene (MAPT) rs242557 variant is associated with multiple tauopathies and dementia. This study investigated whether it was correlated with brain tau-PET uptake in non-demented elders. Ninety non-demented elders were identified from the Alzheimer's Disease Neuroimaging Initiative cohort. We compared standardized uptake value ratios (SUVRs) of tau-PET tracer 18F-AV-1451 between rs242557 variant carriers and non-carriers in 25 regions of interest (ROIs). The minor allele A was associated with increased hippocampus 18F-AV-1451 uptake in non-demented elders (left: ? = 0.111, Bonferroni corrected p = 0.035; right: ? = 0.103, Bonferroni corrected p = 0.031). A?-positive participants (left: ? = 0.206, Bonferroni corrected p = 0.029; right: ? = 0.198, Bonferroni corrected p = 0.035) and APOE ?4 non-carriers (left: ? = 0.140, Bonferroni corrected p = 0.006; right: ? = 0.134, Bonferroni corrected p = 0.004) exhibited approximately the same findings in hippocampus. Considering no obvious associations in other regions, we confirmed the significant correlation of MAPT rs242557 risk variant with increased hippocampus tau deposition in non-demented elders. With higher magnitude signals in the hippocampus that is more likely to be uniquely affected in AD, the tau PET ligand 18F-AV-1451 seemed to possess a specific binding property for AD-like tau pathology.
View details for DOI 10.18632/aging.101783
View details for Web of Science ID 000459482200011
View details for PubMedID 30708351
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Time-dependent data collected in studies of Alzheimer's disease usually has missing and irregularly sampled data points. For this reason time series methods which assume regular sampling cannot be applied directly to the data without a pre-processing step. In this paper we use a random forest to learn the relationship between pairs of data points at different time separations. The input vector is a summary of the time series history and it includes both demographic and non-time varying variables such as genetic data. To test the method we use data from the TADPOLE grand challenge, an initiative which aims to predict the evolution of subjects at risk of Alzheimer's disease using demographic, physical and cognitive input data. The task is to predict diagnosis, ADAS-13 score and normalised ventricles volume. While the competition proceeds, forecasting methods may be compared using a leaderboard dataset selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and with standard metrics for measuring accuracy. For diagnosis, we find an mAUC of 0.82, and a classification accuracy of 0.73 compared with a benchmark SVM predictor which gives mAUC = 0.62 and BCA = 0.52. The results show that the method is effective and comparable with other methods.
View details for DOI 10.1371/journal.pone.0211558
View details for Web of Science ID 000458763900015
View details for PubMedID 30763336
View details for PubMedCentralID PMC6375557
Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by a decline in cognitive functions with no validated disease modifying treatment. It is critical for timely treatment to detect AD in its earlier stage before clinical manifestation. Mild cognitive impairment (MCI) is an intermediate stage between cognitively normal older adults and AD. To predict conversion from MCI to probable AD, we applied a deep learning approach, multimodal recurrent neural network. We developed an integrative framework that combines not only cross-sectional neuroimaging biomarkers at baseline but also longitudinal cerebrospinal fluid (CSF) and cognitive performance biomarkers obtained from the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI). The proposed framework integrated longitudinal multi-domain data. Our results showed that 1) our prediction model for MCI conversion to AD yielded up to 75% accuracy (area under the curve (AUC)?=?0.83) when using only single modality of data separately; and 2) our prediction model achieved the best performance with 81% accuracy (AUC?=?0.86) when incorporating longitudinal multi-domain data. A multi-modal deep learning approach has potential to identify persons at risk of developing AD who might benefit most from a clinical trial or as a stratification approach within clinical trials.
View details for DOI 10.1038/s41598-018-37769-z
View details for Web of Science ID 000458572500013
View details for PubMedID 30760848
View details for PubMedCentralID PMC6374429
Whole brain segmentation from structural magnetic resonance imaging (MRI) is a prerequisite for most morphological analyses, but is computationally intense and can therefore delay the availability of image markers after scan acquisition. We introduce QuickNAT, a fully convolutional, densely connected neural network that segments a MRI brain scan in 20?s. To enable training of the complex network with millions of learnable parameters using limited annotated data, we propose to first pre-train on auxiliary labels created from existing segmentation software. Subsequently, the pre-trained model is fine-tuned on manual labels to rectify errors in auxiliary labels. With this learning strategy, we are able to use large neuroimaging repositories without manual annotations for training. In an extensive set of evaluations on eight datasets that cover a wide age range, pathology, and different scanners, we demonstrate that QuickNAT achieves superior segmentation accuracy and reliability in comparison to state-of-the-art methods, while being orders of magnitude faster. The speed up facilitates processing of large data repositories and supports translation of imaging biomarkers by making them available within seconds for fast clinical decision making.
View details for DOI 10.1016/j.neuroimage.2018.11.042
View details for Web of Science ID 000455968400064
View details for PubMedID 30502445
The entorhinal-hippocampal circuit is a strategic hub for cognition and the first site affected by Alzheimer's disease (AD). We investigated magnetic resonance imaging patterns of brain atrophy and functional connectivity in an Alzheimer's Disease Neuroimaging Initiative data set that included healthy controls, mild cognitive impairment (MCI), and patients with AD. Individuals with MCI were clinically evaluated 24 months after the first magnetic resonance imaging scan, and the cohort subdivided into sets of individuals who either did or did not convert to AD. The MCI group was also divided into patients who did show or not the presence of AD-related alterations in the cerebrospinal fluid. Patients with AD exhibited the collapse of the long-range hippocampal/entorhinal connectivity, pronounced cortical/subcortical atrophy, and a dramatic decline in cognitive performances. Patients with MCI who converted to AD or patients with MCI who showed the presence of AD-related alterations in the cerebrospinal fluid showed memory deficits, entorhinal/hippocampal hypoconnectivity, and concomitant atrophy of the two regions. Patients with MCI who did not convert to AD or patients with MCI who did not show the presence of AD-related alterations in the cerebrospinal fluid had no atrophy but showed hippocampal/entorhinal hyperconnectivity with selected neocortical/subcortical regions involved in memory processing and brain metastability. This hyperconnectivity may represent a compensatory strategy against the progression of cognitive impairment.
View details for DOI 10.1016/j.neurobiolaging.2018.10.004
View details for Web of Science ID 000455193900003
View details for PubMedID 30408719
The International Genomics of Alzheimer's Project (IGAP) is a consortium for characterizing the genetic landscape of Alzheimer's disease (AD). The identified and/or confirmed 19 single-nucleotide polymorphisms (SNPs) associated with AD are located on non-coding DNA regions, and their functional impacts on AD are as yet poorly understood. We evaluated the roles of the IGAP SNPs by integrating data from many resources, based on whether the IGAP SNP was (1) a proxy for a coding SNP or (2) associated with altered mRNA transcript levels. For (1), we confirmed that 12 AD-associated coding common SNPs and five nonsynonymous rare variants are in linkage disequilibrium with the IGAP SNPs. For (2), the IGAP SNPs in CELF1 and MS4A6A were associated with expression of their neighboring genes, MYBPC3 and MS4A6A, respectively, in blood. The IGAP SNP in DSG2 was an expression quantitative trait loci (eQTL) for DLGAP1 and NETO1 in the human frontal cortex. The IGAP SNPs in ABCA7, CD2AP, and CD33 each acted as eQTL for AD-associated genes in brain. Our approach for identifying proxies and examining eQTL highlighted potentially impactful, novel gene regulatory phenomena pertinent to the AD phenotype.
View details for DOI 10.1016/j.neurobiolaging.2018.10.017
View details for Web of Science ID 000455193900013
View details for PubMedID 30448613
View details for PubMedCentralID PMC6331247
Amyloid beta (A?) deposition and cognitive decline are key features of Alzheimer's disease. The relationship between A? status and changes in neuronal function over time, however, remains unclear. We evaluated the effect of baseline A? status on reference region spontaneous brain activity (SBA-rr) using resting-state functional magnetic resonance imaging and fluorodeoxyglucose positron emission tomography in patients with mild cognitive impairment. Patients (N = 62, [43 A?-positive]) from the Alzheimer's Disease Neuroimaging Initiative were divided into A?-positive and A?-negative groups via prespecified cerebrospinal fluid A?42 or 18F-florbetapir positron emission tomography standardized uptake value ratio cutoffs measured at baseline. We analyzed interaction of biomarker-confirmed A? status with SBA-rr change over a 2-year period using mixed-effects modeling. SBA-rr differences between A?-positive and A?-negative subjects increased significantly over time within subsystems of the default and visual networks. Changes exhibit an interaction with memory performance over time but were independent of glucose metabolism. Results reinforce the value of resting-state functional magnetic resonance imaging in evaluating Alzheimer''s disease progression and suggest spontaneous neuronal activity changes are concomitant with cognitive decline.
View details for DOI 10.1016/j.neurobiolaging.2018.10.002
View details for Web of Science ID 000455193900018
View details for PubMedID 30471630
Clinical observations of patients with chronic diseases are often restricted in terms of duration. Therefore, obtaining a quantitative and comprehensive understanding of the chronology of chronic diseases is challenging, because of the inability to precisely estimate the patient's disease stage at the time point of observation. We developed a novel method to reconstitute long-term disease progression from temporally fragmented data by extending the nonlinear mixed-effects model to incorporate the estimation of "disease time" of each subject. Application of this method to sporadic Alzheimer's disease successfully depicted disease progression over 20 years. The covariate analysis revealed earlier onset of amyloid-? accumulation in male and female apolipoprotein E ?4 homozygotes, whereas disease progression was remarkably slower in female ?3 homozygotes compared with female ?4 carriers and males. Simulation of a clinical trial suggests patient recruitment using the information of precise disease time of each patient will decrease the sample size required for clinical trials.
View details for DOI 10.1002/cpt.1166
View details for Web of Science ID 000457465200029
View details for PubMedID 29951994
We present an algorithm for creating high resolution anatomically plausible images consistent with acquired clinical brain MRI scans with large inter-slice spacing. Although large data sets of clinical images contain a wealth of information, time constraints during acquisition result in sparse scans that fail to capture much of the anatomy. These characteristics often render computational analysis impractical as many image analysis algorithms tend to fail when applied to such images. Highly specialized algorithms that explicitly handle sparse slice spacing do not generalize well across problem domains. In contrast, we aim to enable application of existing algorithms that were originally developed for high resolution research scans to significantly undersampled scans. We introduce a generative model that captures fine-scale anatomical structure across subjects in clinical image collections and derive an algorithm for filling in the missing data in scans with large inter-slice spacing. Our experimental results demonstrate that the resulting method outperforms state-of-the-art upsampling super-resolution techniques, and promises to facilitate subsequent analysis not previously possible with scans of this quality. Our implementation is freely available at https://github.com/adalca/papago.
View details for DOI 10.1109/TMI.2018.2866692
View details for Web of Science ID 000457604700017
View details for PubMedID 30136936
Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid-? deposition.Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET).Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF A?1-42 ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05).This is the first study to show serum-based BA metabolites are associated with "A/T/N" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.
View details for PubMedID 30337152
The aim was to create readily available algorithms that estimate the individual risk of ?-amyloid (A?) positivity.The algorithms were tested in BioFINDER (n = 391, subjective cognitive decline or mild cognitive impairment) and validated in Alzheimer's Disease Neuroimaging Initiative (n = 661, subjective cognitive decline or mild cognitive impairment). The examined predictors of A? status were demographics; cognitive tests; white matter lesions; apolipoprotein E (APOE); and plasma A?42/A?40, tau, and neurofilament light.A? status was accurately estimated in BioFINDER using age, 10-word delayed recall or Mini-Mental State Examination, and APOE (area under the receiver operating characteristics curve = 0.81 [0.77-0.85] to 0.83 [0.79-0.87]). When validated, the models performed almost identical in Alzheimer's Disease Neuroimaging Initiative (area under the receiver operating characteristics curve = 0.80-0.82) and within different age, subjective cognitive decline, and mild cognitive impairment populations. Plasma A?42/A?40 improved the models slightly.The algorithms are implemented on http://amyloidrisk.com where the individual probability of being A? positive can be calculated. This is useful in the workup of prodromal Alzheimer's disease and can reduce the number needed to screen in Alzheimer's disease trials.
View details for DOI 10.1016/j.jalz.2018.08.014
View details for Web of Science ID 000457693500002
View details for PubMedID 30365928
The aim of this study was to verify the reliability and generalizability of an automatic tool for the detection of Alzheimer-related hypometabolic pattern based on a Support-Vector-Machine (SVM) model analyzing 18F-fluorodeoxyglucose (FDG) PET data.The SVM model processed metabolic data from anatomical volumes of interest also considering interhemispheric asymmetries. It was trained on a homogeneous dataset from a memory clinic center and tested on an independent multicentric dataset drawn from the Alzheimer's Disease Neuroimaging Initiative. Subjects were included in the study and classified based on a diagnosis confirmed after an adequate follow-up time.The accuracy of the discrimination between patients with Alzheimer Disease (AD), in either prodromal or dementia stage, and normal aging subjects was 95.8%, after cross-validation, in the training set. The accuracy of the same model in the testing set was 86.5%. The role of the two datasets was then reversed, and the accuracy was 89.8% in the multicentric training set and 88.0% in the monocentric testing set. The classification rate was also evaluated in different subgroups, including non-converter mild cognitive impairment (MCI) patients, subjects with MCI reverted to normal conditions and subjects with non-confirmed memory concern. The percent of pattern detections increased from 77% in early prodromal AD to 91% in AD dementia, while it was about 10% for healthy controls and non-AD patients.The present findings show a good level of reproducibility and generalizability of a model for detecting the hypometabolic pattern in AD and confirm the accuracy of FDG-PET in Alzheimer disease.
View details for DOI 10.1007/s00259-018-4197-7
View details for Web of Science ID 000455817600009
View details for PubMedID 30382303
Alzheimer's Disease (AD) is characterized by a cascade of biomarkers becoming abnormal, the pathophysiology of which is very complex and largely unknown. Event-based modeling (EBM) is a data-driven technique to estimate the sequence in which biomarkers for a disease become abnormal based on cross-sectional data. It can help in understanding the dynamics of disease progression and facilitate early diagnosis and prognosis by staging patients. In this work we propose a novel discriminative approach to EBM, which is shown to be more accurate than existing state-of-the-art EBM methods. The method first estimates for each subject an approximate ordering of events. Subsequently, the central ordering over all subjects is estimated by fitting a generalized Mallows model to these approximate subject-specific orderings based on a novel probabilistic Kendall's Tau distance. We also introduce the concept of relative distance between events which helps in creating a disease progression timeline. Subsequently, we propose a method to stage subjects by placing them on the estimated disease progression timeline. We evaluated the proposed method on Alzheimer's Disease Neuroimaging Initiative (ADNI) data and compared the results with existing state-of-the-art EBM methods. We also performed extensive experiments on synthetic data simulating the progression of Alzheimer's disease. The event orderings obtained on ADNI data seem plausible and are in agreement with the current understanding of progression of AD. The proposed patient staging algorithm performed consistently better than that of state-of-the-art EBM methods. Event orderings obtained in simulation experiments were more accurate than those of other EBM methods and the estimated disease progression timeline was observed to correlate with the timeline of actual disease progression. The results of these experiments are encouraging and suggest that discriminative EBM is a promising approach to disease progression modeling.
View details for DOI 10.1016/j.neuroimage.2018.11.024
View details for Web of Science ID 000455968400048
View details for PubMedID 30471388
Gene regulatory networks (GRNs) play an important role in cellular systems and are important for understanding biological processes. Many algorithms have been developed to infer the GRNs. However, most algorithms only pay attention to the gene expression data but do not consider the topology information in their inference process, while incorporating this information can partially compensate for the lack of reliable expression data. Here we develop a Bayesian group lasso with spike and slab priors to perform gene selection and estimation for nonparametric models. B-spline basis functions are used to capture the nonlinear relationships flexibly and penalties are used to avoid overfitting. Further, we incorporate the topology information into the Bayesian method as a prior. We present the application of our method on DREAM3 and DREAM4 datasets and two real biological datasets. The results show that our method performs better than existing methods and the topology information prior can improve the result.
View details for DOI 10.1093/cercor/bhx322
View details for Web of Science ID 000459518500019
View details for PubMedID 28133490
View details for PubMedCentralID PMC5241943
Existing literature on factors associated with supportive care service (SCS) use is limited. A better understanding of these factors could help tailor SCS to the needs of frequent users, as well as facilitate targeted outreach to populations that underutilize available services.To investigate the prevalence of SCS use and to identify factors associated with, and barriers to, service use.California Alzheimer's Disease Center patients with AD (n?=?220) participated in the study from 2006-2009. Patients and their caregivers completed assessments to determine SCS use. Cognitive, functional, and behavioral status of the patients were also assessed. A two-part hurdle analysis identified 1) factors associated with any service use and 2) service use frequency among users.Forty percent of participants reported using at least one SCS. Patients with more impaired cognition and activities of daily living and more of the following: total number of medications, comorbid medical conditions, and years of education were more likely to use any SCS (p?0.05). Factors associated with more frequent SCS use included younger age, more years of education, older age of AD onset, female gender, and having a spouse or relative for a caregiver (p?0.05). Caregivers frequently indicated insufficient time as a reason for not receiving enough services.Factors associated with any SCS use mostly differed from those associated with SCS frequency, suggesting different characteristics between those who initiate versus those who continue SCS use. Our findings highlight the importance of targeted education on services and identifying barriers to long-term SCS use.
View details for DOI 10.3233/JAD-190438
View details for PubMedID 31743997
Alzheimer's disease (AD), including its mild cognitive impairment (MCI) phase that may or may not progress into the AD, is the most ordinary form of dementia. It is extremely important to correctly identify patients during the MCI stage because this is the phase where AD may or may not develop. Thus, it is crucial to predict outcomes during this phase. Thus far, many researchers have worked on only using a single modality of a biomarker for the diagnosis of AD or MCI. Although recent studies show that a combination of one or more different biomarkers may provide complementary information for the diagnosis, it also increases the classification accuracy distinguishing between different groups. In this paper, we propose a novel machine learning-based framework to discriminate subjects with AD or MCI utilizing a combination of four different biomarkers: fluorodeoxyglucose positron emission tomography (FDG-PET), structural magnetic resonance imaging (sMRI), cerebrospinal fluid (CSF) protein levels, and Apolipoprotein-E (APOE) genotype. The Alzheimer's Disease Neuroimaging Initiative (ADNI) baseline dataset was used in this study. In total, there were 158 subjects for whom all four modalities of biomarker were available. Of the 158 subjects, 38 subjects were in the AD group, 82 subjects were in MCI groups (including 46 in MCIc [MCI converted; conversion to AD within 24 months of time period], and 36 in MCIs [MCI stable; no conversion to AD within 24 months of time period]), and the remaining 38 subjects were in the healthy control (HC) group. For each image, we extracted 246 regions of interest (as features) using the Brainnetome template image and NiftyReg toolbox, and later we combined these features with three CSF and two APOE genotype features obtained from the ADNI website for each subject using early fusion technique. Here, a different kernel-based multiclass support vector machine (SVM) classifier with a grid-search method was applied. Before passing the obtained features to the classifier, we have used truncated singular value decomposition (Truncated SVD) dimensionality reduction technique to reduce high dimensional features into a lower-dimensional feature. As a result, our combined method achieved an area under the receiver operating characteristic (AU-ROC) curve of 98.33, 93.59, 96.83, 94.64, 96.43, and 95.24% for AD vs. HC, MCIs vs. MCIc, AD vs. MCIs, AD vs. MCIc, HC vs. MCIc, and HC vs. MCIs subjects which are high relative to single modality results and other state-of-the-art approaches. Moreover, combined multimodal methods have improved the classification performance over the unimodal classification.
View details for DOI 10.3389/fncom.2019.00072
View details for PubMedID 31680923
Dementia can be empirically described by the latent dementia phenotype "?" and its various composite "homologs". We have explored ?'s blood-based protein biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) study. However, it would be convenient to replicate those associations in the Alzheimer's Disease Neuroimaging Initiative (ADNI). To this end, we have engineered a ? homolog from observed cognitive performance measures common to both projects. Our findings were replicated in randomly selected 50% splits of TARCC data (Group 1, N?=?1,747; Group 2, N?=?1,755), and then independently in ADNI (N?=?1,737). The new ? homolog, i.e., "dT2A" (d-TARCC to ADNI), fit the data of both studies well, and was strongly correlated with dementia severity, as rated by the Clinical Dementia Rating Scale "sum of boxes" (TARCC: r?=?0.99, p?0.001; ADNI: r?=?0.96, p?0.001). dT2A achieved an area under the receiver operating characteristic curve of 0.981 (0.976-0.985) for the discrimination of Alzheimer's disease from normal controls in TARCC, and 0.988 (0.983-0.993) in ADNI. dT2A is the 12th ? homolog published to date, and opens the door to independent replications across these and similar studies.
View details for PubMedID 30507569
Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia.To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE) and prion protein (PRNP) genes were also assessed.We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping.We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN, VCP, MAPT, FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants (APOE and PRNP), and one did not show any risk mutation/variant. Overall, 69% (n?=?9) of our early onset Alzheimer's disease (EAOD) patients, compared with 34% (n?=?13) of sporadic late onset Alzheimer's disease (LOAD) patients and 27% (n?=?73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations.This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD.
View details for DOI 10.3233/JAD-180482
View details for Web of Science ID 000457778000020
View details for PubMedID 30530974
The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI is a multisite, longitudinal, observational study that has collected many biomarkers since 2004. Recent publications highlight the multifactorial nature of late-onset AD. We discuss selected topics that provide insights into AD progression and outline how this knowledge may improve clinical trials.We used standard methods to identify nearly 600 publications using ADNI data from 2016 and 2017 (listed in Supplementary Material and searchable at http://adni.loni.usc.edu/news-publications/publications/).(1) Data-driven AD progression models supported multifactorial interactions rather than a linear cascade of events. (2) ?-Amyloid (A?) deposition occurred concurrently with functional connectivity changes within the default mode network in preclinical subjects and was followed by specific and progressive disconnection of functional and anatomical networks. (3) Changes in functional connectivity, volumetric measures, regional hypometabolism, and cognition were detectable at subthreshold levels of A? deposition. 4. Tau positron emission tomography imaging studies detailed a specific temporal and spatial pattern of tau pathology dependent on prior A? deposition, and related to subsequent cognitive decline. 5. Clustering studies using a wide range of modalities consistently identified a "typical AD" subgroup and a second subgroup characterized by executive impairment and widespread cortical atrophy in preclinical and prodromal subjects. 6. Vascular pathology burden may act through both A? dependent and independent mechanisms to exacerbate AD progression. 7. The APOE ?4 allele interacted with cerebrovascular disease to impede A? clearance mechanisms. 8. Genetic approaches identified novel genetic risk factors involving a wide range of processes, and demonstrated shared genetic risk for AD and vascular disorders, as well as the temporal and regional pathological associations of established AD risk alleles. 9. Knowledge of early pathological changes guided the development of novel prognostic biomarkers for preclinical subjects. 10. Placebo populations of randomized controlled clinical trials had highly variable trajectories of cognitive change, underscoring the importance of subject selection and monitoring. 11. Selection criteria based on A? positivity, hippocampal volume, baseline cognitive/functional measures, and APOE ?4 status in combination with improved cognitive outcome measures were projected to decrease clinical trial duration and cost. 12. Multiple concurrent therapies targeting vascular health and other AD pathology in addition to A? may be more effective than single therapies.ADNI publications from 2016 and 2017 supported the idea of AD as a multifactorial disease and provided insights into the complexities of AD disease progression. These findings guided the development of novel biomarkers and suggested that subject selection on the basis of multiple factors may lower AD clinical trial costs and duration. The use of multiple concurrent therapies in these trials may prove more effective in reversing AD disease progression.
View details for DOI 10.1016/j.jalz.2018.08.005
View details for Web of Science ID 000455493000011
View details for PubMedID 30321505
Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD).Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing.In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7?-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles.We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.
View details for PubMedID 30337151
This study examines the atrophy rates of subjects with mild cognitive impairment (MCI) compared to controls in four regions within the medial temporal lobe: the transentorhinal cortex (TEC), entorhinal cortex (ERC), hippocampus, and amygdala. These regions were manually segmented and then corrected for undesirable longitudinal variability via Large Deformation Diffeomorphic Metric Mapping (LDDMM) based longitudinal diffeomorphometry. Diffeomorphometry techniques were used to compare thickness measurements in the TEC with the ERC. There were more significant changes in thickness atrophy rate in the TEC than medial regions of the entorhinal cortex. Volume measures were also calculated for all four regions. Classifiers were constructed using linear discriminant analysis to demonstrate that average thickness and atrophy rate of TEC together was the most discriminating measure compared to the thickness and volume measures in the areas examined, in differentiating MCI from controls. These findings are consistent with autopsy findings demonstrating that initial neuronal changes are found in TEC before spreading more medially in the ERC and to other regions in the medial temporal lobe. These findings suggest that the TEC thickness could serve as a biomarker for Alzheimer's disease in the prodromal phase of the disease.
View details for DOI 10.1016/j.nicl.2018.101617
View details for Web of Science ID 000460337700030
View details for PubMedID 30552075
The value of 18F-fluorodeoxyglucose (FDG) PET for the prognosis of conversion from mild cognitive impairment (MCI) to Alzheimer's dementia (AD) is controversial. In the present work, the identification of cerebral metabolic patterns with significant prognostic value for conversion of MCI patients to AD is investigated with voxel-based Cox regression, which in contrast to common categorical comparisons also utilizes time information.FDG PET data of 544 MCI patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were randomly split into two equally-sized datasets (training and test). Within a median follow-up duration of 47?months (95% CI: 46-48?months) 181 patients developed AD. In the training dataset, voxel-wise Cox regressions were used to identify regions associated with conversion of MCI to AD. These were compared to regions identified by a classical group comparison (analysis of covariance (ANCOVA) with statistical parametric mapping (SPM) 8) between converters and non-converters (both adjusted for apolipoprotein E (APOE) genotype, mini-mental state examination (MMSE) score, age, sex and education). In the test dataset, normalized FDG uptake within significant brain regions from voxel-wise Cox- and ANCOVA analyses (Cox- and ANCOVA- regions of interest (ROI), respectively) and clinical variables APOE status, MMSE score and education were tested in different Cox models (adjusted for age, sex) including: (1) only clinical variables, (2) only normalized FDG uptake in ANCOVA-ROI, (3) only normalized FDG uptake from Cox-ROI, (4) clinical variables plus FDG uptake in ANCOVA-ROI, (5) clinical variables plus FDG uptake from Cox-ROI.Conversion-related regions with relative hypometabolism comprised parts of the temporo-parietal and posterior cingulate cortex/precuneus for voxel-wise ANCOVA, plus frontal regions for voxel-wise Cox regression (both p?.01, false discovery rate (FDR) corrected). The clinical-only model (1) and the models based on normalized FDG uptake from Cox-ROI only (2) and ANCOVA-ROI only (3) all significantly predicted conversion to AD (Wald Test (WT): p?.001). The clinical model (1) was significantly improved by adding imaging information in model (4) (Akaike information criterion (AIC) relative likelihood (RL) (1) vs (4): RL?0.018). There were no significant differences between models (2) and (3), as well as (4) and (5).Voxel-wise Cox regression identifies conversion-related patterns of cerebral glucose metabolism, but is not superior to classical group contrasts in this regard. With imaging information from both FDG PET patterns, the prediction of conversion to AD was improved.
View details for DOI 10.1016/j.nicl.2018.101637
View details for Web of Science ID 000460337700050
View details for PubMedID 30553760
View details for Web of Science ID 000455045600323
View details for Web of Science ID 000458654000062
A novel multi-atlas based image segmentation method is proposed by integrating a semi-supervised label propagation method and a supervised random forests method in a pattern recognition based label fusion framework. The semi-supervised label propagation method takes into consideration local and global image appearance of images to be segmented and segments the images by propagating reliable segmentation results obtained by the supervised random forests method. Particularly, the random forests method is used to train a regression model based on image patches of atlas images for each voxel of the images to be segmented. The regression model is used to obtain reliable segmentation results to guide the label propagation for the segmentation. The proposed method has been compared with state-of-the-art multi-atlas based image segmentation methods for segmenting the hippocampus in MR images. The experiment results have demonstrated that our method obtained superior segmentation performance.
View details for Web of Science ID 000455045600033
View details for PubMedID 30079126
View details for PubMedCentralID PMC6070300
View details for Web of Science ID 000455045600124
To clarify associations between APOE ?4 allele and age on longitudinal rates of ?-amyloid (A?) accumulation within A?+ and A?- older individuals without dementia.We analyzed 595 older adults without dementia classified cross-sectionally as A?- (n = 325) and A?+ (n = 270) using longitudinal florbetapir PET. The influence of age and APOE genotype on longitudinal accumulation of A? was examined with linear mixed models.APOE ?4 and older age were associated with higher risk of being classified as A?+ at baseline. The annual rate of A? accumulation was significantly greater than zero for A?- ?3 (0.0021 ± 0.0007 standardized uptake value ratio [SUVR] units) and A?- ?4 (0.0044 ± 0.0010 SUVR units), as well as A?+ ?3 (0.0141 ± 0.0019 SUVR units) and A?+ ?4 (0.0126 ± 0.0018 SUVR units). A? accumulation was significantly faster in A?- ?4 compared to A?- ?3 and A?- ?2. Rates of A? accumulation did not differ significantly between A?+ APOE groups. Older age was associated with higher rates of A? accumulation in the A?- group.APOE ?4 carriage and older age were predictors of longitudinal A? accumulation within the A?- group but not the A?+ group. APOE ?2 carriage was protective against longitudinal A? accumulation within the A?- group. APOE genotype in conjunction with chronologic age may aid in participant selection for primary prevention trials aimed at halting A? accumulation before abnormal levels are reached.
View details for PubMedID 28794245
View details for PubMedCentralID PMC5589795
Background: Ongoing research is focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to Alzheimer's disease (AD). We investigated whether recognition memory tasks in combination with delayed recall measure of episodic memory and CSF biomarkers can predict MCI to AD conversion at 24-month follow-up. Methods: A total of 397 amnestic-MCI subjects from Alzheimer's disease Neuroimaging Initiative were included. Logistic regression modeling was done to assess the predictive value of all RAVLT measures, risk factors such as age, sex, education, APOE genotype, and CSF biomarkers for progression to AD. Estimating adjusted odds ratios was used to determine which variables would produce an optimal predictive model, and whether adding tests of interaction between the RAVLT Delayed Recall and recognition measures (traditional score and d-prime) would improve prediction of the conversion from a-MCI to AD. Results: 112 (28.2%) subjects developed dementia and 285 (71.8%) subjects did not. Of the all included variables, CSF A?1-42 levels, RAVLT Delayed Recall, and the combination of RAVLT Delayed Recall and d-prime were predictive of progression to AD (?2 = 38.23, df = 14, p < 0.001). Conclusions: The combination of RAVLT Delayed Recall and d-prime measures may be predictor of conversion from MCI to AD in the ADNI cohort, especially in combination with amyloid biomarkers. A predictive model to help identify individuals at-risk for dementia should include not only traditional episodic memory measures (delayed recall or recognition), but also additional variables (d-prime) that allow the homogenization of the assessment procedures in the diagnosis of MCI.
View details for PubMedID 28344552
To compare the outcome of donepezil treatment in ethnically diverse Alzheimer disease (AD) patients with ethnically diverse AD patients who did not receive donepezil.Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least 1 year in this prospective, observational study. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. Patients self-identified their ethnicity.The 64 ethnically diverse AD patients who completed the study and received donepezil treatment had an average 1-year decline of 2.30 points (standard deviation: 3.9) on the 30-point Mini-Mental State Exam compared with a 1.70-point (standard deviation: 4.2) decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the study period. This difference was not statistically significant. The overall Cohen effect size of this treatment-associated difference was estimated at -0.15. After using propensity analyses and other techniques to assess factors that could bias prescribing decisions, the lack of benefits associated with donepezil treatment remained. The lack of donepezil benefits also remained when more traditional analyses were applied to these data.Ethnically diverse AD patients in this study apparently did not benefit from 1 year of donepezil treatment. These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients.
View details for DOI 10.1016/j.jagp.2014.09.007
View details for PubMedID 25747405
Alzheimer's disease (AD) shortens life-expectancy, but the effects of pharmacological treatments for this disorder on mortality have not been studied. We compared two commonly prescribed medications, donepezil and memantine, with respect to the length of survival of veterans presumed to have AD. The Computerized Medical Records System at the Veterans Affairs Palo Alto Health Care System (VAPAHCS) was used to identify all patients prescribed these medications between 1997 and 2008. The VAPAHCS approved donepezil in 1997 and memantine in 2004. Kaplan-Meier and Cox regression analyses were used to test for chronological and drug-related associations with survival in 2,083 male veterans aged 55 years and older receiving prescriptions for donepezil, memantine, or both. Overall patient mortality decreased in the 2004 to 2008 era, compared with the 1997 to 2003 era, pre-memantine (HR: 0.75; 95% CI: 0.63, 0.89; p = 0.001). In analyses confined to the 2004 to 2008 era, patients prescribed memantine alone survived significantly longer (median survival 8.9 years) than those prescribed donepezil alone (HR: 2.24; 95% CI: 1.53, 3.28; p < 0.001) or both donepezil and memantine (HR: 1.83; 95% CI: 1.14, 2.94; p = 0.012). While this study has several limitations, these findings suggest that memantine treatment is associated with an increased life-expectancy relative to donepezil treatment. Additional research is needed to replicate these unexpected findings and identify potential mechanisms to explain this apparent association, to establish if the relationship applies to other cholinesterase inhibitors, and to discover whether the findings generalize to women and patient populations with characteristics different from those of the veterans in this study.
View details for DOI 10.3233/JAD-130662
View details for Web of Science ID 000322738000016
View details for PubMedID 23703151
AD is a public health epidemic, which seriously impacts cognition, mood and daily activities; however, one type of activity, exercise, has been shown to alter these states. Accordingly, we sought to investigate the relationship between exercise and mood, in early-stage AD patients (N=104) from California, over a 1-year period. Patients completed the Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), and Blessed-Roth Dementia Rating Scale (BRDRS), while their caregivers completed the Yale Physical Activity Survey (YALE), Profile of Mood States (POMS), the Neuropsychiatric Inventory (NPI) and Functional Abilities Questionnaire (FAQ). Approximately half of the participants were female, from a variety of ethnic groups (Caucasian=69.8%; Latino/Hispanic Americans=20.1%). Our results demonstrated that the patients spent little time engaged in physical activity in general, their overall activity levels decreased over time, and this was paired with a change in global cognition (e.g., MMSE total score) and affect/mood (e.g., POMS score). Patients were parsed into Active and Sedentary groups based on their Yale profiles, with Active participants engaged in walking activities, weekly, over 1 year. Here, Sedentary patients had a significant decline in MMSE scores, while the Active patients had an attenuation in global cognitive decline. Importantly, among the Active AD patients, those individuals who engaged in walking for more than 2 h/week had a significant improvement in MMSE scores. Structured clinical trials which seek to increase the amount of time AD patients were engaged in walking activities and evaluate the nature and scope of beneficial effects in the brain are warranted.
View details for DOI 10.1016/j.archger.2012.06.016
View details for Web of Science ID 000311343300017
View details for PubMedID 22959822
We examined whether the effect of the apolipoprotein E (APOE) genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ?4 carriers compared with ?3 homozygotes. More important, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ?4 carriers showed significantly reduced default mode connectivity compared with either female ?3 homozygotes or male ?4 carriers, whereas male ?4 carriers differed minimally from male ?3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer's disease, i.e., spinal fluid levels of tau, provided corresponding evidence for this gender-by-APOE interaction. Together, these results converge with previous work showing a higher prevalence of the ?4 allele among women with Alzheimer's disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.
View details for DOI 10.1523/JNEUROSCI.0305-12.2012
View details for Web of Science ID 000305295600017
View details for PubMedID 22699906
View details for PubMedCentralID PMC3394933
Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.
View details for DOI 10.1073/pnas.1105829109
View details for PubMedID 22343285
One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes.One week of ad libitum ambulatory sleep data collection.At-home collection of sleep data and in-laboratory questionnaire.Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimer's Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimer's Disease Neuroimaging Initiative data set.Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in per3) was also determined.Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance.It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD.
View details for DOI 10.1097/JGP.0b013e31820d92b2
View details for PubMedID 21709609
View details for Web of Science ID 000289791000068
To determine if results from randomized clinical trials of donepezil in Alzheimer disease (AD) patients can be applied to AD patients in clinical practice by comparing the findings from a Nordic one-year randomized AD donepezil trial with data from a one-year prospective, observational study of AD patients.AD patients from a consortium of California sites were systematically followed for at least one year. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria.The 148 California patients treated with donepezil had a one-year decline of 1.3 (3.5 SD) points on the Mini-Mental State Exam compared to a decline of 3.3 (4.4 SD) in the 158 AD patients who received no anti-Alzheimer drugs. The Mini-Mental State Exam decline in Nordic sample was approximately 0.25 points for the 91 patients receiving donepezil and approximately 2.2 for the 98 placebo patients. The overall effect sizes were estimated at about 0.49 in both studies. The California data were further analyzed using propensity methods; after taking into account differences that could bias prescribing decisions, benefits associated with taking donepezil remained.A comparison of a randomized clinical trial of donepezil in AD patients and this observational study indicates that if appropriate methodological and statistical precautions are undertaken, then results from randomized clinical trials can be predictive with AD patients in clinical practice. This California study supports the modest effectiveness of donepezil in AD patients having clinical characteristics similar to those of the Nordic study.
View details for Web of Science ID 000250617800005
View details for PubMedID 17974866
A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.
View details for DOI 10.1038/nm1653
View details for Web of Science ID 000250736900029
View details for PubMedID 17934472
The aim of this study was to use a signal detection method to examine the prevalence of, and patient characteristics associated with, medication with potential to impair cognition and cholinesterase inhibitor use in patients with Alzheimer's disease.A cross-sectional study was conducted of 1,954 patients with a diagnosis of probable or possible Alzheimer's disease. Concurrent medications were measured, specifically: (1) a medication with potential to impair cognition or (2) a cholinesterase inhibitor. Predictor variables included age, gender, ethnic group, education, age of symptom onset, number of prescriptions, number of medical diagnoses, Mini-Mental State Examination (MMSE), Blessed-Roth Dementia Rating Scale (BRDRS), probable versus possible AD diagnosis.Fifteen percent of the Alzheimer's disease patients were on a medication with potential to impair cognition, and 44% were on a cholinesterase inhibitor. Patient characteristics associated with the prescription of a medication with potential to impair cognition included total number of prescription medications, low education, low MMSE, older age, reported lack of vitamin use, and more medical diagnoses. Patient characteristics associated with the prescription of a cholinesterase inhibitor included reported use of vitamins, the total number of prescription medications, fewer medical diagnoses, lower age of symptom onset, and higher education.Determining the patient characteristics associated with the prescription of a medication with potential to impair cognition can help clinicians identify patients who are at risk for drug-related morbidity. Patient characteristics unassociated with dementia appear to influence the prescription of cholinesterase inhibitors. Signal detection analysis is well suited to this type of research.
View details for DOI 10.1016/j.jalz.2006.08.003
View details for PubMedID 19595905
Clinical researchers often propose (or review committees demand) pilot studies to determine whether a study is worth performing and to guide power calculations. The most likely outcomes are that (1) studies worth performing are aborted and (2) studies that are not aborted are underpowered. There are many excellent reasons for performing pilot studies. The argument herein is not meant to discourage clinical researchers from performing pilot studies (or review committees from requiring them) but simply to caution against their use for the objective of guiding power calculations.
View details for Web of Science ID 000237215800002
View details for PubMedID 16651505
Off-label prescribing of medications, polypharmacy, and other questionable prescribing practices have led investigators to examine a large VA pharmacy database to determine if physician prescribing decisions appear reasonable.The current study addresses the question of physician prescribing of atypical antipsychotics in 34,925 veterans with schizophrenia, using a series of signal detection analyses.These results suggest that only three factors (hospital size, age, and secondary diagnosis) allow classification of patients prescribed atypicals into three groups with frequencies of use of atypicals ranging from 43% to 79%, and that these results are consistent with reasonable clinical practice.Results of two-stage signal detection analyses are readily interpretable by clinicians and administrators who are faced with the task of evaluating how physicians prescribe medications in clinical practice. Physicians' decisions to prescribe atypical antipsychotics are based on both patient and fiscal considerations. This likely reflects a combination of clinical judgment and institutional guidelines.
View details for DOI 10.1016/j.jpsychires.2005.06.004
View details for Web of Science ID 000235641200009
View details for PubMedID 16150458
It is largely unknown why some patients with Alzheimer's disease (AD) decline cognitively more rapidly than others. Genetic differences among patients could influence rate of decline. Brain-derived neurotrophic factor (BDNF) is a neurotrophin important in the survival neurons and in memory function. BDNF levels are reduced in the brain in AD. The Val66Met polymorphism in the BDNF gene modifies neuronal BDNF secretion, and affects hippocampal function and memory performance. We tested the hypothesis that the BDNF Val66Met polymorphism influences rate of cognitive decline in AD. In a sample of 149 AD patients followed for an average of 3.9 years, we found no effect of BDNF Val66Met genotype on rate of change in the Mini Mental State Examination. Results were similar when we excluded patients taking an acetylcholinesterase inhibitor, those placed in a nursing home during the study, or those with a neuropathological diagnosis that included AD plus an entity other than AD. We also found no evidence that the effects of the BDNF Val66Met genotype depend on APOE genotype, which itself had no effect on rate of cognitive change. These findings suggest that the functional BDNF Val66Met variant is not a major determinant of rate of cognitive decline in AD.
View details for Web of Science ID 000237795900004
View details for PubMedID 16627933
The current study used Department of Veteran's Affairs (VA) clinical records, State of California pesticide application records, spatial maps of distribution of Parkinson's disease patients, and pesticide applications to determine if there was evidence for "blow-in" of pesticides as a factor in explaining the prevalence of Central Valley Parkinson's disease. The results did not support the hypothesis of increasing prevalence of Parkinsonism attributable to wind drift.
View details for DOI 10.1177/0891988705284707
View details for Web of Science ID 000235366800006
View details for PubMedID 16449758
There is paucity of medical literature on the use of lamotrigine in elderly patients who have behavior problems and diverse psychiatric syndromes. This article is a retrospective case series summarizing the authors' experience with this medication. In a 20-patient case series from an institutional review board-approved retrospective chart review, the tolerability and efficacy of lamotrigine was evaluated for the management of agitated and aggressive behaviors in nursing home patients with a range of psychiatric and medical diagnoses. Nineteen of the elderly nursing home patients tolerated lamotrigine treatment, and 18 showed modest clinical improvement. These results support the authors' belief that controlled clinical investigations of this medication should be performed.
View details for DOI 10.1177/0891988704271762
View details for Web of Science ID 000226923100002
View details for PubMedID 15681622
The objective of this study was to assess the convergent validity of a 26-point Telephone Mini-Mental State Examination (MMSE) in a longitudinal cohort of 46 Alzheimer's disease (AD) patients. Paired in-person and telephone MMSE observations were collected within 35 days of each other. The setting was the Stanford/VA Alzheimer's Center in Palo Alto, California, and patients' residences. The 30-point Folstein MMSE was administered in-person, and a 26-point telephone version of the MMSE, adapted from the Adult Lifestyles and Function Interview (ALFI)-MMSE. Total scores for the in-person and telephone MMSE versions correlated strongly (Pearson's r =.88, P <.001). Hearing impairment and education level did not significantly affect telephone-based performance. The Telephone MMSE can be used to validly estimate in-person MMSE scores of patients with AD. Use of this practical measure can enhance reassessment if returning to the clinic is difficult or if a change in the patient's medical condition merits a check of mental status by telephone.
View details for DOI 10.1177/0891988704264534
View details for Web of Science ID 000223475100005
View details for PubMedID 15157348
The purpose of this study was to assess whether pharmacy database information from US Department of Veterans Affairs (VA) medical centers could be used to screen for areas of higher Parkinson's disease prevalence in patients exposed to pesticides. The authors used pharmacy data sets and compared the use of antiparkinsonian medications at 2 VA medical centers in California: one in Palo Alto, near the ocean, and one in Fresno, downwind from extensively farmed parts of the Central Valley. They found that patients at Fresno had higher odds ratios (1.5-1.8) for the use of Parkinson's disease medications than patients at Palo Alto. These data are consistent with the observations of prior epidemiologic studies and suggest that VA pharmacy databases can prioritize locations for further epidemiologic research. However, a thorough exploration of alternative explanations is needed to reach definitive conclusions regarding the findings suggested by this method.
View details for DOI 10.1117/0891988703258672
View details for Web of Science ID 000223474900007
View details for PubMedID 15018696
Disturbed sleep is a major clinical problem in Alzheimer's disease (AD). Apolipoprotein epsilon4 (APOE epsilon4) carrier status may increase risk of AD, yet there are no data on relations between APOE status and progression of sleep disturbance in AD. The objective of this study was to determine if sleep parameters in AD patients change over time as a function of APOE carrier status. Forty-four community-dwelling AD patients with diagnosis of probable AD were followed from early stages of disease. Their sleep/wake parameters were compared according to APOE status. For APOE epsilon4 carriers, only wake after sleep onset (WASO) increased in association with lower cognitive function as indicated by the Mini-Mental State Examination (MMSE); for non-epsilon4 subjects, increases in WASO and declines in total sleep time, sleep efficiency, and the amplitude of the rest/activity circadian rhythm over time were associated with lower performance on the MMSE. In these data, APOE status was associated with the progression of sleep/wake disturbances in AD. Overall, there was greater deterioration on sleep parameters in patients negative for the epsilon4 allele.
View details for DOI 10.1117/0891988703261994
View details for Web of Science ID 000223474900004
View details for PubMedID 15018693
We used a novel application of a signal detection technique, receiver operator characteristics (ROC), to describe factors entering a physician's decision to switch a patient from a typical high potency neuroleptic to a particular atypical, olanzapine (OLA) or risperidone (RIS).ROC analyses were performed on pharmacy records of 476 VA patients who had been treated on a high potency neuroleptic then changed to either OLA or RIS.Overall 68% patients switched to OLA and 32% to RIS. The best predictor of neuroleptic choice was age at switch, with 78% of patients aged less than 55 years receiving OLA and 51% of those aged greater than or equal to 55 years receiving OLA (chi(2)=38.2, P<0.001). Further analysis of the former group indicated that adding the predictor of one or more inpatient days to age increased the likelihood of an OLA switch from 78% to 85% (chi(2)=7.3, P<0.01) while further analysis of the latter group indicated that adding the predictor of less than 10 inpatients days to age decreased the likelihood of an OLA switch from 51% to 45% (chi(2)=7.0, P<0.01).ROC analyses have the advantage over other analyses, such as regression techniques, insofar as their "cut-points" are readily interpretable, their sequential use forms an intuitive "decision tree" and allows the potential identification of clinically relevant "subgroups". The software used in this analysis is in the public domain (http://mirecc.stanford.edu).
View details for DOI 10.1016/S0022-3956(03)00053-0
View details for Web of Science ID 000186239700010
View details for PubMedID 14563385
View details for Web of Science ID 000185187000038
View details for Web of Science ID 000222209400569
Part of the challenge in research on degenerative neurologic disease relates to distinguishing those measurements that essentially describe patient characteristics stable across the course of illness (traits) from those that vary systematically within subjects (states), particularly those specifically related to stage or duration of illness. A components-of-variance approach was used to examine the state versus trait aspects of the Alzheimer's Disease Assessment Scale (ADAS) Cognitive and Noncognitive subscales, a clinical instrument frequently used in research on Alzheimer disease. Subjects were 190 patients with probable AD followed longitudinally. Stage of illness was indexed by mental status scores. Analysis of variance was used to partition total variance into that associated with subjects (trait), stages (state: stage), subjects x stages (state: other), and error. ADAS Cognitive scores were strongly related to stage of illness (83% of true variance). ADAS Noncognitive scores were modestly related to stage (approximately 21% of true variance) and moderately related to state: other (47%). We discuss how state-trait analyses can be helpful in focusing attention on those areas of assessment most likely to accomplish specific objectives.
View details for Web of Science ID 000179640800007
View details for PubMedID 12468900
We report a randomized, double-blind, parallel group, placebo-controlled study to test the effects of the acetylcholinesterase inhibitor, donepezil (5 mg/d for 30 days), on aircraft pilot performance in 18 licensed pilots with mean age of 52 years. After 30 days of treatment, the donepezil group showed greater ability to retain the capacity to perform a set of complex simulator tasks than the placebo group, p < 0.05. Donepezil appears to have beneficial effects on retention of training on complex aviation tasks in nondemented older adults.
View details for Web of Science ID 000176622600025
View details for PubMedID 12105320
Major advances in understanding the physiology and genetics of circadian rhythm in the past decade challenge the researcher of sleep/wake disorders in Alzheimer's disease (AD) to distinguish patient characteristics stable across the course of illness ("traits") from characteristics that vary with stage of illness ("states"). A components-of-variance approach with a repeated measures model was used to examine the between-subjects variance over time ("trait") vs. within-subjects ("state") variance in 42 patients with probable AD followed, on average, over 2 years on actigraphic sleep/wake measures. Mental status scores indexed stage of illness. Actigraphic measures of sleep efficiency and circadian rhythmicity appeared predominantly "trait," with between-individual differences accounting for over 55% of variance compared to the less than 5% of variance related to stage of cognitive impairment. We discuss how "state-trait" analyses can be helpful in identifying areas of assessment most likely to be fruitful objectives of physiologic and genetic research on sleep/wake disturbance in AD.
View details for Web of Science ID 000176217400008
View details for PubMedID 12094910
In the current study of 1062 Alzheimer's disease (AD) patients, we employed receiver operating characteristic curve analysis to identify characteristics of patients at increased risk for rapid cognitive decline. The patients are participants at one of the nine Alzheimer's Disease Research Centers of California. Rapid decline was defined as a 3-point or greater loss on the Mini-Mental State Examination (MMSE) per year, post visit. The independent variables were age at clinic visit, age at symptom onset of AD, MMSE at patient visit, years of education, gender, ethnicity, living arrangement, presence of aphasia, delusions, hallucinations, and extrapyramidal signs. Receiver operating characteristic curve analysis indicated that AD patients presenting with moderate to severe aphasia, age at clinic visit of 75 years or less, and an MMSE greater than 7 were at increased risk for rapid cognitive decline. This information could help clinicians target these patients for pharmacologic interventions, facilitate long-term care planning, and potentially create savings by delaying or stabilizing the course of the disease.
View details for Web of Science ID 000179584400009
View details for PubMedID 12489920
The reason for differences in rate of cognitive decline in AD is unknown. The interleukin-1 alpha (IL-1 alpha) -889 *2 allele is associated with increased risk for AD. Surprisingly, in a sample of 114 patients followed for an average of 3.8 years, individuals homozygous for the IL-1 alpha -889 *1 allele declined significantly more rapidly on the Mini-Mental State Examination than did others. There was no difference in rate of decline between patients with and without the APOE epsilon 4 allele. These results support the hypothesis that inflammation is important in the clinical course of AD.
View details for Web of Science ID 000169187100033
View details for PubMedID 11402127
The authors recorded event-related brain potentials (ERPs) to picture primes and word targets (picture-name verification task) in patients with Alzheimer's disease (AD) and in elderly and young participants. N400 was more negative to words that did not match pictures than to words that did match pictures in all groups: In the young, this effect was significant at all scalp sites; in the elderly, it was only at central-parietal sites; and in AD patients, it was limited to right central-parietal sites. Among AD patients pretested with a confrontation-naming task to identify pictures they could not name, neither the N400 priming effect nor its scalp distribution was affected by ability to name pictures correctly. This ERP evidence of spared knowledge of these items was complemented by 80% performance accuracy. Thus, although the name of an item may be inaccessible in confrontation naming, N400 shows that knowledge is intact enough to prime cortical responses.
View details for DOI 10.1037//0882-7922.214.171.124
View details for Web of Science ID 000171004800014
View details for PubMedID 11302364
This study examined the relationships between regional cortical and hippocampal brain volumes and components of remote memory (recall, recognition, sequencing, and photo naming of presidential candidates) in 13 individuals with Alzheimer's disease (AD). Recognition and sequencing of remote memory for public figures were associated with regional cortical volumes. Specifically, lower recognition and sequencing scores were associated with smaller parietal-occipital cortical volumes; poorer sequencing was also associated with smaller prefrontal cortical volumes. By contrast, poorer anterograde but not remote memory scores were correlated with smaller hippocampal volumes. Within the constraints of the brain regions measured, these findings highlight the importance of the posterior cortical areas for selective remote memory processes and provide support for the dissociation between cortically mediated remote memory and hippocampally mediated anterograde memory.
View details for Web of Science ID 000168425100012
View details for PubMedID 11311039
In a 24-patient case series from retrospective chart review, the authors examined the use of gabapentin for the treatment of aggressive and agitated behaviors in nursing home patients with a DSM-IV diagnosis of dementia. On Clinical Global Rating Scale scores, 17 of 22 patients were much or greatly improved; 4 were minimally improved; and only 1 remained unchanged. Two of the 24 patients discontinued use of the medication because of excessive sedation. No other significant side effects were noted in treatment lasting up to 2 years.
View details for Web of Science ID 000088230700007
View details for PubMedID 10910420
Comparative study of CSF levels of tau and AD7C-neuronal thread protein (NTP) in patients with AD and control subjects.AD is characterized by neurofibrillary tangles composed of the abnormally hyperphosphorylated microtubule-associated protein tau. AD7C-NTP is a proposed AD marker expressed at early stages of neurofibrillary degeneration.Enzyme-linked immunosorbent assays specific for tau and AD7C-NTP. CSF samples were obtained from 35 demented patients (25 with antemortem clinical diagnosis of probable AD, 5 with neuropathologic diagnosis of definite AD, 5 with Lewy body pathology), 29 nondemented patients with PD, and 16 elderly healthy control subjects. Receiver operating characteristics (ROC) and multivariate discriminant analysis for AD versus controls. Correlational analysis of CSF tau and AD7C-NTP and of each marker with Mini-Mental State Examination (MMSE) scores was performed.Levels of both tau and AD7C-NTP were significantly elevated in the AD patients compared with control subjects. ROC analysis showed that CSF tau distinguished between patients with AD and nondemented control subjects with 63% sensitivity and 89% specificity, AD7C-NTP with 70% sensitivity and 87% specificity. Combined evaluation of both markers with discriminant analysis raised the specificity to 93% at a 63% sensitivity level. Both markers positively correlated with each other within the AD group, but not among control subjects. CSF levels of AD7C-NTP, but not of tau, showed a small but significant inverse correlation (r = -0.43) with MMSE scores of AD patients.CSF levels of tau and AD7C-NTP may be useful biomarkers for AD.
View details for Web of Science ID 000086460900021
View details for PubMedID 10751266
Content and contextual memory for remote public figures and events was assessed with a modified version of the Presidents Test in patients with Alzheimer's disease (AD) or Parkinson's disease (PD). Contributions of executive functioning, semantic memory, and explicit anterograde memory to remote memory abilities were also examined. The AD group had temporally extensive deficits in content and contextual remote memory not accountable for by dementia severity. The PD group did not differ from the control group in remote memory, despite anterograde memory impairment. These results support the position that different component processes characterize remote memory, various mnemonic and nonmnemonic cognitive processes contribute to remote memory performance, and anterograde and remote memory processes are dissociable and differentially disrupted by neurodegenerative disease.
View details for DOI 10.1037//0894-4126.96.36.1995
View details for Web of Science ID 000087480700010
View details for PubMedID 10791866
Several clinical criteria have been developed to standardize the diagnosis of vascular dementia (VaD). Significant differences in patient classification have been reported, depending on the criteria used. Few studies have examined interrater reliability.To assess the concordance in classification and interrater reliability for the following 4 clinical definitions of VaD: the Hachinski Ischemic Score (HIS), the Alzheimer Disease Diagnostic and Treatment Centers (ADDTC), National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN), and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).Structured diagnostic checklists were developed for 4 criteria for VaD, 2 criteria for Alzheimer disease (AD), and 4 criteria for dementia. Twenty-five case vignettes, representing a spectrum of cognitive impairment and subtypes of dementia, were prepared in a standardized clinical format. Concordance in case classification using different criteria and interrater reliability among 7 ADDTCs given a specific set of criteria was assessed using the kappa statistic.The frequency of a diagnosis of VaD was highest using the modified HIS or DSM-IV criteria, intermediate using the original HIS and ADDTC criteria, and lowest using the NINDS-AIREN criteria. Scores for interrater reliability ranged from kappa = 0.30 (ADDTC) to kappa = 0.61 (original HIS).Clinical criteria for VaD are not interchangeable. Depending on the criteria selected, the reported prevalence of VaD will vary significantly. The traditional HIS has higher interrater reliability than the newer criteria for VaD. Prospective longitudinal studies with clinical-pathological correlation are needed to compare validity.
View details for Web of Science ID 000085208700004
View details for PubMedID 10681076
alpha2 Macroglobulin is a panproteinase inhibitor that is found immunohistochemically in neuritic plaques, a requisite neuropathologic feature of AD. Recently, a pentanucleotide deletion near the 5' end of the "bait region" of the alpha2 macroglobulin (A2M) gene was reported to be associated with AD in a large cohort of sibpairs, in which the mutation conferred a similar odds ratio with AD as the APOE-epsilon4 allele for carriers of at least one copy of the A2M gene (Mantel-Haenszel odds ratio, 3.56).We studied three independent association samples of AD patients (n = 309) with an age range of 50 to 94 years and representative controls (n = 281) to characterize the allele frequency of the pentanucleotide deletion in this cohort. We detected the mutation near the 5' splice site of exon 18 using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender, education, and APOE polymorphism.We found that the A2M gene polymorphism conferred an increased risk for AD, with an estimated Mantel-Haenszel ratio of 1.5 (95% CI 1.1 to 2.2; p = 0.025). There was no age- or gender-dependent increase in A2M gene allele frequencies in AD patients compared with controls. The combined sample showed the expected association between AD and APOE-epsilon 4. In one of our three samples there was an interaction between the A2M and APOE-epsilon4 genes, but the other two samples showed no interaction between the two risk factors.Our data support an association between the A2M gene and AD. This association is less pronounced, however, in our cohort than in the previously reported sample of sibpairs.
View details for Web of Science ID 000085043800030
View details for PubMedID 10668709
This study examined the relationships between regional brain volumes and semantic, phonological, and nonverbal fluency in 32 participants with Alzheimer's disease (AD). Object but not animal semantic fluency correlated with frontal and temporal gray matter volumes. Phonological fluency was not significantly associated with any brain volume examined. Nonverbal fluency was selectively associated with bilateral frontal gray matter volumes. Hippocampal volumes, although markedly reduced in these patients, were not related to any of the fluency measures. Results lend evidence to the importance of the frontal lobes in the directed generation of nonverbal and verbal exemplars by AD patients. Furthermore, both left- and right-hemisphere regions contribute to the generation of verbal and nonverbal exemplars.
View details for Web of Science ID 000085020000003
View details for PubMedID 10674796
The Clock Drawing Test (CDT) is widely used in the assessment of dementia and is known to be sensitive to the detection of deficits in neurodegenerative disorders such as Alzheimer's disease (AD). CDT performance is dependent not only on visuospatial and constructional abilities, but also on conceptual and executive functioning; therefore, it is likely to be mediated by multiple brain regions. The purpose of the present study was to identify component cognitive processes and regional cortical volumes that contribute to CDT performance in AD. In 29 patients with probable AD, CDT performance was significantly related to right-, but not left-hemisphere, regional gray matter volume. Specifically, CDT score correlated significantly with the right anterior and posterior superior temporal lobe volumes. CDT scores showed significant relationships with tests of semantic knowledge, executive function, and visuoconstruction, and receptive language. These results suggest that in AD patients, CDT performance is attributable to impairment in multiple cognitive domains but is related specifically to regional volume loss of right temporal cortex.
View details for Web of Science ID 000083339700003
View details for PubMedID 10561930
The pattern of deterioration in patients with Alzheimer's disease is highly variable within a given population. With recent speculation that the apolipoprotein E allele may influence rate of decline and claims that certain drugs may slow the course of the disease, there is a compelling need for sound statistical methodology to address these questions. Current statistical methods for describing decline do not adequately take into account between-patient variability and possible floor and/or ceiling effects in the scale measuring decline, and they fail to allow for uncertainty in disease onset. In this paper, the authors analyze longitudinal Mini-Mental State Examination scores from two groups of Alzheimer's disease subjects from Palo Alto, California, and Minneapolis, Minnesota, in 1981-1993 and 1986-1988, respectively. A Bayesian hierarchical model is introduced as an elegant means of simultaneously overcoming all of the difficulties referred to above.
View details for Web of Science ID 000080305200010
View details for PubMedID 10342806
View details for Web of Science ID 000080699400005
'Stages', as used in clinical practice and research, are defined, their value described, and criteria are proposed for their evaluation. The specific interest is in staging Alzheimer's disease (AD). Two staging systems, one based on the Global Deterioration Scale (GDS) and one based on the Mini-Mental State Exam (MMSE), are compared in terms of these criteria, as an illustration of the process involved. We propose that there is not one unique staging system, that different staging criteria might be appropriate to different research or clinical needs, depending on which part of the temporal course of the disease is of primary interest, and on whether the focus is on cognitive, functional, neurological, behavioral, economic, or other issues. GDS staging seems a better choice for the later stages of AD when the focus is on functional change. MMSE staging seems a better choice for tracking the earlier stages of AD when the focus is on cognitive change.
View details for Web of Science ID 000076711600001
View details for PubMedID 9769442
View details for Web of Science ID 000076220500005
View details for Web of Science ID 000073240700078
View details for Web of Science ID 000073196500091
Neuroimaging and lesion studies have demonstrated that hippocampal volume correlates with memory performance, but material-specific lateralization of this structure-function relationship has been inconsistent. This MRI study examined the relative contributions of left and right temporal lobe volumes to verbal and nonverbal recognition memory in a group of 20 Alzheimer's disease (AD) patients. There was a significant relationship between extent of right hippocampal and right temporal gray matter tissue volume deficit and performance on the face recognition subtest of the Warrington Recognition Memory Test. The face recognition test correlated with right hemisphere volume but not to left, indicating a material-specific relationship between brain structure and function in this patient group. Right temporal horn volume did not account for a significant proportion of variance in face recognition memory. Although word recognition was not significantly correlated with either left or right hippocampal volume in the total group, there was a strong correlation between left hippocampal volume and word recognition memory in the female AD patients. Thus, face recognition shows a material specific relationship with select lateralized hippocampal and temporal cortical volumes in AD patients, regardless of gender, whereas the verbal recognition-left-hippocampal volume relationship may be mediated by gender.
View details for Web of Science ID 000075146200002
View details for PubMedID 9529820
We investigated the relationship between basal cortisol and dehydroepiandrosterone (DHEA) levels and impairment in different cognitive and noncognitive measures and the possible interaction of DHEA with hypercortisolemia in dementia in 27 patients diagnosed with Alzheimer's disease (AD). There were 17 men and 10 women. Patients were mildly to moderately cognitively impaired at the time of the initial cortisol measures. Patients were administered the Alzheimer's Disease Assessment Scale (ADAS) and Folstein Mini-Mental State Examination (MMSE) at approximately 6-month intervals. Cortisol and DHEA were determined using conventional 125I radioimmunoassay procedures. Pearson product-moment correlations among cortisol and DHEA measures and both initial and longitudinal clinical measures were calculated. There was a relationship between baseline 8 a.m. cortisol levels and cognitive function at the initial testing as measured by the ADAS cognitive measure, with higher cortisol levels being associated with a greater level of impairment. We did not document a relationship between cortisol or DHEA levels and noncognitive measures. There was a significant correlation between both the initial MMSE and ADAS cognitive measures and initial DHEA level, with lower DHEA levels unexpectedly being associated with better performance on these measures. The initial DHEA levels did not predict decline in cognitive function over time. These findings bring into question the potential usefulness of DHEA as a therapeutic agent.
View details for PubMedID 9629527
To estimate the dollar savings in costs attainable from drug or other treatments for Alzheimer disease (AD) that stabilize or reverse patients' cognitive decline.Medical and other disease-related utilization data were collected from the caregivers of 64 patients diagnosed as having probable AD. The quantities of utilization were priced at national levels to generate measures of illness costs. Costs per patient were then estimated as regression functions of scores on the Mini-Mental State Examination (MMSE), which was used as an index of patient cognitive function. Potential savings in illness costs were estimated by comparing predicted costs at various baseline and intervention-level values of the patient's MMSE score.The potential savings in illness costs attainable from treatment are small for mildly and very severely demented patients with AD. However, for moderately to severely demented home-dwelling patients having, say, an MMSE score of 7 at baseline, prevention of a 2-point decline in the score would save about $3700 annually, and a 2-point increase in an MMSE score rather than a 2-point decline would save about $7100.Large savings in the costs of caring for moderately to severely demented home-dwelling patients with AD may be achievable from disease interventions that have minor effects on patients' cognitive status.
View details for Web of Science ID A1997XE00100004
View details for PubMedID 9193203
To examine whether each of the 5 Mattis Dementia Rating Scale (DRS) scores related to magnetic resonance imaging-derived volumes of specific cortical or limbic brain regions in patients with Alzheimer disease (AD).Relations between DRS measures and regional brain volume measures were tested with bivariate and multivariate regression analyses.The Aging Clinical Research Center of the Stanford (Calif) University Department of Psychiatry and Behavioral Science and the Geriatric Psychiatry Rehabilitation Unit of the Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif.Fifty patients with possible or probable AD. Magnetic resonance imaging data from 136 healthy control participants, age 20 to 84 years, were used to correct brain volumes for normal variation arising from intracranial volume and age.The DRS scores and volumes of regional cortical gray matter and of the hippocampus.Memory scores of the patients with AD were selectively related to hippocampal volumes. Attention and construction scores were related to several anterior brain volume measures, with attention showing a significantly greater association to right than left hemisphere measures. Initiation/perseveration scores were not significantly correlated with any measure of regional gray matter volume, but performance was related to prefrontal sulcal widening, with a greater association with the left than right sulcal volume.Certain DRS subtests are predictably correlated with selective regional brain volumes in AD. The specific relation between memory and hippocampal volumes and the nonsignificant relations between memory and regional cortical volumes suggest a dissociation between cortical and hippocampal contributions to explicit memory performance.
View details for Web of Science ID A1997XE00100008
View details for PubMedID 9193207
The relationship between number of apolipoprotein E epsilon 4 (APOE epsilon 4) alleles and the rate of cognitive decline in patients with Alzheimer's disease was examined.Rate of decline in score on the Mini-Mental State was measured during the active phase of the decline curve between Mini-Mental State scores of 23 and 0. To characterize onset, the authors also estimated for each subject the age at which the Mini-Mental State score fell below 23 and obtained a retrospective report of age at onset from the caregiver. The number of APOE epsilon 4 alleles carried by each subject was determined from genomic DNA samples. The study included 86 subjects with probable Alzheimer's disease who had had at least two cognitive evaluations (a mean of 5.6 evaluations per subject over an average period of 3.6 years).The results did not support an association between APOE epsilon 4 dosage and rate of cognitive decline. Age at onset and age at which the Mini-Mental State score fell below 23 were also not related to APOE epsilon 4 dosage. The APOE allele frequencies were similar to those in other studies of subjects with Alzheimer's disease, showing an enrichment of the epsilon 4 allele.Although the APOE epsilon 4 allele is a risk factor for Alzheimer's disease, there is no support of a strong association between APOE epsilon 4 dosage and rate of cognitive decline. The epsilon 4 allele did not predict age at onset. Methodological inconsistencies may account for discrepancies between these results and previous findings.
View details for Web of Science ID A1997WX13000004
View details for PubMedID 9137113
The alpha 1-antichymotrypsin (ACT) A allele was recently associated with Alzheimer's disease (AD), and the ACT AA genotype was reported to be more frequent in AD subjects with the apolipoprotein E (APOE) epsilon4 allele. We examined ACT and APOE genotypes in a sample of 160 subjects with probable AD and in 102 elderly control subjects. ACT A allele frequencies were similar in AD subjects (0.503) and elderly controls (0.519). In addition, we found no evidence that in AD the AA genotype is more frequent in subjects with the APOE epsilon4 allele than in those without it. Our results do not support an association between the ACT A allele and AD.
View details for Web of Science ID A1997WZ77800030
View details for PubMedID 9153464
The purpose of this preliminary report was to explore overall level and diurnal patterning of caregiver reports of abnormal behavior and to explore relationships with actigraphic measures of sleep/wake activity in Alzheimer's disease (AD) patients. Our primary behavioral measure was the Time-based Behavioral Disturbance Questionnaire (TBDQ). The overall score on this measure was shown to have adequate test-retest reliability and convergent validity with another behavioral measure. Significant correlations were obtained between the TBDQ overall score and actigraphically scored sleep efficiency (r = -.35, P < .05) and wake after sleep onset (r = .43, P < .01) in 41 subjects. The data suggest a moderate relationship between actigraphic measures of sleep/wake and disturbed behavior in home-dwelling AD patients.
View details for Web of Science ID A1997XC89900004
View details for PubMedID 9188020
Automatic and effortful processes were investigated using event-related brain potentials (ERPs) recorded from moderately impaired subjects with probable Alzheimer's Disease (AD), normal elderly, and normal young controls. The effects of effortful attention on ERPs to loud noises and the effects of stimulus intrusiveness on effortfully elicited ERPs were studied. First, ERPs to task relevant and irrelevant startling noises were compared. Second, ERPs to startling noises and moderate tones were compared when both were targets. The effects of age (young vs. elderly controls) and effects of dementing disease (AD subjects vs. elderly controls) were also assessed. Effortful attention augmented noise-elicited P300 amplitude in elderly subjects, but not in young. Intrusiveness augmented task-relevant P300 amplitude in young subjects, but not in elderly. Neither variable affected P300 amplitude in AD subjects. Thus, effects of age and disease depended on how P300 was elicited: when effortfully elicited, P300 amplitude was affected by disease but not age; when automatically elicited, P300 amplitude was affected by age but not disease. N1 effects differed from P300 effects.
View details for Web of Science ID A1997XP01300006
View details for PubMedID 9258894
Concerns have been expressed that patients with dementia will display disinhibited, inappropriate sexual behavior. Retrospective research suggests that this is rare, but no observational research has been reported. The purpose of this study was to conduct such an observational study.Subjects were 40 patients with a dementia diagnosis who were living in institutional settings; subjects ranged in age from 60 to 98. Coders observed subjects on nine separate occasions, three in the morning, three in the afternoon, and three in the evening. Subjects were observed in multiple situations; coding included appropriate, ambiguous, and inappropriate sexual behaviors. Reliability coding was obtained for 42% of the patients on 11% of coded episodes.Behaviors could be coded with high reliability (94% to 100% across categories of behavior). On average, patients displayed 43 appropriate sexual behaviors, 1.48 ambiguous behaviors, and .83 inappropriate behaviors across the nine observation periods. This was not evenly distributed across patients, however; only 18% of patients ever displayed a sexually inappropriate behavior, and these were usually brief and minor. Inappropriate sexual behavior was observed in only 1.6% of the observed one-minute time segments.Observational research documents what had been previously suggested by retrospective reports: inappropriate sexual behavior is uncommon in dementia patients and brief and minor even when it occurs. Ambiguous behaviors, such as appearing in public incompletely dressed, which could suggest exhibitionism but more likely reflects self-care deficits, were more common. Misinterpretation of these events may be the source for some of the persistent lore regarding sexually disinhibited behavior in dementia patients.
View details for Web of Science ID A1996WD35200022
View details for PubMedID 8914506
Patients with Alzheimer's disease (AD) show considerable heterogeneity in the rate at which they decline cognitively. The biological basis for this heterogeneity is unknown. We genotyped 86 subjects with diagnoses of probable AD to determine if they carried the alpha-1-antichymotrypsin (ACT) A allele, which has been associated with AD, or the CYP2D6 B mutant, found at increased frequency in the Lewy body variant (LBV) of AD. We then examined longitudinally-collected cognitive data to determine if these genetic markers were associated with rate of cognitive decline. Our results indicate that neither the ACT A allele nor the CYP2D6 B allele have a significant association with rate of decline on the Folstein Mini Mental State examination. Further, subjects with both the ACT A allele and the apolipoprotein epsilon 4 allele showed no evidence of accelerated decline. These findings suggest that any increased risk of developing AD or LBV conferred by these markers is not necessarily accompanied by a more rapid rate of decline.
View details for Web of Science ID A1996VQ39800033
View details for PubMedID 8916107
The status of semantic priming in Alzheimer's disease (AD) was examined using the speech elicited N400 component of the event-related brain potential (ERP). Speech was naturally paced, with 1 s of silence before the final word. In the semantic task, subjects attended to the meaning of the sentences for a subsequent memory test. In the phonemic monitoring task, they counted the words beginning with the letter 'p'. The effects of age were assessed by comparing young and elderly, and the effects of disease by comparing elderly and AD subjects. In healthy young and elderly subjects, N400s were large to semantically unprimed words and small to semantically primed words. In AD subjects, N400s were large to primed words, reflecting a failure of the sentence stem to prime the final word, and probably an impairment in semantic knowledge. The N400 priming effect was not smaller during the phonemic than semantic task in any group, suggesting that the semantic qualities of speech are processed even when subjects are attending to phonemic qualities. N400 latency was delayed with age and further delayed with dementia.
View details for Web of Science ID A1996VL66900004
View details for PubMedID 8862113
Youth violence poses a major public health problem. It is important to find treatable predictors of recidivism. Our Subjects had committed offenses of physical and sexual assault. The personality dimensions of restraint and distress were rated by two independent and blind raters from narratives of offender's committing offenses, which were obtained at baseline during incarceration. Inter and intrarater kappas for each narrative were significant. In a 10-13 year follow-up, subjects lowest in self- restraint had significantly higher recidivism and their reoffenses differed in quality. Restraint may be influenced by clinical intervention and constitutes a new target in the treatment of delinquents.
View details for Web of Science ID A1996VP57900001
View details for PubMedID 8936793
This study used a semiautomated image analysis technique to quantify the rate and regional pattern of cerebrospinal fluid (CSF) volume changes in the computed tomographic brain examinations of healthy adults and patients with Alzheimer's disease (AD).Longitudinal, within-subject design, with statistical correction for longitudinal method error (eg, head repositioning effects).Palo Alto (Calif) Department of Veterans Affairs Medical Center.The 41 patients with AD were recruited from the Geriatric Psychiatry Research Unit and the National Institute of Mental Health Clinical Research Center of the Palo Alto Department of Veterans Affairs Medical Center. The 35 healthy control subjects were recruited from the local community.Cerebrospinal fluid volumes estimated from computed tomographic scans.Even after accounting for an estimate of method error (eg, head positioning effects) across computed tomographic examinations, the patients with AD showed greater annual CSF volume increases than did the control group. This CSF volume enlargement was not uniform across brain regions of interest; rather, the patients with AD showed disproportionate volume increases in the ventricular system and the sylvian fissures. Greater CSF volume changes in the patients with AD were significantly associated with greater cognitive decline on the Mini-Mental State Examination. Furthermore, younger patients with AD showed more rapid progression on computed tomographic scans than did older patients.The rate of CSF volume enlargement is region specific, with the most marked annual rate of change occurring in the ventricular system and the sylvian fissures. In addition, younger patients show more rapid progression in the ventricular and frontal sulcal brain regions of interest than do older patients.
View details for Web of Science ID A1995QR98600014
View details for PubMedID 7710375
To study the relationship between estrogen hormone replacement therapy and recall of proper names and words in cognitively intact older women.A case-control study using subjects matched on age and education.From a group of 278 older (age range 55 to 93 years) community-dwelling women volunteers for memory research, 72 older women taking estrogen replacement therapy were matched on age and education with a group of 72 women not taking estrogen.Dependent measures were performances on: a proper name recall test and a word recall test.Proper name recall was significantly better in those receiving estrogen (mean = 4.3; SD = 3.3) than in those not receiving estrogen (mean = 3.1; SD = 2.5), P = 0.01. There was also significantly greater variance in the name recall scores of the group taking estrogen than in the group not taking estrogen. For word recall, there was no significant difference between those subjects taking estrogen (mean = 6.4; SD 3.8) and those not taking estrogen (mean = 5.8; SD 3.7), P > 0.10.Estrogen use was associated with enhanced recall of proper names. Previous failures to find differences associated with estrogen use may reflect the memory measures used or an increased inter-individual variability of the estrogen-taking group, as was observed in the present study. Interpretation of these results should be tempered by their retrospective nature.
View details for Web of Science ID A1994PE83200002
View details for PubMedID 8064097
To expand on a recent study of 42 patients with probable Alzheimer's Disease that found that the only significant predictors of certain clinical end points were the degree of severity features at entry ("how far").A case series study of a cohort of 81 patients with Alzheimer's disease that used survival analysis methods similar those of the previous study but included a new technique for calculating rate of progression ("how fast") as well as entry characteristics ("how far").A university medical center and its affiliated Veterans Affairs Medical Center.All patients with probable and definite Alzheimer's disease studied at the Aging Clinical Research Center at Stanford University, Palo Alto, Calif, in the years 1981 and 1992 who met the following criteria: a mild to moderate level of severity of the disease (Mini-Mental State Examination score of 15 or above) at entry into the study and a minimum of three test points spaced approximately 6 months apart (to allow estimation of rate of progression). A total of 81 such patients were identified. These patients had been followed up for a mean of 4.53 +/- 2.3 years, with a range of 1.0 to 14.5 years.The outcome measure was the average rate of decline on the Mini-Mental State Examination.The results of our study replicated a previous finding that the degree of severity is a strong predictor of time course, but in addition we found that the rate of progression also appears to be a strong predictor of clinical course.There appears to be substantial heterogeneity in the rate of progression in patients with Alzheimer's disease, and, like initial degree of severity, rate of progression appears to be a strong predictor of clinical course.
View details for Web of Science ID A1994NA08900013
View details for PubMedID 8129639
We examined the relation between selected psychiatric symptoms and the average rate of decline in different areas of cognition in patients with Alzheimer's disease. Measures of decline were computed by determining patients' average rates of decline on the underlying factors of the Mini-Mental State Examination (MMSE). Patients with agitation or wandering declined more rapidly on the total MMSE score than did patients without either symptom. The Following Commands factor accounted for almost all of this decline. The findings suggest a relation between the presence of certain behavioral problems in Alzheimer's disease and decline in particular cognitive areas.
View details for Web of Science ID A1993MA73400010
View details for PubMedID 8251053
The purpose of this paper was to use the Wechsler Adult Intelligence Scale (WAIS) to further define the nature of the underlying factors of the Mini-Mental State Examination (MMSE) as proposed by Tinklenberg et al. (1990). The MMSE was administered to 51 patients once every 6 months for at least one year; the WAIS was administered only at the beginning of the study. Stepwise regression analyses yielded these results: for the Following Commands factor, the best correlate was the Comprehension subtest; for the Language Repetition factor, the best correlate was the Picture Arrangement subtest; and for the Language Expression factor, the best correlates were the Digit Symbol and Object Assembly subtests. These relations help clarify the correlates of decline of AD patients on the MMSE.
View details for PubMedID 8292767
The reverse transcription and polymerase chain reaction technique (RT-PCR) was assessed for the quantification of changes in mRNA levels from primary astrocyte cultures. The effects of dibutyryl cyclic AMP (dBcAMP) on glial fibrillary acidic protein (GFAP) mRNA and the effects of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and lipopolysaccharide (LPS) on interleukin-6 (IL-6) mRNA were examined. Two quantitative PCR methods were used: one involved carrying out the reaction in the exponential phase and the other involved the coamplification of a competitive target sequence. Increased GFAP mRNA in response to chronic dBcAMP treatment and increased IL-6 mRNA in response to TNF-alpha/IL-1 beta were readily detected. Both RT-PCR techniques were found to be suitable for the detection of large as well as smaller (twofold) changes in mRNA levels. The advantages and limitations of RT-PCR for mRNA quantification are discussed.
View details for PubMedID 7692077
This study examined the time-course of alcohol impairment of general aviation pilot simulator performance. We tested 14 young (mean age 25.8 years) and 14 older (mean age 37.9 years) pilots in a Frasca 141 simulator during alcohol and placebo conditions. In the alcohol condition, pilots drank alcohol and were tested after reaching 0.10% BAL, and then 2, 4, 8, 24, and 48 h after they had stopped drinking. They were tested at the same times in the placebo condition. Alcohol impaired overall performance. Alcohol impairment also depended on the order in which subjects participated in the alcohol and placebo sessions, with larger decrements for the alcohol-placebo order than for the opposite order. To examine the influence of alcohol independent of session order effects, we compared performance in the first alcohol session with performance in the first placebo session. This analysis showed that alcohol significantly reduced mean performance in the alcohol condition at 0.10% BAL and at 2 h. In addition, alcohol increased variability in performance in the alcohol session from 0.10% BAL to 8 h, suggesting that some subjects were more susceptible to alcohol than others. Older pilots tended to perform some radio communication tasks less accurately than younger pilots.
View details for Web of Science ID A1993LP56600003
View details for PubMedID 8368982
The purpose of this study was to compare the stage and the subtype models of disease progression in Alzheimer's disease. The authors address the issue of whether the overall rate of clinical decline is different in Alzheimer's disease patients with and without early development of aphasia, apraxia, or agnosia.The study was a case series study. Two separate cohorts of Alzheimer's disease patients were used, one from an ongoing single center study at Stanford University (N = 57) and the other from a multicenter project across the state of California (N = 70). Patients were assessed every 6 months in the Stanford study and yearly in the state study. All patients were assessed at least three times. The outcome measure was the average rate of decline on the Mini-Mental State examination.The average rates of decline on the Mini-Mental State were computed for each subject. Subjects were then divided among groups according to whether and when they exhibited aphasia, agnosia, or apraxia. The effects of the presence of aphasia, agnosia, or apraxia were assessed by comparing the average rates of decline on the Mini-Mental State.Alzheimer's disease patients who developed aphasia or apraxia declined more rapidly than those patients who did not develop either sign. These results were not attributable to differences in Mini-Mental State scores at entry into the study. The results suggest the presence of subtypes of Alzheimer's disease in which accelerated decline is associated with the early appearance of certain neurological signs.
View details for Web of Science ID A1993LA32300010
View details for PubMedID 8480819
This study used a semiautomated analysis technique to quantify differences in regional brain cerebrospinal fluid volumes observed with computed tomography between healthy adults and patients with Alzheimer's disease (AD).Cross-sectional, between-subject design, using an age-regression model.Palo Alto (Calif) Department of Veterans Affairs Medical Center.The 117 patients with probable or definite AD were recruited from the Geriatric Psychiatry Research Unit and National Institute of Mental Health Clinical Research Center of the Palo Alto Department of Veterans Affairs Medical Center. The 114 healthy volunteers were recruited from the local community.Cerebrospinal fluid volumes estimated from computed tomographic scans and neuropsychological test scores.The computed tomographic estimates of ventricular and sulcal cerebrospinal fluid volumes increased significantly in all sampled brain regions in normal aging and were vastly larger in AD than in normal aging. Furthermore, younger patients with AD had significantly greater cerebrospinal fluid volume enlargement than did older patients with AD compared with healthy controls of their age. When the AD group was divided on the basis of reported age at symptom onset, patients in the early-onset group (onset before age 65 years) were quantitatively more abnormal than and showed a different pattern of abnormality from the patients in the late-onset group. This onset difference was also evident in neuropsychological test performance.This cross-sectional study revealed a number of converging findings that suggested greater abnormality in the early-onset than in the late-onset group of patients with AD. The possibility remains, however, that the two onset groups represent different stages along a continuum of pathologic changes.
View details for Web of Science ID A1993KV70200007
View details for PubMedID 8460957
We examined how pilot age influences radio communication and routine flying tasks during simulated flight, and if practice reduces age differences in these tasks. The communication task involved reading back and executing messages with four commands (heading, altitude, communication frequency, transponder code). Routine flying tasks included takeoff, visual approach, and landing. Fifteen older (X = 38.4 years) and 16 younger (X = 26.1 years) private-license pilots flew 12 flights involving these tasks. Age differences were found in the communication task; older pilots read back and executed controller messages less accurately. However, age differences were not significant for any of the routine flying tasks except the approach. Age differences in communication performance were not reduced by practice, with older and young pilots improving at roughly the same rate across flights. These results are consistent with previous research showing age-related declines in working memory capacity. Capacity declines would produce greater age differences on communication than on routine flying tasks because the communication tasks imposed a greater load on working memory.
View details for Web of Science ID A1993KN48000005
View details for PubMedID 8444267
1. Alzheimer's disease (AD) is likely to have a significant effect on sexual behavior, but both patient and partner will still have sexual feelings and needs. 2. Research has shown that a high proportion of men with AD develop erection problems, but causes of their erection difficulties are not understood. 3. Research has shown that inappropriate sexual behavior in AD patients is uncommon, although it can be very troubling to the family and health-care provider if it occurs. 4. More professionals need to be trained to discuss sexual issues openly and sensitively with AD patients and partners and to offer useful clinical suggestions.
View details for PubMedID 1494148
View details for Web of Science ID A1992KC01100010
The nucleus basalis of Meynert (nbM) was examined using immunocytochemistry for beta-amyloid precursor protein (beta APP) expression in Alzheimer's disease (AD). In mild AD cases, light labeling of the cell body and proximal processes was observed, and small intracellular structures were labeled rarely. In the more severe cases, intense cytoplasmic beta APP labeling was seen, often along with small beta APP-positive structures. Double-labeling experiments demonstrated that in the more severe cases these small structures were also decorated by a neurofibrillary tangle (NFT) antiserum. Other neurons in the severe cases showed incorporation of beta APP into large inclusions, which were also labeled with the NFT antiserum. However, some large inclusions in the severe cases were labeled by the NFT antiserum but contained no beta APP. Extraneuronal NFTs did not show beta APP labeling and did not react with an antibody to the beta-amyloid peptide. These results suggest that increased expression of beta APP coincides with intracellular NFT formation in the nbM, but that the formation of extraneuronal NFTs results in a loss of beta APP immunoreactivity.
View details for Web of Science ID A1992JH62500011
View details for PubMedID 1386714
Change in memory performance and its correspondence to change in speed of performance and self-reported memory functioning were investigated longitudinally in 30 older adults with memory complaints. Subjects were assessed by self-report questionnaires and cognitive tests 3 times, at near 2-year intervals. A significant decline in word-recall scores was found, which was accompanied at the group level by significant self-reported decline in everyday memory functioning and nonsignificant decline in Wechsler Adult Intelligence Scale Digit Symbol scores (alpha = .05). The oldest subjects showed the most substantial declines in memory performance. At the individual level, however, memory change did not significantly correlate with either change in self-reports or change in Digit Symbol scores. Although these results do not support a cognitive slowing model of decline at the intraindividual level, they do have implications for intervention of age-related memory decline.
View details for Web of Science ID A1992HY69000002
View details for PubMedID 1610506
View details for Web of Science ID A1992BW50H00017
View details for Web of Science ID A1992BX24B00040
beta-Amyloid precursor protein (beta APP) mRNA was examined in peripheral mononuclear blood cells (PMBCs) in Alzheimer's disease, Down's syndrome and control subjects. Total RNA from PMBCs was reverse transcribed and then amplified using the polymerase chain reaction (PCR). The 3 major beta APP transcripts were expressed in PMBCs from all subjects. These results suggest that PMBCs could be a circulating source for abnormal amyloid deposition in the brain and in peripheral tissues.
View details for Web of Science ID A1991GN66500029
View details for PubMedID 1838578
The anatomic distributions of beta-amyloid peptide (beta AP) and beta-amyloid precursor protein (beta APP) in the medial temporal lobe were examined with immunocytochemistry in Alzheimer's disease. beta AP-containing plaques were found most frequently in the cortical and basal regions of the amygdala, and in the hippocampal CA1, subiculum, and dentate molecular layer. beta APP expression in plaques was found in a similar distribution, with some, but not all beta AP plaques also showing beta APP. In the cortical and basal amygdala, some cases showed beta APP in the centers of plaques, whereas in the hippocampus, all cases displayed beta APP mainly in plaque neurites. The lateral regions of the amygdala contained mainly diffuse beta AP plaques which had little beta APP. These findings suggest that although beta APP expression and beta AP deposition generally colocalize, processing of beta APP may vary among closely interconnected anatomic regions.
View details for Web of Science ID A1991GK15300024
View details for PubMedID 1791966
We treated 149 patients meeting criteria for age-associated memory impairment (AAMI) for 12 weeks with a formulation of phosphatidylserine (100 mg BC-PS tid) or placebo. Patients treated with the drug improved relative to those treated with placebo on performance tests related to learning and memory tasks of daily life. Analysis of clinical subgroups suggested that persons within the sample who performed at a relatively low level prior to treatment were most likely to respond to BC-PS. Within this subgroup, there was improvement on both computerized and standard neuropsychological performance tests, and also on clinical global ratings of improvement. The results suggest that the compound may be a promising candidate for treating memory loss in later life.
View details for Web of Science ID A1991FK92800006
View details for PubMedID 2027477
We investigated the relationship between extrapyramidal signs (EPSs) in patients diagnosed with Alzheimer disease (AD) and the average rate of decline in different areas of cognition. The presence of tremors, cogwheel rigidity, or bradykinesia were scored as EPS using the California State Department of Health Services AD Diagnostic and Treatment Center Form. Measures of decline were computed by determining patients' average rates of decline on the Mini-Mental State Examination (MMSE). Of the 81 patients, 24 were determined to have EPS not related to medications. Overall, patients with EPS deteriorated 67% faster on MMSE (4.5 points per year) than did patients with no evidence of EPS (2.7 points per year). Our findings indicate that the clinical presence of EPS is a poor overall prognostic sign in patients with a clinical diagnosis of AD.
View details for PubMedID 1781967
View details for Web of Science ID A1991BU83L00032
Most patients with Down's syndrome (DS) undergo a premature cognitive decline with aging, and eventually develop the neuropathologic changes of Alzheimer's disease (AD), including amyloid-containing neuritic plaques, and the formation of neurofibrillary tangles. The amygdala is a focus of marked neuropathologic change in older patients with DS and in AD. We examined the amygdala with immunocytochemical and histochemical methods in 6 cases with DS, ages 19, 20, 27, 29, 56 and 64 years and compared them to 4 cases with AD, ages 54, 76, 77 and 80 years. An antiserum to the A4 amyloid peptide demonstrated amyloid deposition in plaques in all 10 cases. Plaques were also revealed in all cases by the Alcian blue stain for glycosaminoglycans and by the Bielschowsky and Bodian silver stains. An antiserum to alpha-1-antichymotrypsin (ACT) showed plaques in the AD cases and in the 19, 56 and 64 year old DS cases. Neurofibrillary tangles were observed with silver stains only in the older DS and in the AD cases, and not in the 19, 20, 27 and 29 year old DS cases. Likewise, antisera to paired helical filament, to microtubule associated proteins tau and microtubule associated protein-2 (MAP-2), and to ubiquitin, all of which are components of neurofibrillary tangles, reacted with tangles and abnormal neurites only in the older DS and the AD cases. An antiserum to neurofilament epitopes labeled NFTs in the older DS cases and the AD cases, but not in the younger DS cases, except for two intraneuronal NFTs in the 27 year old case.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1990EP96100013
View details for PubMedID 1707726
Patients with presumptive Alzheimer's disease (AD) and healthy community volunteers received computed tomographic (CT) brain scans and cognitive tests. The CT scans were quantitatively analyzed with a semiautomated thresholding technique to derive volumetric measures of cerebrospinal fluid (CSF)-to-tissue ratios in six regions of interest (ROIs): lateral ventricles; vertex sulci, frontal sulci, Sylvian fissures, parieto-occipital sulci, and third ventricle. Regression analysis was performed on CT data from 85 older volunteers (ages 51-82) to generate age norms for each ROI. Within this group, tissue loss, as measured by the % CSF in each ROI, was highly correlated with age, although each ROI showed different rates of change over age. For all ROIs, the AD group had significantly more tissue loss than expected in normal aging. In addition, AD patients with a presenescent onset (before age 65) tended to have greater vertex sulcal and frontal sulcal tissue reduction than AD patients with a senescent onset (age 65 or after). When regional tissue reduction, corrected for age, was correlated with cognitive test scores, two sets of double dissociations emerged within the AD group: large CT z scores (i.e., decreased tissue and increased CSF) of frontal sulci, but not of the third ventricle, correlated with low Comprehension and Boston Naming Test scores, whereas large CT z scores of the third ventricle, but not of the frontal sulci, correlated with low scores on Digit Symbol and Picture Arrangement. These results suggest that heterogeneity of structural and functional integrity exists among patients with AD.
View details for Web of Science ID A1990EU28600003
View details for PubMedID 2100804
The Mini-Mental State Examination (MMSE) is a commonly used instrument for assessing mental impairment. Previous proposals for its underlying structure have focused on scores obtained from a single administration of the test. Because the MMSE is widely used in longitudinal studies, we examined the pattern of relations among the rates of chance of the items. Data were obtained from 63 subjects for 1.5 years or more. The relations among the rates of change of the MMSE items were described by a five-factor solution that accounted for 75% of the variance and comprised factors pertaining to orientation and concentration, obeying commands, learning and repetition, language, and recall. This was in contrast to the structure of the scores obtained from a single administration of the MMSE, which was best described by a two-factor solution. In order to provide a clinical validation, factor scores derived from the MMSE factors were used to predict scores on the Memory and Behavior Problems Checklist and the Brief Cognitive Rating Scale.
View details for PubMedID 2101301
Dexmedetomidine, a highly selective and potent agonist at alpha-2 adrenoceptors, produces a hypnotic-anesthetic action in rats. The mechanism for this response may involve an inhibitory G-protein and increased conductance through a potassium channel. To investigate this, the effects of pertussis toxin, a specific inactivator of inhibitory G-proteins, and 4-aminopyridine, a blocker of potassium channels, on the hypnotic-anesthetic response to dexmedetomidine were studied in rats. Pertussis toxin and 4-aminopyridine both decreased the hypnotic-anesthetic action of dexmedetomidine in a dose-dependent fashion. To preclude the possibility that pertussis toxin and 4-aminopyridine attenuated the hypnotic-anesthetic action of dexmedetomidine via indirect central nervous system excitation, the effects of pertussis toxin and 4-aminopyridine on the hypnotic-anesthetic action of pentobarbital also were assessed. Pentobarbital-induced hypnosis was not attenuated by either treatment. These results suggest that the receptor-effector mechanism for the hypnotic-anesthetic action of dexmedetomidine involves an inhibitory G-protein and increased conductance through a potassium channel.
View details for Web of Science ID A1990DV59100019
View details for PubMedID 1974396
Loss of erection was reported in 53% of 55 male Alzheimer's disease patients with a mean age of 70.25. Loss of erection is not related to degree of cognitive impairment, age, or depression. Modal time of onset of erectile problems is concurrent with onset of Alzheimer's symptoms. Patients with erectile problems were not taking more medications overall than those without problems and had no greater overall incidence of concurrent physical problems. Thus, the evidence suggests that there may be an elevated incidence of erectile failure in patients with Alzheimer's disease as a primary problem not attributable to other age-related factors.
View details for Web of Science ID A1990DT23600002
View details for PubMedID 2400296
1. Amyloid deposition is one of the pathologic hallmarks of Alzheimer's disease. Since the isolation of the beta-amyloid gene, which revealed that the amyloid forming 4 kD protein is part of a larger precursor, interest has focused on the process by which amyloid is generated and deposited. 2. The authors have developed an immunologic means of detecting amyloid precursor proteins in human brain. 3. The method involves the expression of human beta-amyloid precursor cDNA in a recombinant vaccinia virus, so that antibodies are produced against the precursor proteins in their native forms. 4. By using this expression system, the amyloid precursor immunogens incorporate post-translational modifications that normally occur in vivo; this cannot be achieved with small synthetic peptides. 5. Using antibodies to the 695 residue amyloid precursor, we have detected using Western blot analysis a protein of approximately 120 kD in samples of cerebral cortex from three subjects with Alzheimer's disease and one control subject. 6. Additional antibodies to other amyloid-related proteins have been developed. These are being used to assess the differential expression of the various amyloid precursors and subdomains in additional cases.
View details for Web of Science ID A1990DC78100004
View details for PubMedID 2113696
Mental deterioration accompanying sleep apnea has been noted frequently. Because sleep apnea increases with age, such deficits raise the possibility that dementia in the elderly could be related to sleep apnea. In this study we investigated this possibility cross-sectionally by comparing respiration during sleep in 28 patients with Alzheimer's disease (AD) and 25 nondemented controls. We hypothesized that higher levels of sleep apnea would be present in AD patients. Our results indicated no significant differences between AD patients and controls but those few AD patients who desaturated during sleep experienced morning confusion. The findings imply that AD and sleep apnea are two separate conditions which may still interact in the aged.
View details for Web of Science ID A1989AK79000008
View details for PubMedID 2812195
Latency to the first episode of rapid eye movement sleep (REML) has been proposed as a potential biomarker for Alzheimer's disease (AD). In this study, we compared REML values from 28 AD patients and 28 age- and sex-matched controls. We employed multiple definitions of REML and multiple cutoffs to classify patients and controls. Results indicated that the best REML definition and optimal cutoff criterion resulted in only 65% correct classifications. We discuss the longer REML in AD patients relative to controls in terms of both overall sleep disturbance and selective deterioration of the REM-cholinergic system. As REML may be relatively short in other forms of psychopathology (e.g., affective disorders), REML may still hold promise in the differential diagnosis of dementia and pseudodementia.
View details for Web of Science ID A1989R741100008
View details for PubMedID 2914155
We report the clinical and neuropathological characteristics occurring in 180 demented individuals from 24 kindreds with familial Alzheimer's disease (FAD). Each family had at least two affected generations, and at least one autopsy or brain biopsy was compatible with the diagnosis of AD. Forty-nine neuropathological specimens or reports were reviewed. Mean age of onset for the total group was 54.7 years +/- 11.5, with a large range of 30 to 84 years. Mean age at death was 63.5 years +/- 12.2, with a range of 46 to 85. Mean duration of disease was 8.8 years +/- 4.4, with a range of 1 to 23 years. Six findings suggested phenotypic heterogeneity in FAD. (1) Five families represented an early age of onset group with mean onset at 42 years (range 30 to 51 years) and mean disease duration of 6.7 years. (2) Eight families represented a late onset group with mean onset at 68 years (range 59 to 78 years) and a mean duration of 8.5 years. (3) Seven families were of Volga German ancestry, all originating from the same two villages in Russia. Mean age of onset was 55.9 years (range 40 to 72 years), with a mean disease duration of 10 years. This group probably represents the genetic founder effect of an autosomal dominant gene for AD. (4) One family had the unusual characteristics of neurofibrillary tangles and granulovacuolar change but no amyloid plaques, a mean disease duration of more than 11 years, and a "schizophrenia-like" onset. (5) One family with late onset also had clinical and pathological evidence for anterior horn cell disease. (6) Two autopsies in 1 family both showed remarkable rarefaction of myelin and expansion of perivascular spaces in centrum semiovale (état criblé), with marked leptomeningeal and cortical amyloid angiopathy, distinct from the other FAD brains. It remains to be determined whether the clinical and pathological differences between these families represent genetic heterogeneity at the biochemical or molecular level.
View details for Web of Science ID A1989R970300002
View details for PubMedID 2913924
Alzheimer's disease, an autosomal dominant disorder, is characterized by the presence of neurofibrillary tangles and senile extracellular plaques in the brain of affected individuals. An amyloid beta protein has been isolated from the core of these plaques, and the gene encoding this protein has been mapped to region q11.2 to q22.2 of chromosome 21. Independent linkage studies have shown that the locus responsible for familial Alzheimer's disease also maps to the long arm of chromosome 21. It is thus very tempting to speculate that a defect (or defects) of the amyloid beta protein gene is the cause of Alzheimer's disease. For this reason, we have done association studies between Alzheimer's disease and restriction fragment length polymorphisms of the amyloid beta protein gene locus. We report a study of six restriction fragment length polymorphisms at the human amyloid beta protein gene locus. Several haplotypes constitute very informative marker systems for this region of chromosome 21. One of the six polymorphisms, a 6.6/7.3 kb (kb = 10(3) base-pairs) EcoRI restriction fragment length polymorphism, is loosely associated with the presence of Alzheimer's disease in a population of 34 subjects.
View details for Web of Science ID A1988T295100004
View details for PubMedID 2907602
View details for Web of Science ID A1988P435200072
A study of 67 rapes by 63 California adolescents has yielded a highly representative composite picture of the typical rape episode by a juvenile assailant. Previously unexplored behavior patterns have emerged, including prior drug use, impulsivity, and lack of victim provocation. These findings have practical implications for clinicians treating rape victims and for the rehabilitation of adolescent rapists.
View details for Web of Science ID A1988M728400002
View details for PubMedID 3369538
In two studies, we studied the comparative sensitivity of different subjective and objective measures to methylphenidate (10 and 20 mg) and secobarbital (100 mg) versus placebo, and diphenhydramine (50 mg) and diazepam (10 and 20 mg) versus placebo in abstinent alcoholics. Subjective measures used were the Visual Analog Mood Scale and the Profile of Mood States. Objective measures were the Stroop and two microcomputer-controlled tasks developed in our lab - a dual pursuit tracking/reaction time task (P-Trak) and a reaction time task with regular and irregular preparatory intervals (PI) of varying length (Reactest). In addition, several baseline measures (Eysenck Personality Inventory, Spielberger State-Trait Anxiety Inventory and NIMH Mood Scale Elderly) were evaluated for their correlation to drug response. All three central nervous system depressants impaired performance on Reactest at the longer PIs and showed a main effect with irregular PIs, but only the 20-mg dose of diazepam impaired reaction time at the shortest PI and showed a main effect with regular PIs. On P-Trak, secobarbital and diazepam 20 mg impaired both tracking and reaction time, while methylphenidate 20 mg improved only the reaction time component. Only diazepam 20 mg affected mood. No effects were noted on the Stroop. The implications of these findings are discussed. Both P-Trak and Reactest with long PIs were more sensitive than VAMS, POMS or Stroop to drug effects. As lower doses of central nervous system depressants impaired reaction time only with longer PIs and showed a main effect only with irregular PIs, cognitive effects of these drugs may be missed if only subjective or short, regular PI tasks are examined.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1988Q485200007
View details for PubMedID 3226529
This randomized, double-blind study was designed to evaluate the effect of prostacyclin (epoprostenol) on the incidence and severity of postoperative neuropsychologic dysfunction in patients undergoing coronary artery operation. Four days before operation and 1 week after operation, 100 patients having coronary artery bypass grafting underwent detailed neurologic and psychologic examinations and computed tomographic scans of the brain. The psychologic examination was repeated 2 months after operation. During cardiopulmonary bypass, all patients received 300 U/kg of heparin and then either buffer-diluent or prostacyclin (12.5 ng/kg/min from the time of heparinization until onset of cardiopulmonary bypass and 25 ng/kg/min during cardiopulmonary bypass). No deaths or major neurologic complications occurred in this series. Ninety-six patients completed the psychologic and neurologic evaluations 1 week after operation; 74 of these patients were evaluated psychologically 2 months after operation. Psychologic testing demonstrated similar declines in postoperative performance in both the prostacyclin-treated and the control groups; these changes were no longer present in either group 2 months after operation. Results of neurologic examinations and computed tomographic scans of the brain were unchanged. We conclude that the administration of prostacyclin during cardiopulmonary bypass in patients undergoing routine coronary artery operation has no effect on perioperative cognitive changes.
View details for Web of Science ID A1987G751000021
View details for PubMedID 3550299
Fourteen Alzheimer subjects participated in a parallel group study of desamino-D-arginine-vasopressin (DDAVP, desmopressin). All subjects received one week of single-blind placebo. Then on a double-blind basis, the active group received DDAVP intranasally in doses starting at 30 micrograms per day and increasing over a 3 week period to 180 micrograms per day; the control group received an identical placebo. Using a repeated measures ANOVA, three measures out of thirty-one were found to be statistically significant for DDAVP treatment: the Hamilton depression scale and the affect and interpersonal subscales of the SCAG. However, the magnitude of these changes was probably too small to be clinically significant. Except for one subject who transiently became hyponatremic (Na of 120) and confused while receiving 180 micrograms of DDAVP, there were no adverse effects. There were no significant group changes in sodium, potassium, plasma osmolality, blood pressure, and weight.
View details for Web of Science ID A1986D706200010
View details for PubMedID 3528891
View details for PubMedID 2872330
Memory is not a unitary process. Rather it is comprised of several psychobiologically distinct elements which may be selectively affected by drugs or by disease processes. An understanding of these distinctions allows a greater appreciation of normal and altered cognitive functioning. In this article, we review several different conceptual approaches to memory and underscore certain methodological issues that are particularly important in studying the psychopharmacology of memory.
View details for Web of Science ID A1985AXQ7300010
View details for PubMedID 3937068
View details for Web of Science ID A1985AHP1000002
In this article we review the effects of specific drugs or neurotransmitter systems on cognitive functions. While much of what we know about drugs' effects on memory is derived from animal experiments, this review focuses on studies relevant to human clinical conditions. We conclude with a speculative analysis or taxonomy of the pharmacology of memory which broadly highlights the utility of viewing memory as being comprised of several differentiated processes.
View details for Web of Science ID A1985A485400006
View details for PubMedID 2421196
Ten normal male volunteers were administered oral diazepam (0.25 mg/kg) or placebo followed 45 min later by IV naloxone (1.2 mg) or placebo. Diazepam produced a marked decrement in performance on tests of memory, visual psychomotor skills, reaction time, and time production. Naloxone alone had no effect on these measures and failed to interact with the diazepam. These findings do not support a role of the endogenous opioid system in normal human cognitive processes or in the behavioral effects of diazepam.
View details for Web of Science ID A1985AHM3100019
View details for PubMedID 3925486
Vasopressin peptides have been shown to facilitate learning and memory in both animals and humans; however, the effectiveness in humans is controversial. In a double blind parallel group study, 17 demented subjects (either Alzheimer's or alcoholic) were given either desglycinamide-9-arginine-8-vasopressin (DGAVP) 92 micrograms intranasally TID or an identical placebo for 1 week after having received 1 week of placebo. To our knowledge, this is the first report of DGAVP being used in subjects with dementia. The DGAVP group had a statistically significant improvement on the Buschke list learning of low imagery words. However, for various reasons discussed in the paper, we feel this finding needs to be replicated before any definite conclusions can be drawn. Since there were no other appreciable behavioral effects of this DGAVP regimen, our results should be considered negative. There was no evidence of any DGAVP-related adverse effects, except for possible weight gain.
View details for Web of Science ID A1985ALA3700002
View details for PubMedID 3895014
The purpose of this paper is to present certain psychological tests adapted for computerized testing of subjects. The reasons why we have considered such tests are numerous: computerized test facilitate measurement of reaction time, testing conditions are standardized without reliance on performance of research assistants, data can be recorded on disc storage without paper handling, preliminary analyses and individual results can be available immediately after testing, simulation of certain real-life situations is possible, randomization of testing materials is facilitated. The computerized testing paradigms for use in gerontology to be discussed are: one an attention task of possible use in psychological research; the second a memory task aimed at basic cognitive psychological research and finally a performance task relating to a complex motor ability (flying). All provide inexpensive, reliable, quantified data and all use the same hardware. It is expected that this area will expand enormously and rapidly.
View details for Web of Science ID A1983RX04000030
View details for PubMedID 6228935
View details for Web of Science ID A1983RG39800007
View details for PubMedID 7156291
In a single-blind study, 12 men (mean age 63 years) with senile dementia were given nafronyl in a dosage of 100 mg eight times daily for a week, followed by 100 mg four times daily for 12 weeks. Rigorous clinical, laboratory and psychometric assessments revealed no toxicity and no significant effects on vital functions. In the cerebrospinal fluid, the ratio of lactate to pyruvate decreased--a finding consistent with an increase in the aerobic metabolism of glucose.
View details for Web of Science ID A1982NF70700005
View details for PubMedID 6173407
Ten healthy old and 10 healthy young subjects each received a series of trials in a memory retrieval task similar to that devised by Sternberg (1967). On each trial the subject saw a memory set of 2 or 4 digits (set size) followed by a probe. The task was to indicate whether the probe was a positive or negative instance (response type) of the memory set for that trial. On half the trials, the probe digits were degraded by a mask of random dots (stimulus quality). For both young and old subjects, RT was later to probes following the larger set size, later to degraded probes, and later to negative probes. For the young subjects only, P3 latency was delayed by the same variables affecting RT although to a lesser degree. P3 latency in the elderly responded quite differently: it was unaffected by set size or response type. However, P3 was somewhat delayed by the degraded probes suggesting that the failure to reflect set size or ceiling effect in the elderly. The correlation between single-trial P3 latency and RT in the elderly is lower than in the young. The data are discussed in terms of age-related differences in the meaning of P3 latency.
View details for Web of Science ID A1982PH34000007
View details for PubMedID 6179758
Cranial computed tomography (CT) scans were obtained in 46 male chronic alcoholics and 31 normal male volunteers. Automated methods were used to estimate the cerebrospinal fluid (CSF) volume in various intracranial zones. Measures of the ventricular fluid volume, the volume of fluid in cortical areas on CT sections at the level of the ventricles, and the sulcal fluid volumes on two convexity sections were computed. The alcoholic group, excluding subjects with chronic liver disease, had significantly more fluid than the control group on all sulcal measures. The group difference on the ventricular measure fell short of significance. Within the alcoholic group, no significant correlation was found between the number of years of alcoholism and any fluid measure when normal age effects were taken into account. A striking degree of variability in the sulcal volumes was observed within the alcoholic group, with many subjects showing normal values while a large group showed markedly elevated values. Further studies will be necessary to determine the significance of these variations.
View details for Web of Science ID A1982PE56600002
View details for PubMedID 6957902
This article is a review of the pharmacotherapy of senile dementia in Europe and the United States. Neurophysiological and neuropathological studies of demented elderly have suggested that a change from the attempt to improve cerebral blood flow to the attempt to improve neuronal intermediary (glycolytic) metabolism may be more fruitful therapeutically. Clinical studies of drugs which are direct smooth relaxant vasodilators are compared with studies of drugs claimed to improve neuronal intermediary metabolism in order to test this hypothesis. Comparison of 102 clinical studies of these two types of medications finds that a significant (p less than .005) number of studies of drugs with metabolic action claim positive results than to studies of drugs with vasodilatator action alone. Three new studies addressing questions of dose and spinal fluid effects of these medications are presented. Two studies provide evidence for the superiority of 6 mg/day of dihydroergotoxine mesylate to 3 mg/kg in the elderly. One study suggests that the medication naftidrofuryl, in doses of 800 mg/day and 400 mg/day, may have similar effects.
View details for Web of Science ID A1981LS58000003
View details for PubMedID 7020520
View details for PubMedID 7454927
Young normal subjects received 16 g of choline chloride in a double-blind A-B-A design. Short- and long-term memory function was evaluated. Comparison of group means indicated that choline chloride did not significantly affect short-term memory or long-term memory. However, individual subjects may have had some aspects of long-term memory affected by choline chloride treatments. The results suggest that the effect of lower doses of choline on long-term memory should be evaluated.
View details for Web of Science ID A1980JB37100012
View details for PubMedID 7350901
Auditory brain stem and cortical evoked potentials were recorded from 15 schizophrenics and 15 controls. There were significant cortical evoked potential differences between the two groups. However, brain stem evoked potentials were almost identical, suggesting that the cortical evoked potential differences are not due to peripheral factors such as inability to match sensory thresholds or defects in auditory acuity.
View details for Web of Science ID A1980JK81900003
View details for PubMedID 7417612
Sternberg's memory scanning task, Buschke's selective reminding task, and a time production task were given to 18 male subjects after they had received 10 mg of methamphetamine, 100 mg of secobarbital and placebo on separate days. Time production and learning that involved storage and retrieval of information in long-term memory were most sensitive to drug effects. Other measures of learning and memory scanning performance were not affected by either drug.
View details for Web of Science ID A1980JB29400007
View details for PubMedID 7353472
Choline chloride (2 g QID) and placebo were administered to 10 subjects over age 60 in a placebo-drug placebo design. Subjects first took placebo for 7 days, followed by choline for 21 days and finally took placebo for another 21 days. Memory tests were given at the end of both placebo periods and twice during choline administration. Choline did not significantly affect performance on a test of memory storage, a test of retrieval from memory or on the digit span test. In addition, a correlational analysis showed that the difference between memory performance during choline administration and during placebo administration was not significantly related to baseline memory performance. These results, together with results of previous studies indicate that choline is not an effective agent for improving memory in nondemented elderly patients.
View details for Web of Science ID A1980LJ31400003
View details for PubMedID 7266731
Rhesus monkeys, pretreated with alpha-methyl-para-tryosine (AMPT) and subsequently injected with phenylethylamine (PEA), did not demonstrate the characteristic amphetamine-like PEA effects. However, when AMPT pretreatment was followed with l-dopa and then PEA injection, PEA effects were restored. These results are compatible with a dopamine theory of schizophrenia.
View details for Web of Science ID A1979GL37400009
View details for PubMedID 105644
The effects of ethanol and meperidine on the auditory evoked potential (AEP) to stimuli of different intensities were investigated. Sixteen normal male volunteers received ethanol, 0.8 ml/kg, 100 mg meperidine, and a placebo on different days in a double-blind study. AEPs were recorded from Fz, Cz and Pz electrode placements. The stimuli were 500 msec 1000 Hz tones at 50, 60, 70 and 80 dB sound pressure level presented in a pseudo-random sequence. Meperidine had no significant effect on AEP variables. Ethanol reduced AEP activity between 24 and 250 msec but had no effect on the sustained potential measured between 300 and 450 msec.
View details for Web of Science ID A1979GY68200001
View details for PubMedID 510179
Seventeen normal volunteers received either 0.5 mg, 1.5 mg, or 2.5 mg physostigmine i.v. in a placebo-drug-placebo single-blind design. EEG was recorded simultaneously and analyzed by computerized spectral analysis. Eleven healthy elderly volunteers (mean age = 69.1 years) with mild memory impairment were treated with placebo, followed by oral choline chloride (either 8 g/day for 3 weeks, or 16 g/day for 1 week), and then, again, placebo. Recordings of spontaneous EEG and EEG event-related potentials (contingent negative variation) were obtained during both placebo and choline treatments. The larger doses of physostigmine produced an increase in low frequency activity and a slowing of the peak alpha frequency. Oral choline chloride had no effect on the EEG as measured by spectral analysis, but appears to have differential effects on contingent negative variation (CNV) amplitude and reaction time, depending upon the initial CNV amplitude.
View details for Web of Science ID A1979GW41600004
View details for PubMedID 111288
The rationale for the use of vasodilators in the aged has changed from the attempt to increase cerebral blood flow to the attempt to improve cerebral metabolism. Review of 102 studies of eight vasodilators showed that significantly more controlled studies claimed practical clinical benefit from drugs supposed to improve neuronal intermediary metabolism with secondary vasodilatation than from drugs supposed to have only vasodilator action (P less than .005). Studies of both classes of drugs often suffered from poor study design, inappropriate and inconsistent application of outcome measurements, as well as negative bias due to selection of severely demented subjects. Future studies should be placebo-controlled investigations of drugs with primarily metabolic action, address questions of dose and time response, consistently use appropriate outcome measurement, and concentrate on the elderly in whom cognitive improvement is possible.
View details for Web of Science ID A1979GL00500012
View details for PubMedID 420543
Eight elderly patients with mild memory impairment were given choline chloride, a drug that increases brain acetylcholine concentrations. After 16 g/day of choline for 7 days, average memory performance was not different from performance during pre- and postcholine placebo treatment, although the patient with the poorest baseline performance improved considerably on choline.
View details for Web of Science ID A1979HN59900005
View details for PubMedID 484722
Beta-endorphin, morphine, and saline were given intravenously to a single schizophrenic subject on separate occasions in a double-blind design. EEG spectral analyses performed on data collected before and after drug injection demonstrated that beta-endorphin and morphine produced similar increases in alpha power within 5 to 15 minutes after injection. This effect could be distinguished from two placebo (saline) injections. These data suggest that intravenous beta-endorphin can produce changes in the central nervous system in humans.
View details for Web of Science ID A1979HN77000011
View details for PubMedID 298341
In controlled experiments rhesus monkeys that had received phenylethylamine (PEA) demonstrated behavior similar to that reported after the administration of amphetamines, except that tolerance to PEA did not develop. These findings are of psychiatric interest because PEA is found in the human body and is a specific substrate for type B MAO, which is found in decreased quantities in certain schizophrenic patients.
View details for Web of Science ID A1978EX57300012
View details for PubMedID 417638
Sixteen college-educated male subjects were given an object description task during placebo conditions and while intoxicated with marijuana extract cookies calibrated to 0.3 mg/kg delta-9-tetrahydrocannabinol, a dose within the range of usual social use. The task was scored for fluency, flexibility, elaboration, and uniqueness, all of which represent associational thinking and are considered to be components of creativity. Marijuana did not enhance any of these measures.
View details for Web of Science ID A1978FA84600008
View details for PubMedID 650201
Twelve male college students received orally on different days NIMH marijuana extract calibrated to contain 0.7 mg/kg delta-9-tetrahydrocannabinol, 1.0 ml/kg 95% ethanol, and placebo in a double-blind balanced-order design. The contingent negative variation (CNV), auditory evoked potential (EP), heart rate (HR), and subjective measures of intoxication were recorded prior to drug ingestion and at regular intervals for 4.5 h postdrug. Both drugs produced significant subjective effects. Marijuana increased HR but did not have a significant effect on CNV amplitude or EP peak amplitudes and latencies. Ethanol increased HR, but not significantly, and reduced CNV amplitude and N1-P2 amplitude. Time-action curves for ethanol's effect on subjective high, HR, and N1-P2 amplitude were parallel, peaking between 0.5 and 1.5 h postdrug and returning to baseline by the end of testing. Time-action curve for ethanol's effect on the CNV showed continuing amplitude reduction throughout the test session.
View details for Web of Science ID A1978EL13300003
View details for PubMedID 415321
Three cognitive tasks in which performance depends primarily on the rate of cognitive processing were given to 24 male subjects before and after oral doses of methamphetamine (10 mg), diphenhydramine hydrochloride (100 mg), and placebo. Each subject was tested on Monday, Wednesday, and Friday of one week with drug orders balanced across subjects. Compared with placebo and diphenhydramine, methamphetamine increased the rate at which a visual display was scanned for a target stimulus. Methamphetamine affected neither a time-production task nor a divided attention task that required the subject to perform two cognitive tasks in a limited amount of time. This suggests that methamphetamine can increase cognitive processing speed on tasks involving familiar cognitive operations but that an increase is not likely in tasks involving more complicated decision processes. Compared with placebo and methamphetamine, diphenhydramine caused subjects no experience geophysical time as passing more slowly, but the drug had no significant effects on the visual search or divided-attention tasks. This suggests that time perception is more likely to be altered by diphenhydramine than is performance on tasks requiring short periods of rapid cognitive processing.
View details for Web of Science ID A1978FR58000003
View details for PubMedID 100808
Hospitalized alcoholics taking disulfiram were found to process information in short-term memory at a slower rate than hospitalized controls, although short-term memory capacity was similar in the two groups.
View details for Web of Science ID A1978GF66500007
View details for PubMedID 739771
Nineteen normal male subjects received 1.0 milligram of physostigmine or 1.0 milligram of saline by a slow intravenous infusion on two nonconsecutive days. Physostigmine significantly enhanced storage of information into long-term memory. Retrieval of information from long-term memory was also improved. Short-term memory processes were not significantly altered by physostigmine.
View details for Web of Science ID A1978FF63800020
View details for PubMedID 351807
The ability of 16 college-educated male subjects to recall from long-term memory a series of common facts was tested during intoxication with marijuana extract calibrated to 0.3 mg/kg delta-9-tetrahydrocannabinol and during placebo conditions. The subjects' ability to assess their memory capabilities was then determined by measuring how certain they were about the accuracy of their recall performance and by having them predict their performance on a subsequent recognition test involving the same recall items. Marijuana had no effect on recall or recognition performance. These results do not support the view that marijuana provides access to facts in long-term storage which are inaccessible during non-intoxication. During both marijuana and placebo conditions, subjects could accurately predict their recognition memory performance. Hence, marijuana did not alter the subjects' ability to accurately assess what information resides in long-term memory even though they did not have complete access to that information.
View details for Web of Science ID A1977DH01300005
View details for PubMedID 406626
Sixteen college-educated male subjects were tested on free-recall lists during intoxication with marijuana extract calibrated to 0.3 mg/kg delta-9-tetrahydrocannabinol and during placebo conditions. On each testing day subjects studied six lists using a regular overt rehearsal procedure and six lists using an association-overt rehearsal procedure in which they were to rehearse alound both list items and associations to those items. Both marijuana and the association-rehearsal procedure reduced the number of correct recalls and increased the number of intrusions (nonlist items which were incorrectly recalled as having been on the list to be learned). The intrusions were divided into three categories: a) words found on prior lists; b) associates spoken during the rehearsal; or c) totally new works not previously mentioned. Marijuana significantly increased the number of new intrusions; the association-rehearsal procedure did not. This result suggests that one of the effects of marijuana on cognitive functions in humans is to increase the number of intrusive thoughts and this may be the mechanism involved in some of the thought disorder observed with marijuana intoxication.
View details for Web of Science ID A1977EF05800003
View details for PubMedID 591936
Twelve men performed the Sternberg memory retrieval task under three experimental conditions: after oral doses of marihuana extract calibrated to contain 0.7 mg/kg delta9-tetrahydrocannabinol (THC), 1.0 ml/kg 95% ethanol, or placebo. Simultaneously, the EEG was recorded from Ca to linked ears and the EOG from leads above and below the right eye. In this task, subjects saw a set of 1 to 4 digits follwed by a warning tone that was followed 1.5 sec later by a test digit. Subjects indicated by pressing one of two buttons whether the test digit was in-set or out-of-the-set. There were no drug effects on N1 in the evoked potential to the warning tone, but P3 amplitude was smaller under THC and ethanol than under placebo. CNV amplitude in the interval between the warning tone and the test digit showed no drug effects, indicating that the subject was equally prepared for the test digit regardless of drug received. However, the latency of 50% resolution of the CNV was longer under THC than under placebo. THC also increased the reaction time for each set size by about 75 msec above the values for ethanol and placebo, the latter two not differing significantly. Set size affected N1 and P3 amplitudes and latencies and CNV amplitude, as well as 50% CNV resolution latency and reaction time, but there were no drug chi set size interactions.
View details for Web of Science ID A1977CY78100008
View details for PubMedID 65273
Auditory evoked potentials (AEPs) to tone pips at three monopolar scalters were systematically varied: tone intensity (3.0, 1.5 and 0.75 sec), and direction of attention. Interstimulus intervals were computed separately for the 9 different combinations of the three possible first prior intervals (intervals between the test stimulus and the stimulus immediately preceding it) and the three possible second prior intervals (intervals between the stimulus preceding the test stimulus and the stimulus prior to that). Our results show that temporal amplitude recovery of N1 and P2 can be based solely on the first prior interval had not effect on amplitude. Furthermore, they show that it is inadvisable to use combined N1-P2 amplitude measures since the two peaks appear to be governed by separate processes. Recovery for N1 was different from that of P2, N1 showed no intensity effects while P2 did, and N1 and P2 had different topographic distributions. Directing attention to the tones did not affect N1 or P2 amplitudes but caused a highly significant increase in both N1 and P2 latency. Attention to the tones also produced a frontal negative baseline shift following them.
View details for Web of Science ID A1976BR67400006
View details for PubMedID 57048
Performance on a time production task, heart rate, and subjective responses were studied in twelve male sujects given oral doses of marijuana (0.7 mg of delta-9-tetrahydrocannabinol/kg), ethanol (1.0 ml/kg), and placebo, on three testing days which were each separated by 1 week. Orders were balanced across subjects and testing conditions were double-blind. Compared to ethanol and placebo, marijuana induced a significant under-production of time intervals, suggesting an acceleration of the internal rate of time perception. The onset of this acceleration of time sense in which geophysical time seemed to pass slowly corresponded with the characteristic increase in heart rate and the onset of the subjective feelings of drug effects. Initial phases of alcohol intoxication were associated with the opposite effects on the time production task. These findings replicate previous work and indicate that an easily administered time production task provides a consistent, non-motor measure of acute marijuana intoxication and also reflects ethanol intoxication.
View details for Web of Science ID A1976CH51700010
View details for PubMedID 826945
View details for PubMedID 1144772
Evoked potentials were recorded from the human scalp during performance of a memory retrieval task modeled after a paradigm originated by Sternberg (1966). Subjects were required to decide whether a probe digit was contained in a series of one to four target digits presented a few seconds before. The amplitude of the contingent negative variation (CNV) preceding the probe digit and the speed of CNV resolution after the probe varied as a function of target set size. CNV amplitude was greatest when the set size was one. The smaller the set size, the more positive the evoked potential 300 msec after the probe, regardless of whether a motor response was required.
View details for Web of Science ID A1975V450300007
View details for PubMedID 45947
In a double-blind study, 72 normal male subjects were given either placebo or marihuana containing 20 mg. Delta-9-tetrahydrocannabinol. Stories written to cards selected from the Thematic Apperception Test did not differ on hostile or sexual content scales between drug and placebo conditions, but 6 out of 10 scales specifically constructed to detect marihuana effects were successful at differentiating the two conditions. Under marihuana the stories had a timeless, non-narrative quality, with greater discontinuity in thought sequence and more frequent inclusion of contradictory ideas. Novelty of content was somewhat increased by marihuana, while relation to the picture, imagery, repetition, and closure were not significantly affected.
View details for Web of Science ID A1975AR45700011
View details for PubMedID 1103209
Contingent negative variations (CNVs) composed of 32 trials had a median subject consistency of 0.68 in retests separated from 5 min to 7 days. Hand measurement of the CNV was highly reliable with a median reliability of 0.96. Subject consistencies for the amplitudes and latencies of N1 and P2 components of a auditory evoked potential (AEP) had a median of 0.59 when 265 trials were averaged. These consistencies for N1 and P3 components had a median of 0.45 when only 16 trials were averaged. Median measurement reliabilities for the AEP were 0.92 for amplitudes and 0.66 for latencies.
View details for Web of Science ID A1975V066200006
View details for PubMedID 45903
View details for PubMedID 4431879
View details for PubMedID 4844119
View details for PubMedID 4431995
Following presentation and immediate free recall testing of 10 20-word lists, 48 Ss were divided into two groups, one of which received an oral dose of marihuana extract calibrated to 20 mg of ?(1)-THC and one of which received placebo. One hour later, all Ss were administered delayed recall, recognition, and order tests on the first set of words. Presentation of another set of 10 lists followed, and there were immediate recall and delayed recall, recognition, and order tests on these words. Performance of drug and placebo Ss did not differ significantly for any of the first delayed tests. However, the performance of drug Ss was poorer than that of placebo Ss on immediate recall, delayed recall, and delayed recognition of the second set of lists. We concluded that retrieval of information relevant to the occurrence or nonocurrence of an event was not affected by marihuana intoxication. Storage difficulties probably account for memory deficits due to the drug, and these difficulties appear to occur in the process of transferring information from short-term to long-term memory.
View details for DOI 10.3758/BF03198094
View details for PubMedID 24214517
View details for PubMedID 4785907
View details for Web of Science ID A1973R656600005
View details for PubMedID 5117506
View details for PubMedID 4916452
High oral doses of marihuana extract, calibrated for content of 1 (-)-Delta(1)-tetrahydrocannabinol, significantly impaired the serial coordination of cognitive operations during a task that required sequential adjustments in reaching a goal. This disintegration of sequential thought is related to impaired immediate memory.
View details for PubMedID 4909766
View details for Web of Science ID A1970G368400029