Greer Murphy M.D., Ph.D.

Abstract

The polymorphic variation in the val158met position of the catechol-O-methyltransferase (COMT) gene is associated with differences in executive performance, processing speed, and attention. The purpose of this study is: (1) replicate previous COMT val158met findings on cognitive performance; (2) determine whether COMT val158met effects extend to a real-world task, aircraft navigation performance in a flight simulator; and (3) determine if aviation expertise moderates any effect of COMT val158met status on flight simulator performance. One hundred seventy two pilots aged 41-69 years, who varied in level of aviation training and experience, completed flight simulator, cognitive, and genetic assessments. Results indicate that although no COMT effect was found for an overall measure of flight performance, a positive effect of the met allele was detected for two aspects of cognitive ability: executive functioning and working memory performance. Pilots with the met/met genotype benefited more from increased levels of expertise than other participants on a traffic avoidance measure, which is a component of flight simulator performance. These preliminary results indicate that COMT val158met polymorphic variation can affect a real-world task.

View details for DOI 10.1007/s10519-010-9436-z

View details for Web of Science ID 000294297200008

View details for PubMedID 21193954

Abstract

The goal of the study was to improve prediction of longitudinal flight simulator performance by studying cognitive factors that may moderate the influence of chronological age.We examined age-related change in aviation performance in aircraft pilots in relation to baseline cognitive ability measures and aviation expertise. Participants were aircraft pilots (N = 276) aged 40-77.9. Flight simulator performance and cognition were tested yearly; there were an average of 4.3 (± 2.7; range 1-13) data points per participant. Each participant was classified into one of the three levels of aviation expertise based on Federal Aviation Administration pilot proficiency ratings: least, moderate, or high expertise.Addition of measures of cognitive processing speed and executive function to a model of age-related change in aviation performance significantly improved the model. Processing speed and executive function performance interacted such that the slowest rate of decline in flight simulator performance was found in aviators with the highest scores on tests of these abilities. Expertise was beneficial to pilots across the age range studied; however, expertise did not show evidence of reducing the effect of age.These data suggest that longitudinal performance on an important real-world activity can be predicted by initial assessment of relevant cognitive abilities.

View details for DOI 10.1093/geronb/gbr031

View details for Web of Science ID 000293251900007

View details for PubMedID 21586627

Abstract

Little is known about how APOE ?4-related differences in cognitive performance translate to real-life performance, where training and experience may help to sustain performance. We investigated the influences of APOE ?4 status, expertise (FAA pilot proficiency ratings), and their interaction on longitudinal flight simulator performance. Over a 2-year period, 139 pilots aged 42-69 years were tested annually. APOE ?4 carriers had lower memory performance than noncarriers (p = .019). APOE interacted with Expertise (p = .036), such that the beneficial influence of expertise (p = .013) on longitudinal flight simulator performance was more pronounced for ?4 carriers. Results suggest that relevant training and activity may help sustain middle-aged and older adults' real-world performance, especially among APOE ?4 carriers.

View details for DOI 10.1037/a0021697

View details for Web of Science ID 000291668800026

View details for PubMedID 21668123

Abstract

To examine the effectiveness of transdermal selegiline for producing cigarette smoking abstinence.Adult smokers were randomly assigned to receive selegiline transdermal system (STS) or placebo given for 8 weeks. All participants received cognitive behavior therapy (CBT). Follow-ups were conducted at 25 and 52 weeks.Community smoking cessation clinic.243 adult smokers (> or =18 years of age; > or =10 cigarettes/day).Expired-air carbon monoxide confirmed 7-day point prevalence abstinence.STS was not superior to placebo. More women than men were abstinent at 52 week follow-up (28% vs 16%, P < 0.05). Behavioral activation (BAS) moderated treatment response (P = 0.01). The survival rate through week 52 for those with high 'drive' scores on the BAS was 47% if assigned to selegiline and 34% if assigned to placebo. The survival rate for those with low 'drive scores' on the BAS was 35% if assigned to selegiline compared to 53% if assigned to placebo.Transdermal selegiline does not appear generally effective in aiding smoking cessation though there may be a selective effect in those smokers with low 'behavioral activation'.

View details for DOI 10.1111/j.1360-0443.2010.03020.x

View details for Web of Science ID 000280668200027

View details for PubMedID 20707784

Abstract

The apolipoprotein (APOE) epsilon4 allele is associated with cognitive deficits and hippocampal atrophy in nondemented middle-aged and older adults. It is not known to what extent this genetic risk factor for Alzheimer's disease (AD) impacts performance in late middle-aged and older workers in cognitively demanding occupations. This cross-sectional analysis examines brain-cognitive-genetic relationships in actively flying general aviation pilots, half of whom are APOE epsilon4 carriers. Fifty pilots were studied with structural MRI and memory tasks. Average visual paired associate memory recall performance was lower in APOE epsilon4 carriers than non-carriers. Memory performance correlated positively with hippocampal volume, but no structural differences were found in hippocampal or frontal volumes with respect to APOE epsilon4 allele. These results were evident in healthy professionals without any presenting memory problems and without selection for a family history of AD. These findings point to basic memory testing as a sensitive tool for detecting APOE epsilon4-related influences on memory in aging workers.

View details for DOI 10.1016/j.neurobiolaging.2008.07.017

View details for Web of Science ID 000277246400018

View details for PubMedID 18760504

Abstract

Microglia clear amyloid beta (Abeta) after immunization. The interaction of Abeta with the microglial cell surface also results in cytokine expression. Soluble oligomers and protofibrils of Abeta may be more neurotoxic than Abeta fibrils. We investigated the effects of oligomeric, protofibrillar and fibrillar Abeta40 and Abeta42 peptides on uptake and IL-1alpha expression by primary microglia. Abeta peptide assemblies were extensively characterized. Primary microglial cells were exposed to different Abeta40 and Abeta42 assemblies and IL-1alpha expression was quantified. To study uptake, microglial cells were exposed to different assemblies of Cy3-labeled Abeta. We found that Abeta42 and Abeta40 oligomers and fibrils induced IL-1alpha expression, but protofibrils did not. We also observed that all forms of Abeta42 (oligomer, protofibril and fibril) and Abeta40 fibrils were taken up by the microglial cells. These results demonstrate that microglial cells can take up non-fibrillar Abeta and that oligomeric peptide induces an inflammatory response. The uptake of oligomeric and protofibrillar Abeta by microglia merits further investigation as a potential means for removing these neurotoxic species from the brain.

View details for DOI 10.1016/j.neurobiolaging.2008.01.011

View details for Web of Science ID 000270374000008

View details for PubMedID 18339452

Abstract

The APOE epsilon 4 allele is a strong risk factor for Alzheimer's disease (AD). However, the molecular basis for this effect remains unclear. We examined expression of approximately 12,000 genes and expressed sequence tags in the hippocampus and cortex of PDAPP (APP(V717)) mice modeling AD that show extensive amyloid beta (A beta) deposition, and in PDAPP mice lacking murine APOE expression, which show marked attenuation of A beta deposition in the brain. Wild type and APOE knockout animals were also examined. Expression levels were determined at the initial stage of A beta deposition, as well as in older animals showing extensive neuropathological changes. Fifty-four transcripts were identified using our statistical analysis as differentially regulated between the PDAPP and PDAPP/APOE ko mice, whereas 31 transcripts were classified as differentially regulated among PDAPP mice and WT animals, and seven transcripts were identified as regulated between the PDAPP/APOE ko animals and the APOE ko animals. Interestingly, many of the differentially regulated genes we detected can be related to biological processes previously shown to be important in AD pathophysiology, including inflammation, calcium homeostasis, cholesterol transport and uptake, kinases and phosphatases involved in tau phosphorylation and dephosphorylation, mitochondrial energy metabolism, protein degradation, neuronal growth, endoplasmic reticulum (ER) stress related proteins, antioxidant activity, cytoskeletal organization, and presenilin binding proteins. Regulated genes also included some not directly associated with AD in the past but likely to be involved in known AD pathophysiologic mechanisms, and others that may represent completely novel factors in the pathogenesis of AD. These results provide a global molecular profile of hippocampal and cortical gene expression during the initial and intermediate stages Abeta deposition, and the effects of APOE deletion on this process.

View details for DOI 10.1016/j.neurobiolaging.2007.08.006

View details for Web of Science ID 000264579500013

View details for PubMedID 17904698

Abstract

PRIMARY AIM: Examine the effectiveness of extended cognitive behavior therapy (CBT) in promoting longer-term smoking abstinence.Open-label treatment phase followed by extended treatment phase. Randomization conducted prior to entry into open-label treatment phase; analysis based on intention-to-treat to avoid threat of selection bias.Community smoking cessation clinic.A total of 304 adult smokers (> or = 18 years of age; > or = 10 cigarettes/day).Open-label (8 weeks): all participants received bupropion SR, nicotine patch, CBT. Extended treatment (12 weeks): participants received either CBT + voicemail monitoring and telephone counseling or telephone-based general support.Seven-day point prevalence abstinence, expired-air carbon monoxide.At week 20 follow-up, CBT produced a higher 7-day point prevalence abstinence rate: 45% versus 29%, P = 0.006; at 52 weeks the difference in abstinence rates (31% versus 27%) was not significant. History of depression was a moderator of treatment. Those with a positive history had a better treatment response at 20 weeks when assigned to the less intensive telephone support therapy (P < 0.05).The superiority of CBT to 20 weeks suggests that continued emphasis on the development of cognitive and behavioral strategies for maintaining non-smoking during an extended treatment phase may help smokers to maintain abstinence in the longer term. At present, the minimum duration of therapy is unknown.

View details for DOI 10.1111/j.1360-0443.2008.02273.x

View details for Web of Science ID 000257692800021

View details for PubMedID 18855829

Abstract

Detection of preclinical cognitive deficits is important for identifying those at greatest risk for such disorders as Alzheimer's disease. However, available neuropsychological measures may not be sufficiently sensitive to preclinical cognitive impairment, particularly in high functioning or younger older adults. This study utilizes a battery of computerized cognitive tests (Cognometer) designed to provide a more sensitive measure of age-related cognitive performance by incorporating speed-of-processing components. Fifty-one community-dwelling older adults were administered the Cognometer battery, which incorporates speed-of-processing components into measures of verbal, spatial and working memory, attention, and visuo-spatial ability. Performance of 18 subjects with the epsilon4 allele was compared to that of 33 subjects without the epsilon4 allele. A brief battery of standard neuropsychological measures was also administered. No significant differences were observed between the two groups with respect to performance on any of the neuropsychological measures. However, with respect to the Cognometer battery, individuals with the epsilon4 allele were significantly slower in performing all the cognitive tasks, with the exception of the visuo-spatial task. With respect to performance, the two genotype groups did not differ significantly except on immediate memory, with the epsilon4 group exhibiting increased errors. Overall, the epsilon4 group was significantly slower in performing all of the Cognometer memory tasks. These findings provide continued support for the negative impact of the epsilon4 allele on cognition and further suggest that speed-of-processing during memory tasks may have the potential to detect subtle cognitive deficits.

View details for DOI 10.1016/j.jpsychires.2006.12.001

View details for Web of Science ID 000253397900004

View details for PubMedID 17250852

Abstract

The mammalian circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus conveys 24-h rhythmicity to sleep-wake cycles, locomotor activity, and other behavioral and physiological processes. The timing of rhythms relative to the light/dark (LD12:12) cycle is influenced in part by the endogenous circadian period and the time of day specific sensitivity of the clock to light. We now describe a novel circadian rhythm phenotype, and a locus influencing that phenotype, in a segregating population of mice.By crossbreeding 2 genetically distinct nocturnal strains of mice (Cast/Ei and C57BL/6J) and backcrossing the resulting progeny to Cast/Ei, we have produced a novel circadian phenotype, called early runner mice.Early runner mice entrain to a light/dark cycle at an advanced phase, up to 9 hours before dark onset. This phenotype is not significantly correlated with circadian period in constant darkness and is not associated with disruption of molecular circadian rhythms in the SCN, as assessed by analysis of period gene expression. We have identified a genomic region that regulates this phenotype-a major quantitative trait locus on chromosome 18 (near D18Mit184) that we have named era1 for Early Runner Activity locus one. Phase delays caused by light exposure early in the subjective night were of smaller magnitude in backcross offspring that were homozygous Cast/Ei at D18Mit184 than in those that were heterozygous at this locus.Genetic variability in the circadian response to light may, in part, explain the variance in phase angle of entrainment in this segregating mouse population.

View details for Web of Science ID 000250019300003

View details for PubMedID 17969459

Abstract

Despite numerous clinical trials, it is unknown whether ethnicity affects treatment response to cognitive enhancers in Alzheimer's disease (AD). There is convincing evidence of ethnic and genetic variability in drug metabolism. This article reviews the available data on ethnicity in clinical trials for AD to answer two questions: (1) what are the challenges to diagnose and treat AD across different ethnic groups, and (2) are there differences in response to pharmacologic interventions for AD across these different ethnic groups?Available data from Alzheimer's Disease Cooperative Study (ADCS) randomized controlled clinical trials and from randomized controlled industry-sponsored trials for four cognitive enhancers (donepezil, galantamine, rivastigmine and sabeluzole) were pooled to assess the numbers of non-Caucasian participants.The participation of ethnic minority subjects in clinical trials for AD was dependent on the funding source, although Caucasian participants were over-represented and non-Caucasian participants were under-represented in the clinical trials. Because of the low participation rate of ethnic minorities, there were insufficient data to assess any differences in treatment outcome among different ethnic groups. Strategies to improve diversity in clinical trials are discussed.Greater participation of ethnically diverse participants in clinical trials for AD would generate additional information on possible differences in metabolism, treatment response, adverse events to therapeutic agents, and could foster the investigation of genetic variability among ethnic groups.

View details for DOI 10.1017/S104161020700511X

View details for Web of Science ID 000246984800016

View details for PubMedID 17451614

Abstract

Microarrays can be manufactured to detect hundreds of thousands of polymorphisms in DNA from patients in psychotropic drug trials. Some of these polymorphisms may be useful as pharmacogenetic predictors of treatment outcomes. We tested a microarray designed to detect common polymorphisms in the CYP2D6 gene that encodes debrisoquine hydroxylase (DH). DH is involved in the hepatic metabolism of many psychotropics. CYP2D6 genotypes predicted plasma steady state concentrations of nortriptyline, a classic DH substrate, in a sample of geriatric patients with major depression. However, in a sample of 246 geriatric patients treated with paroxetine or mirtazapine, both of which are metabolized in part by DH, CYP2D6 genotypes determined with microarrays did not predict discontinuations due to adverse events or severity of adverse events. For modern antidepressants such as paroxetine and mirtazapine, pharmacokinetic factors that are regulated by CYP2D6 such as plasma drug concentrations may be less important than pharmacodynamic factors in determining outcomes. Studies of single candidate genes such as CYP2D6 have only begun to utilize the potential of microarrays for pharmacogenetic prediction. Yet, there is controversy as to whether genome-wide studies designed to detect millions of genotypes with microarrays will lead to new pharmacogenetic discoveries, or whether a more focused, hypothesis-driven approach is better.

View details for PubMedID 16785274

Abstract

The authors present results of a randomized clinical trial of the efficacy of extended treatment with bupropion SR in producing longer term cigarette smoking cessation. Adult smokers (N = 362) received open-label treatment (11 weeks) that combined relapse prevention training, bupropion SR, and nicotine patch followed by extended treatment (14 weeks) with bupropion SR or matching placebo. Abstinence percentages were relatively high (week 11: 52%; week 25: bupropion, 42%; placebo, 38%; week 52: bupropion, 33%; placebo, 34%), but bupropion SR did not surpass placebo. Gender and baseline craving level were identified as significant, independent moderators of treatment response. Men were more likely to abstain than women (week 11: 59% vs. 43%, p = .001; week 25: 48% vs. 31%, p = .001; week 52: 39% vs. 27%, p = .01). Because most smokers suffer relapse with any current cessation treatment, the comparatively high abstinence percentages achieved in this trial are of interest.

View details for DOI 10.1037/0022-006X.74.2.286

View details for Web of Science ID 000237667500009

View details for PubMedID 16649873

Abstract

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

Abstract

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

Abstract

The authors investigated the relationship between obstructive sleep apnea/hypopnea (OSAH) and cognition in 36 older adults, 18 APOE epsilon4 carriers, and 18 non-carriers. Greater numbers of respiratory events negatively impacted memory function in epsilon4 carriers only. This is the first study to provide preliminary evidence for a negative interaction of APOE epsilon4 and OSAH on memory in older adults, which may have important implications for treating cognitive decline and delaying dementia onset.

View details for Web of Science ID 000231371600035

View details for PubMedID 16116137

Abstract

Microglia with increased expression of the macrophage colony-stimulating factor receptor (M-CSFR; c-fms) are found surrounding plaques in Alzheimer's disease (AD) and in mouse models for AD and after ischemic or traumatic brain injury. Increased expression of M-CSFR causes microglia to adopt an activated state that results in proliferation, release of cytokines, and enhanced phagocytosis. To determine whether M-CSFR-induced microglial activation affects neuronal survival, we assembled a coculture system consisting of BV-2 microglia transfected to overexpress the M-CSFR and hippocampal organotypic slices treated with NMDA. Twenty-four hours after assembly of the coculture, microglia overexpressing M-CSFR proliferated at a higher rate than nontransfected control cells and exhibited enhanced migration toward NMDA-injured hippocampal cultures. Surprisingly, coculture with c-fms-transfected microglia resulted in a dramatic reduction in NMDA-induced neurotoxicity. Similar results were observed when cocultures were treated with the teratogen cyclophosphamide. Biolistic overexpression of M-CSFR on microglia endogenous to the organotypic culture also rescued neurons from excitotoxicity. Furthermore, c-fms-transfected microglia increased neuronal expression of macrophage colony-stimulating factor (M-CSF), the M-CSFR, and neurotrophin receptors in the NMDA-treated slices, as determined with laser capture microdissection. In the coculture system, direct contact between the exogenous microglia and the slice was necessary for neuroprotection. Finally, blocking expression of the M-CSF ligand by exogenous c-fms-transfected microglia with a hammerhead ribozyme compromised their neuroprotective properties. These results demonstrate a protective role for microglia overexpressing M-CSFR in our coculture system and suggest under certain circumstances, activated microglia can help rather than harm neurons subjected to excitotoxic and teratogen-induced injury.

View details for DOI 10.1523/JNEUROSCI.0514-05.2005

View details for Web of Science ID 000228702900025

View details for PubMedID 15858070

Abstract

The Tg2576 mouse model of Alzheimer's disease (AD) exhibits age-dependent amyloid beta (Abeta) deposition in the brain. We studied electroencephalographically defined sleep and the circadian regulation of waking activities in Tg2576 mice to determine whether these animals exhibit sleep abnormalities akin to those in AD. In Tg2576 mice at all ages studied, the circadian period of wheel running rhythms in constant darkness was significantly longer than that of wild type mice. In addition, the increase in electroencephalographic delta (1-4 Hz) power that occurs during non-rapid eye movement sleep after sleep deprivation was blunted in Tg2576 mice relative to controls at all ages studied. Electroencephalographic power during non-rapid eye movement sleep was shifted to higher frequencies in plaque-bearing mice relative to controls. The wake-promoting efficacy of the acetylcholinesterase inhibitor donepezil was lower in plaque-bearing Tg2576 mice than in controls. Sleep abnormalities in Tg2576 mice may be due in part to a cholinergic deficit in these mice. At 22 months of age, two additional deficits emerged in female Tg2576 mice: time of day-dependent modulation of sleep was blunted relative to controls and rapid eye movement sleep as a percentage of time was lower in Tg2576 than in wild type controls. The rapid eye movement sleep deficit in 22 month-old female Tg2576 mice was abolished by brief passive immunization with an N-terminal antibody to Abeta. The Tg2576 model provides a uniquely powerful tool for studies on the pathophysiology of and treatments for sleep deficits and associated cholinergic abnormalities in AD.

View details for DOI 10.1016/j.neuroscience.2004.11.018

View details for Web of Science ID 000227258400011

View details for PubMedID 15708480

Abstract

The "long/short"polymorphism (5HTTLPR) in the promoter of the serotonin transporter gene (SLC6A4) has been proposed as a pharmacogenetic marker for antidepressant efficacy. Some but not all studies have found that the short form of 5HTTLPR (S allele) results in decreased efficacy of selective serotonin reuptake inhibitors.To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride, 2 frequently prescribed antidepressants with differing pharmacologic profiles, in geriatric depression.Double-blind, randomized 8-week study.Eighteen academic and private outpatient clinics.We evaluated 246 cognitively intact patients 65 years or older with major depression.Antidepressant therapy with 15 to 45 mg/d of mirtazapine (n = 124) or 20 to 40 mg/d of paroxetine (n = 122).The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale, severity of adverse events and dosing compliance indexes, and discontinuations due to adverse events. Outcome measures were stratified according to 5HTTLPR genotypes.Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the 5HTTLPR genotype affected antidepressant efficacy. However, the 5HTTLPR polymorphism had a dramatic effect on adverse events. Among paroxetine-treated subjects, S allele carriers experienced more severe adverse events during the course of the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Surprisingly, among mirtazapine-treated subjects, S allele carriers had fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses.These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors. However, the major effect was on the tolerability of these drugs rather than efficacy. Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action.

View details for Web of Science ID 000224898700011

View details for PubMedID 15520364

Abstract

The receptor for macrophage colony-stimulating factor (M-CSFR; c-fms) is expressed at increased levels by microglia in Alzheimer's disease (AD) and in mouse models for AD. Increased expression of M-CSFR on cultured microglia results in a strong proinflammatory response, but the relevance of this cell culture finding to intact brain is unknown. To determine the effects of increased microglial expression of M-CSFR in a complex organotypic environment, we developed a system for biolistic transfection of microglia in hippocampal slice cultures. The promoter for the Mac-1 integrin alpha subunit CD11b is active in cells of myeloid origin. In the brain, CD11b expression is restricted to microglia. Constructs consisting of the promoter for CD11b and a c-fms cDNA or an enhanced green fluorescent protein (EGFP) cDNA were introduced into monotypic cultures of microglia, neurons, and astrocytes. Strong CD11b promoter activity was observed in microglia, whereas little activity was observed in other cell types. Biolistic transfection of organotypic hippocampal cultures with the CD11b/c-fms construct resulted in expression of the c-fms mRNA and protein that was localized to microglia. Furthermore, biolistic overexpression of M-CSFR on microglia resulted in significantly increased production by the hippocampal cultures of the proinflammatory cytokines interleukin (IL)-1alpha macrophage inflammatory protein (MIP-1alpha), and trends toward increased production of IL-6 and M-CSF. These findings demonstrate that microglial overexpression of M-CSFR in an organotypic environment induces an inflammatory response, and suggest that increased microglial expression of M-CSFR could contribute to the inflammatory response observed in AD brain.

View details for DOI 10.1002/jnr.20168

View details for Web of Science ID 000222881300012

View details for PubMedID 15248298

Abstract

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

Abstract

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

Abstract

The role of microglia in Alzheimer's disease (AD) has come under intense scrutiny recently because microglia may clear amyloid beta (Abeta) by phagocytosis after immunization of transgenic mice. Increased expression of the macrophage colony-stimulating factor receptor (M-CSFR) is an important feature of microglia in AD and transgenic mouse models for AD. Increased expression of M-CSFR on mouse and human microglia accelerates phagocytosis of aggregated Abeta in part through macrophage scavenger receptors. We now show that Abeta phagocytosis by microglia overexpressing M-CSFR is further enhanced by antibody opsonization of Abeta. M-CSFR overexpression increased microglial phagocytosis of opsonized aggregated Abeta in culture medium, and accelerated ingestion of native Abeta from AD brain sections. M-CSFR overexpression also increased microglial expression of Fcgamma receptors, and blocking Fcgamma receptors attenuated the enhanced Abeta uptake observed after M-CSFR overexpression and antibody opsonization. Microglia in AD and in AD mouse models with increased expression of M-CSFR are likely to rapidly ingest opsonized Abeta after immunization, making high intracerebral antibody titers unnecessary.

View details for DOI 10.1016/S0197-4580(02)00237-3

View details for Web of Science ID 000185453200006

View details for PubMedID 12927763

Abstract

Patients vary in response to antidepressant medications. Apolipoprotein E (APOE) genotype affects vulnerability to stress and risk for cognitive impairment. We sought to determine if the APOE epsilon4 allele influences response in geriatric depression to mirtazapine and paroxetine, two frequently prescribed antidepressants. We hypothesized that epsilon4 carriers would show impaired antidepressant response.The study was a double-blind, randomized, 8-week trial with a 16-week extension phase involving 246 cognitively intact patients aged 65 years or older with major depression. Patients were treated with mirtazapine 15-45 mg (n = 124) or paroxetine 20-40 mg (n = 122). The outcome measures were the Hamilton Depression Rating Scale, the Geriatric Depression Scale, and the Clinical Global Impression Scale. APOE genotype was determined by restriction isotyping.Patients carrying the epsilon4 allele showed a rapid onset of mirtazapine action, whereas paroxetine-treated patients with the epsilon4 allele were slow to respond. This difference could not be attributed to dosage, compliance, severity of adverse events, ethnicity, baseline depression or cognition, gender, or age.The APOE epsilon4 allele may affect antidepressant treatment outcome, but the effect depends on the medication. Further studies should determine if this result applies to other samples and medications.

View details for DOI 10.1016/S0006-3223(03)00174-4

View details for Web of Science ID 000185500500001

View details for PubMedID 14512205

Abstract

The authors sought to identify genetic markers for antidepressant medication intolerance. Genetic variation in drug metabolizing enzymes such as cytochrome P450 2D6 (CYP2D6) has been postulated to underlie antidepressant intolerance (pharmacokinetic effect). However, variation in genes encoding serotonin receptors could also explain antidepressant side effects (pharmacodynamic effect).An 8-week, double-blind, randomized pharmacogenetic study compared the widely prescribed antidepressants paroxetine (a selective serotonin reuptake inhibitor [SSRI]) and mirtazapine (not an SSRI) in 246 elderly patients with major depression. Genotypes were determined for the 102 T/C single nucleotide polymorphism (SNP) in the serotonin 2A (5-HT(2A)) locus (HTR2A), previously associated with psychotropic medication treatment outcome. Oligonucleotide microarrays were used to extensively characterize variation in the CYP2D6 gene. Clinical outcomes included treatment discontinuations, adverse events, medication compliance, and change in mood.Survival analysis showed discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. Side effect severity in paroxetine-treated patients with the C/C genotype was also greater. In contrast, HTR2A 102 T/C genotype had no effect on mirtazapine side effects. CYP2D6 genotype did not predict treatment outcome for either medication.Pharmacodynamic differences among patients due to variant 5-HT(2A) receptors appear to be more important than pharmacokinetic variation in determining paroxetine intolerance. Pharmacogenetic markers may be useful in predicting antidepressant treatment outcome.

View details for Web of Science ID 000185880300020

View details for PubMedID 14514498

Abstract

Macrophage colony stimulating factor (M-CSF) and its receptor are upregulated in the brain in Alzheimer's disease. M-CSF induces activation and proliferation of microglial cells and expression of proinflammatory cytokines. Amyloid beta (Abeta) immunization experiments suggest that microglia have the capacity to aggressively clear Abeta from the brain under certain circumstances. We examined the role of M-CSF in phagocytosis of fluorescent microspheres and Abeta by cultured microglia. M-CSF treatment increased microglial cell phagocytosis of both microspheres and of Abeta. Antibody neutralization of M-CSF inhibited Abeta uptake induced by overexpression of the M-CSF receptor on microglia. These results suggest that M-CSF could be important in promoting microglial clearance of abnormal protein aggregates such as Abeta.

View details for DOI 10.1016/S0304-3940(03)00474-9

View details for Web of Science ID 000183621000011

View details for PubMedID 12812836

Abstract

The brain is a heterogeneous tissue in which the numbers of neurons, glia, and other cell types vary among anatomic regions. Gene expression studies performed on brain homogenates yield results reflecting mRNA abundance in a mixture of cell types. Therefore, a method for quantifying gene expression in individual cell populations would be useful. Laser capture microdissection (LCM) is a new technique for obtaining pure populations of cells from heterogeneous tissues. Most studies thus far have used LCM to detect DNA sequences. We developed a method to quantify gene expression in hippocampal neurons from mouse brain using LCM and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). This method was optimized to permit histochemical or immunocytochemical visualization of nerve cells during LCM while minimizing RNA degradation. As an example, gene expression was quantified in hippocampal neurons from the Tg2576 mouse model for Alzheimer's disease.

View details for DOI 10.1002/jnr.10329

View details for Web of Science ID 000177745500002

View details for PubMedID 12210823

Abstract

Macrophage colony stimulating factor (M-CSF) and its receptor are up-regulated in the brain in Alzheimer's disease (AD), in transgenic mouse models for AD, and experimental models for traumatic and ischemic brain injury. M-CSF induces activation and proliferation of microglial cells and expression of proinflammatory cytokines. We examined the role of M-CSF in excitotoxic neuronal cell death in organotypic hippocampal cultures. NMDA treatment induced neuronal apoptosis and caspase-3 activation in organotypic hippocampal cultures, whereas treatment with M-CSF protected hippocampal neurons from NMDA-induced apoptosis. Caspase-3 activation was inhibited by M-CSF treatment to the same degree as with the caspase inhibitor Z-VAD-FMK. These results suggest that M-CSF has neuroprotective properties through inhibition of caspase-3 that could promote neuronal survival after excitotoxic insult. The role of M-CSF in neurological disease should be reevaluated as a microglial activator with potentially neuroprotective effects.

View details for Web of Science ID 000177790000008

View details for PubMedID 12354286

Abstract

Authors studied the efficacy and tolerability of mirtazapine and paroxetine in elderly patients with major depression during an acute phase (8 weeks) and an extension phase (16 weeks).Patients with major depression and without dementia, at least 65 years old, were eligible; they were randomized to mirtazapine or paroxetine once daily, with doses increasing over 42 days. Efficacy was assessed with the Ham-D and Clinical Global Impressions Scale, and tolerability was assessed from adverse events.Of 255 patients randomized, 126 on mirtazapine and 120 on paroxetine were included in the efficacy analysis. Differences favoring mirtazapine were observed for the mean change from baseline in Ham-D-17 score. Other significant differences were in the proportion of patients classified as responders (50% decrease from baseline Ham-D-17 scores) at Day 14 and in remission (Ham-D-17 score of 7 or less) at Day 42. The median time to response was 26 days in the mirtazapine group and 40 days in the paroxetine group. The mirtazapine group also showed more reduction in Ham-D Factor I (Anxiety/Somatization) and Factor VI (Sleep Disturbance) scores. Efficacy of both drugs was maintained during the extension phase. Patients on paroxetine were more likely to discontinue therapy in the acute phase because of adverse events.During the first weeks of treatment, antidepressant effects were more pronounced in the mirtazapine group, suggesting that mirtazapine has an earlier onset of action. Mirtazapine also demonstrated a better tolerability profile and represents a valuable option for the treatment of depression in elderly patients.

View details for Web of Science ID 000177864500007

View details for PubMedID 12213688

Abstract

Microglia surrounding A beta plaques in Alzheimer's disease and in the APPV717F transgenic mouse model of Alzheimer's disease have enhanced immunoreactivity for the macrophage colony-stimulating factor receptor (M-CSFR), encoded by the proto-oncogene c-fms. Increased expression of M-CSFR on cultured microglia results in proliferation and release of pro-inflammatory cytokines and expression of inducible nitric-oxide synthase. We transfected mouse BV-2 and human SV-A3 microglia to overexpress M-CSFR and examined microglial phagocytosis of fluorescein-conjugated A beta. Flow cytometry and laser confocal microscopy showed accelerated phagocytosis of A beta in mouse and human microglia because of M-CSFR overexpression that was time- and concentration-dependent. In contrast, microglial uptake of 1-microm diameter polystyrene microspheres was not enhanced by M-CSFR overexpression. Microglial uptake of A beta was blocked by cytochalasin D, which inhibits phagocytosis. M-CSFR overexpression increased the mRNA for macrophage scavenger receptor A, and fucoidan blocking of macrophage scavenger receptors inhibited uptake of A beta. M-CSFR antibody blocking experiments demonstrated that increased A beta uptake depended on the interaction of the M-CSFR with its ligand. These results suggest that overexpression of M-CSFR in APPV717F mice may prime microglia for phagocytosis of A beta after immunization.

View details for DOI 10.1074/jbc.M200868200

View details for Web of Science ID 000177509300069

View details for PubMedID 12032144

Abstract

Macrophage colony stimulating factor (M-CSF) is a microglial activator expressed at increased levels in the brain in Alzheimer's disease. In monotypic microglial cultures, M-CSF strongly augments amyloid beta (Abeta) induced microglial production of proinflammatory cytokines and nitric oxide. However, this augmentation could be due to strong autocrine and paracrine effects in monotypic cultures. We used hippocampal organotypic cultures to test M-CSF/Abeta augmentation in a system modeling intact brain. Combined M-CSF/Abeta treatment increased interleukin-1 (IL-1) and macrophage inflammatory protein 1-alpha expression by microglia, whereas inducible nitric oxide synthase (iNOS) expression was localized primarily to astroglia. Induction of cytokines and iNOS was also observed after lipopolysaccharide treatment of organotypic hippocampal cultures, but iNOS expression was localized mainly to microglia rather than astrocytes. Treatment with M-CSF/Abeta did not result in neuronal death. These results demonstrate that combined M-CSF/Abeta treatment results in a strong inflammatory response in the organotypic environment without inducing neurotoxicity.

View details for Web of Science ID 000175175600003

View details for PubMedID 11959396

View details for Web of Science ID 000172325000012

View details for PubMedID 11719482

Abstract

Recent advances in oligonucleotide microarray technology ("gene chips") permit rapid screening for DNA sequence variation. The CYP2D6 gene encodes debrisoquine hydroxylase, which metabolizes the antidepressant nortriptyline and other psychotropic medications. Nortriptyline plasma concentrations were obtained after at least three weeks of treatment in 36 geriatric patients with major depression who were taking a mean of 8.6 other medications besides nortriptyline. Oligonucleotide microarrays were used to detect 16 CYP2D6 alleles that affect debrisoquine hydroxylase activity. Subjects carrying alleles encoding impaired debrisoquine hydroxylase activity had significantly greater nortriptyline concentrations and lower nortriptyline doses than did other subjects. Significant correlations were found between the numbers of alleles encoding decreased metabolism and nortriptyline plasma concentration, nortriptyline dose, and nortriptyline plasma concentration standardized for dose, indicating a gene dosage effect. These results demonstrate that CYP2D6 genotyping on a microarray platform can be used to predict plasma antidepressant concentrations despite advanced patient age and numerous concurrent medications.

View details for Web of Science ID 000171952200014

View details for PubMedID 11682257

Abstract

Hormone-sensitive lipase (HSL) hydrolyzes triglyceride (TG) in adipose tissue. HSL is also expressed in heart. To explore the actions of cardiac HSL, heart-specific, tetracycline (Tc)-controlled HSL-overexpressing mice were generated. Tc-responsive element-HSL transgenic (Tg) mice were generated and crossed with myosin heavy chain (MHC)alpha-tTA Tg mice, which express the Tc-responsive transactivator (tTA) in the heart. The double-Tg mice (MHC-HSL) were maintained with doxycycline (Dox) to suppress Tg HSL. Upon removal of Dox, cardiac HSL activity and protein increased 12- and 8-fold, respectively, and the expression was heart specific. Although cardiac TG content increased twofold in control mice after an overnight fast, it did not increase in HSL-induced mice. Electron microscopy showed numerous lipid droplets in the myocardium of fasted control mice, whereas fasted HSL-induced mice showed virtually no droplets. Microarray analysis showed altered expression of cardiac genes for fatty acid oxidation, transcription factors, signaling molecules, cytoskeletal proteins, and histocompatibility antigens in HSL-induced mice. Thus cardiac HSL plays a role in controlling accumulation of triglyceride droplets and can affect the expression of a number of cardiac genes.

View details for Web of Science ID 000171583200026

View details for PubMedID 11551864

Abstract

We examined the effect of the apolipoprotein E (apo E) epsilon4 allele on the relationship between self-reported stress and mood in caregivers of patients with Alzheimer's disease. Eighty-six female subjects between the ages of 28 and 82 years who were community-dwelling AD patient caregivers participated in the study. A cross-sectional analysis of stress and mood was performed using the Revised Memory and Behavior Problem Checklist and the Geriatric Depression Scale. All subjects were evaluated for normal cognitive function (Mini-Mental Status Examination) and apo E genotype. The results indicated that increased levels of stress were associated with increased levels of depressive symptoms in nondemented caregivers with the epsilon4 allele. This relationship was not observed in caregivers without the epsilon4 allele. These results suggest that carriers of the epsilon4 allele may respond differently to psychological stress than do individuals without the epsilon4 allele.

View details for Web of Science ID 000170894200002

View details for PubMedID 11563433

Abstract

Microglia are important in the inflammatory response in Alzheimer's disease (AD). We showed previously that macrophage colony-stimulating factor receptor (M-CSFR), encoded by the c-fms protooncogene, is overexpressed on microglia surrounding amyloid beta (Abeta) deposits in the APP(V717F) mouse model for AD. The M-CSFR is also increased on microglia after experimental brain injury and in AD. To determine the relevance of these findings, we transiently expressed M-CSFR on murine BV-2 and human SV-A3 microglial cell lines using an SV40-promoted c-fms construct. M-CSFR overexpression resulted in microglial proliferation and increased expression of inducible nitric-oxide synthase, the proinflammatory cytokines interleukin-1alpha, macrophage inflammatory protein 1-alpha, and interleukin-6 and of macrophage colony-stimulating factor (M-CSF) itself. Antibody neutralization of M-CSF showed that the M-CSFR-induced proinflammatory response was dependent on M-CSF in the culture media. By using a co-culture of c-fms-transfected murine microglia and rat organotypic hippocampal slices and a species-specific real time reverse transcriptase-polymerase chain reaction assay and enzyme-linked immunosorbent assay, we showed that M-CSFR overexpression on exogenous microglia induced expression of interleukin-1alpha by the organotypic culture. These results show that increased M-CSFR expression induces microglial proliferation, cytokine expression, and a paracrine inflammatory response, suggesting that in APP(V717F) mice increased M-CSFR on microglia could be an important factor in Abeta-induced inflammatory response.

View details for Web of Science ID 000170558000073

View details for PubMedID 11387343

Abstract

Apolipoprotein E epsilon4(ApoE epsilon4) is a well-known risk factor for Alzheimer disease and cardiovascular disease. Sleep-disordered breathing occurs in Alzheimer disease patients and increases risks for cardiovascular disease. Complex interactions among sleep, brain pathology, and cardiovascular disease may occur in ApoE epsilon4 carriers.To study whether genetic variation at the level of ApoE is associated with sleep-disordered breathing or sleep abnormalities in the general population.Ongoing longitudinal cohort study of sleep disorders at a US university beginning in 1989, providing a population-based probability sample of 791 middle-aged adults (mean [SD] age, 49 [8] years; range, 32-68 years).Nocturnal polysomnography to evaluate apnea-hypopnea index.The probability of moderate-to-severe sleep-disordered breathing (apnea-hypopnea index >/=15%) was significantly higher in participants with epsilon4, independent of age, sex, body mass index, and ethnicity (12.0% vs 7.0%; P =.003). Mean (SEM) apnea-hypopnea index was also significantly higher in participants with ApoE epsilon4 (6.5 [0.6] vs 4.8 [0.3]; P =.01). These effects increased with the number of ApoE epsilon4 alleles carried.A significant portion of sleep-disordered breathing is associated with ApoE epsilon4 in the general population.

View details for Web of Science ID 000169156300028

View details for PubMedID 11401610

Abstract

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

Abstract

Inflammation is an important neuropathological change in Alzheimer's disease (AD). However, the pathophysiological factors that initiate and maintain the inflammatory response in AD are unknown. We examined AbetaPP(V717F) transgenic mice, which show numerous brain amyloid-beta (Abeta) deposits, for expression of the macrophage colony-stimulating factor (M-CSF) and its receptor (M-CSFR). M-CSF is increased in the brain in AD and dramatically augments the effects of Abeta on cultured microglia. AbetaPP(V717F) animals 12 months of age showed large numbers of microglia strongly labeled with an M-CSFR antibody near Abeta deposits. M-CSFR mRNA and protein levels were also increased in brain homogenates from AbetaPP(V717F) animals. Dystrophic neurites and astroglia showed no M-CSFR labeling in the transgenic animals. A M-CSF antibody decorated neuritic structures near hippocampal Abeta deposits in transgenic animals. M-CSF mRNA was also increased in AbetaPP(V717F) animals in comparison with wild-type controls. Simultaneous overexpression of M-CSFR and its ligand in AbetaPP(V717F) animals could result in augmentation of Abeta-induced activation of microglia. Because chronic activation of microglia is thought to result in neuronal injury, the M-CSF system may be a potential target for therapeutic intervention in AD.

View details for Web of Science ID 000089207200023

View details for PubMedID 10980129

Abstract

The Apolipoprotein-E (APOE) epsilon 4 allele is a risk factor for Alzheimer's disease (AD) and cognitive decline in older adults. Depression may also be a risk factor for dementia, and depression is important in the differential diagnosis of dementia. The authors performed a 5-year longitudinal study of APOE genotype and change in Geriatric Depression Scale scores in 113 community-dwelling older adults. No association was observed between APOE genotype and change in depressive symptoms. These results do not support the hypothesis that the APOE epsilon 4 allele is associated with depression. Important objections have been raised to APOE genotyping in the diagnosis of AD. However, the specificity of APOE genotyping in AD diagnosis would not appear to be compromised by an association with depression.

View details for Web of Science ID 000088230700003

View details for PubMedID 10910416

Abstract

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

Abstract

This study investigated whether the Apolipoprotein (APOE) epsilon4 allele was associated with cognitive decline in community-dwelling older adults.Longitudinal cognitive performance of older adults with the epsilon3/epsilon4 genotype was compared with that of older adults with the epsilon3/epsilon3 genotype.Aging Clinical Research Center, Stanford University.One hundred community-dwelling older adults were recruited from a pool of 531 individuals who had participated in a memory training study 4 to 5 years earlier. These individuals were concerned about their memory functioning and were recruited through newspaper advertisements and contacts with local senior centers. The 100 individuals who agreed to participate in the follow-up investigation were between 59 and 95 years of age.At both baseline and follow-up, subjects were administered a battery of seven cognitive tests that examined verbal and spatial memory, attention, speed-of-processing, and language abilities. APOE genotype was determined at follow-up.Individuals with the epsilon3/epsilon4 APOE genotype were significantly younger than individuals with the APOE epsilon3/epsilon3 genotype. No significant differences were observed between the two groups on measures of attention, speed-of-processing, vocabulary, immediate verbal memory, and immediate spatial memory. However, those older adults with the epsilon3/epsilon4 genotype exhibited significantly greater decline in performance on delayed recall of verbal material than did those with the epsilon3/epsilon3 APOE genotype.These findings are consistent with previous studies, which suggest that the APOE epsilon4 allele predicts decline on measures of delayed recall.

View details for Web of Science ID 000077358700001

View details for PubMedID 9848808

Abstract

In Alzheimer's disease (AD), a chronic cerebral inflammatory state is thought to lead to neuronal injury. Microglia, intrinsic cerebral immune effector cells, are likely to be key in the pathophysiology of this inflammatory state. We showed that macrophage colony-stimulating factor, a microglial activator found at increased levels in the central nervous system in AD, dramatically augments beta-amyloid peptide (betaAP)-induced microglial production of interleukin-1, interleukin-6, and nitric oxide. In contrast, granulocyte macrophage colony-stimulating factor, another hematopoietic cytokine found in the AD brain, did not augment betaAP-induced microglial secretory activity. These results indicate that increased macrophage colony-stimulating factor levels in AD could magnify betaAP-induced microglial inflammatory cytokine and nitric oxide production, which in turn could intensify the cerebral inflammatory state by activating astrocytes and additional microglia, as well as directly injuring neurons.

View details for Web of Science ID 000075386100039

View details for PubMedID 9694846

Abstract

There is currently controversy as to the frequency of Alzheimer's disease (AD) in elderly persons with schizophrenia. Several studies have reported an increased frequency of AD in elderly schizophrenics, whereas others have found no increase. This issue is important because it has been hypothesized that medications used to treat schizophrenia may exacerbate AD histopathology.We examined autopsy cases from a state psychiatric hospital and a Veterans Affairs medical center. Charts were reviewed on 166 subjects to determine if the history warranted a DSM-IV diagnosis of schizophrenia. All subjects had complete gross and microscopic neuropathologic evaluations, which were reviewed for evidence of Alzheimer's disease.Retrospective chart review identified 51 subjects over the age of 55 who met DSM-IV criteria for schizophrenia (mean age = 71.7 years, SD = 8.6, range 56-95 years). Of these 51, only I met neuropathologic criteria for AD, a frequency of 2%.The frequency of subjects meeting neuropathologic criteria for Alzheimer's disease in our sample of schizophrenics was equal to or less than that found in the general population. Because institutionalized populations may contain an excess of elderly schizophrenic patients with severe behavioral pathologies, which may in turn reflect the presence of neurodegenerative processes such as Alzheimer's disease, our results may actually overestimate the frequency of Alzheimer's in the entire schizophrenic population. The frequency of Alzheimer's disease in the elderly with schizophrenia may be less than that in the general population.

View details for Web of Science ID 000072174800007

View details for PubMedID 9494702

Abstract

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

Abstract

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

Abstract

Mutations in the presenilin (PS)-1 and PS-2 genes have been shown to be linked with the development of Alzheimer's disease (AD). We examined Alzheimer's brain tissue by immunohistochemistry using a set of antibodies raised to sequences shared between PS-1 and PS-2 proteins. These antibodies reacted exclusively with a subset of neurofibrillary tangles and not with neuropil threads or dystrophic neurites. Detection of the presenilin epitope in neurofibrillary tangles was observed in sporadic Alzheimer's disease brain samples and in samples from individuals carrying PS-1 and PS-2 mutations with no qualitative difference. These data indicate that both wild-type and mutant PS proteins are involved in a common pathogenic pathway in AD.

View details for Web of Science ID A1996VW78700007

View details for PubMedID 8952521

Abstract

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

Abstract

The presence of beta-amyloid in brain tissue is characteristic of Alzheimer's disease (AD). A naturally occurring derivative of the beta-amyloid peptide, p3, possesses all of the structural determinants required for fibril assembly and neurotoxicity. p3-specific antibodies were used to examine the distribution of this peptide in brain. p3 reactivity was absent or sparse in aged non-AD brains but was prevalent in selected areas of AD brain in diffuse deposits and in a subset of dystrophic neurites. p3-reactive dystrophic neurites were found both independent in the neuropil and associated with plaques. Little or no reactivity was observed to amyloid cores in classical plaques or to amyloid in the cerebral vasculature. The exclusive appearance of p3 reactivity in AD brain plus the selective localization of p3 reactivity to abnormal structures in the temporal lobe limbic system suggests that p3 may be a contributing factor to AD pathology.

View details for Web of Science ID A1996UZ76300023

View details for PubMedID 8701997

Abstract

beta-Amyloid protein (betaAP) deposition is a neuropathologic hallmark of Alzheimer's disease (AD). Yet, the source of cerebral betaAP in AD is controversial. We examined the production of betaAP by the BV-2 immortalized microglial cell line using a sensitive enzyme immunoassay. Constitutive production of betaAP was detected in conditioned media from unstimulated BV-2 cells. Further, production of betaAP was induced by treatment of cultures by lipopolysaccharide (LPS) or betaAP-(25-35) and was inhibited by the calpain protease inhibitor MDL 28170. Treatment of BV-2 cells with LPS or betaAP-(25-35) did not affect cell-associated beta-amyloid precursor protein levels. These findings suggest that microglia may be an important source of betaAP in AD, and that microglial production of betaAP may be augmented by proinflammatory stimuli or by betaAP itself.

View details for Web of Science ID A1996UW35200036

View details for PubMedID 8663228

Abstract

Tumor necrosis factor-alpha is a pluripotent cytokine that is reportedly mitogenic to astrocytes. We examined expression of the astrocyte intermediate filament component glial fibrillary acidic protein in astrocyte cultures and the U373 glioblastoma cell line after treatment with tumor necrosis factor-alpha. Treatment with tumor necrosis factor-alpha for 72 h resulted in a decrease in content of glial fibrillary acidic protein and its encoding mRNA. At the same time, tumor necrosis factor-alpha treatment increased the expression of the cytokine interleukin-6 by astrocytes. The decrease in glial fibrillary acidic protein expression was greater when cells were subconfluent than when they were confluent. Thymidine uptake studies demonstrated that U373 cells proliferated in response to tumor necrosis factor-alpha, but primary neonatal astrocytes did not. However, in both U373 cells and primary astrocytes tumor necrosis factor-alpha induced an increase in total cellular protein content. Treatment of astrocytes and U373 cells for 72 h with the mitogenic cytokine basic fibroblast growth factor also induced a decrease in glial fibrillary acidic protein content and an increase in total protein level, demonstrating that this effect is not specific for tumor necrosis factor-alpha. The decrease in content of glial fibrillary acidic protein detected after tumor necrosis factor-alpha treatment is most likely due to dilution by other proteins that are synthesized rapidly in response to cytokine stimulation.

View details for Web of Science ID A1995TF55400040

View details for PubMedID 7595570

Abstract

Interleukin-11 (IL-11) is a pleiotropic cytokine with important effects on hematopoietic and other cells. IL-11 was originally described as a product of stromal cell lines and fibroblasts. Using RT-PCR, Northern blotting, and ELISA we demonstrated that the human U373 and U87 glioblastoma cell lines expressed IL-11 and its encoding mRNA when stimulated with IL-1 beta, phorbol ester, and calcium ionophore. The neuroblastoma cell line SH-SY5Y did not express IL-11 mRNA in response to these agents. Cerebral expression of IL-11 by glial cells is important because IL-11 has been shown to have effects on neuronal electrophysiology, has overlapping functions with the neuroactive cytokine interleukin-6, and is part of the gp130-associated neuropoietic family of cytokines.

View details for Web of Science ID A1995RU16500003

View details for PubMedID 7501271

Abstract

Macrophage inflammatory protein 1 (MIP-1) is a recently characterized inflammatory and chemokinetic cytokine. Proinflammatory stimuli have been shown to induce expression of MIP-1 by macrophages. We hypothesized that microglia and astrocytes express MIP-1 alpha because of their many immunologic similarities to macrophages. MIP-1 alpha mRNA was examined with quantitative reverse transcription and polymerase chain reaction in an immortalized mouse microglial cell line (BV-2) and in mouse cortical astrocyte cultures. We found that in both the BV-2 microglial cell line and in astrocyte cultures, MIP-1 alpha mRNA was strongly induced by lipopolysaccharide and the phorbol ester PMA. MIP-1 alpha mRNA was reduced by dBcAMP, interferon-gamma, and PGE1. Dexamethasone decreased MIP-1 alpha mRNA levels in astrocyte cultures, but not in BV-2 microglial cells. Interleukin-1 beta, tumor necrosis factor alpha, and MIP-1 alpha had no effect on MIP-1 alpha mRNA expression. These findings demonstrate that MIP-1 alpha mRNA is expressed by cultured glial cells and is regulated by proinflammatory and anti-inflammatory stimuli. MIP-1 alpha may be expressed by microglia and astrocytes in vivo, and may help modulate cerebral inflammation.

View details for Web of Science ID A1995QW01500006

View details for PubMedID 7629889

Abstract

Leukemia inhibitory factor (LIF) is a multifunctional cytokine synthesized by a variety of cell types. In the nervous system LIF affects neuronal differentiation, and may be important during cerebral infection and inflammation. To clarify the cellular source of LIF in the brain, we examined the expression of LIF mRNA by primary cortical astrocyte cultures and an immortalized microglial cell line. The microglial cell line did not express LIF mRNA in response to pro-inflammatory agents such as lipopolysaccharide (LPS) that induced expression of other cytokine mRNAs. In contrast, primary astrocyte cultures grown in serum-containing medium expressed LIF mRNA constitutively, and this expression was regulated by pro-inflammatory and anti-inflammatory stimuli. Agents which activate the cAMP and protein kinase C second messenger systems also increased LIF mRNA in astrocyte cultures. These results suggest that astrocytes, but not microglia, may be an important source of LIF during cerebral inflammation and infection.

View details for Web of Science ID A1995QD59100013

View details for PubMedID 7739804

View details for Web of Science ID A1995BE39G00020

View details for PubMedID 7568880

Abstract

Neutrophil adherence to vascular endothelium is partially mediated by adhesion molecules, including intracellular adhesion molecule 1 (ICAM-1), on endothelial cells. We examined the effect of transforming growth factor-beta 1 (TGF-beta 1) on the expression of ICAM-1 in human umbilical vein endothelial cells (HUVEC). TGF-beta 1 (1 ng/ml) increased ICAM-1 and ICAM-1 mRNA expression in HUVEC, as assessed by flow cytometry and Northern blot analysis, respectively. In addition, we investigated whether exogenous recombinant TGF-beta 1 can cause neutrophil-mediated lung injury in guinea pigs. The plasma half-life of 125I-labeled TGF-beta 1 in guinea pigs was 4.6 +/- 0.1 min, and the 125I activity was 2.8 +/- 0.2% 8 h after injection. The ratio of 125I-labeled albumin concentration in lung tissue and bronchoalveolar lavage (BAL) fluid to that in plasma, lung wet-to-dry weight ratio, numbers of neutrophils in BAL fluid, and numbers of neutrophils per alveolus in fixed lung sections increased in guinea pigs that received a high dose of TGF-beta 1 (25 micrograms i.v. followed by 2 micrograms/h for 8 h) compared with the control group. These results suggest that TGF-beta 1 causes neutrophil-mediated lung injury, possibly through upregulation of ICAM-1 on endothelial cells, and might be important in the pathogenesis of lung injury.

View details for Web of Science ID A1994PG91600032

View details for PubMedID 7836132

Abstract

The beta-amyloid peptide (beta AP) has been characterized by protein sequencing techniques as a 39-43 amino acid protein with heterogeneous COOH-termini. Controversy exists regarding the predominant form of beta AP in neuritic plaques (NP) and cerebral vasculature of Alzheimer's disease (AD) brain. A monoclonal antibody was developed that selectively recognizes the free COOH-terminal of beta AP 1-42 but not beta AP species with shorter or longer COOH-termini. Brain sections from AD and related disorders were examined using this antibody. In AD samples, the antibody stained diffuse amyloid and NP cores, many intraneuronal and extraneuronal neurofibrillary tangles (NFT), but not cerebrovascular amyloid. Pick and Lewy bodies lacked immunoreactivity. These findings suggest that beta AP 1-42 is present in early and mature amyloid deposits and NFT, but that species of beta AP other than 1-42 comprise human vascular deposits.

View details for Web of Science ID A1994NK79500025

View details for PubMedID 8178931

Abstract

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 Web of Science ID A1993LP67800006

View details for PubMedID 7692077

Abstract

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

View details for Web of Science ID A1992BX24B00040

Abstract

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

Abstract

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

Abstract

Senile plaques and neurofibrillary tangles were quantified in 14 subnuclei of the amygdala in the brains of 3 patients with Down's syndrome (DS), aged 19, 56, and 64 years, and in 1 patient with familial Alzheimer's disease (AD), aged 54 years. The amygdala of the 19-year-old Down's case contained numerous senile plaques (SPs) but no neurofibrillary tangles (NFTs). The distribution of neuropathological change in the amygdala was similar among the Down's and the Alzheimer's cases. Medical and ventral regions contained more SPs and NFTs than did lateral regions, and the SPs in ventromedial subnuclei generally were the "mature" type with a prominent amyloid core. In general, the numbers of SPs and NFTs were parallel in a given subnucleus with the striking exceptions of the deep medial basal, deep cortical, and lateral central nuclei that contained far more SPs than NFTs, and the medial and lateral superficial cortical nuclei that contained numerous NFTs but few SPs. Several subnuclei strongly interconnected with hippocampus and entorhinal cortex were more heavily involved than subnuclei related to the nucleus basalis of Meynert. The patterns of SP and NFT deposition are consistent with amygdaloid abnormalities found by others in sporadic AD. These findings demonstrate the similarity in amygdaloid pathology among Down's syndrome, familial Alzheimer's disease, and sporadic AD. The presence of senile plaques in the amygdala of the 19-year-old patient with DS suggests that the amygdala is a focus of early pathological change in DS and possibly AD.

View details for Web of Science ID A1991FX21600012

View details for PubMedID 1832566

Abstract

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

Abstract

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

Abstract

We present an analysis of observational data on the behavior profiles for two groups of infant langur monkeys (Presbytis entellus): one that had experienced mother loss, and the other, a control group, that had not undergone mother loss. Observations were analyzed in three 2-week time periods: 2 preseparation, 2 separation, and 2 postseparation periods for both groups. The profile analysis application of the multivariate analysis of variance (MANOVA) was employed to test the hypothesis that the two groups had similar patterns of change across time. For each group a vector of 5 difference scores was computed; then MANOVA was used to test the similarity of the mean vectors of difference scores for the two groups. Profiles for the separation and control infants were significantly different for some behaviors, and changes between some time periods were also significant.

View details for Web of Science ID A1983RA81400003

View details for PubMedID 6884906

View details for Web of Science ID A1982MX42100005

View details for PubMedID 7060681

Abstract

Observation for the first 3 months of life of 19 Indian langur monkey infants (Presbytis entellus) living in well-established colony social groups revealed complex and related patterns of social development. This is a period of rapidly increasing infant motor ability and increasing infant-initiated independence. Infant transfer, a behavior initiated by others towards the infant and a characteristic of the species, occurs most frequently in weeks 1 and 2, then steadily declines to low frequency in weeks 11 and 12. Infants are not punished or rejected, and to the extent the mother allows, the infant leaves her. She leaves her infant infrequently. The infant widens its radius of activity and increases the kinds and frequency of active interactions it has with others in the group. Patterns of behavior appear to develop in tandem during key periods of early life. Week 1 is the time of greatest dependence with 100% contact at first. During weeks 3 and 4, the infant efficiently expresses itself and can actively prevent transfers. Week 4 sees a constellation of major changes and a rising infant drive for independence. Play increases as do interactions with other immatures. Carrying decreases as the infant is able to follow. Some restraints are observed because of a new set of infant management problems presented to the mother. Throughout the first 3 months of life the mother is the focus of her infant's attention and activities--she is crucial to its survival. The 3-month-old infant is an active strategist with many options of action and choices of behavior and social partners.

View details for Web of Science ID A1982QA58500008

View details for PubMedID 7166290

Abstract

Cholesterol synthesis in actively growing bovine vascular endothelial cells is regulated by low density lipoprotein (LDL) at a step prior to mevalonate formation, in a manner comparable to that found in aortic smooth muscle cells. LDL uptake by these cells is associated with induction of cholesterol esterification, an increase in total cell cholesterol, and an inhibition of endogenous sterol synthesis. In contrast, cholesterol metabolism in confluent contact-inhibited endothelial cultures was not significantly affected by LDL even though the cells bind the lipoprotein at high affinity receptor sites. Lysosomal degradation and subsequent regulatory effects on cellular cholesterol metabolism, however, were observed in contact-inhibited endothelial cells incubated with cationized rather than native LDL. Cationized LDL enter the cells independently of the high affinity sites. Therefore, the primary regulation of cholesterol metabolism in these cells is neither through the appropriate intracellular enzymes nor through the high affinity surface receptors, but via an inhibition of LDL internalization. It is suggested that this inhibition is due to a strict contact-inhibited morphology which enables the endothelium of the larger arteries to function as a selective barrier to the high circulating levels of plasma LDL.

View details for Web of Science ID A1979GL96600031

View details for PubMedID 216681

Abstract

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

Abstract

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