Sharon Sha, MD, MS

All Publications

• Lewy Body Dementia Association's Research Centers of Excellence Program: Inaugural Meeting Proceedings. Alzheimer's research & therapy Peterson, B., Armstrong, M., Galasko, D., Galvin, J. E., Goldman, J., Irwin, D., Paulson, H., Kaufer, D., Leverenz, J., Lunde, A., McKeith, I. G., Siderowf, A., Taylor, A., Amodeo, K., Barrett, M., Domoto-Reilly, K., Duda, J., Gomperts, S., Graff-Radford, N., Holden, S., Honig, L., Huddleston, D., Lippa, C., Litvan, I., Manning, C., Marder, K., Moussa, C., Onyike, C., Pagan, F., Pantelyat, A., Pelak, V., Poston, K., Quinn, J., Richard, I., Rosenthal, L. S., Sabbagh, M., Scharre, D., Sha, S., Shill, H., Torres-Yaghi, Y., Christie, T., Graham, T., Richards, I., Koehler, M., Boeve, B. 2019; 11 (1): 23

  Abstract

  The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator's meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics.

  View details for DOI 10.1186/s13195-019-0476-1

  View details for PubMedID 30867052

• Ultra-Low-Dose 18F-Florbetaben Amyloid PET Imaging Using Deep Learning with Multi-Contrast MRI Inputs. Radiology Chen, K. T., Gong, E., de Carvalho Macruz, F. B., Xu, J., Boumis, A., Khalighi, M., Poston, K. L., Sha, S. J., Greicius, M. D., Mormino, E., Pauly, J. M., Srinivas, S., Zaharchuk, G. 2018: 180940

  Abstract

  Purpose To reduce radiotracer requirements for amyloid PET/MRI without sacrificing diagnostic quality by using deep learning methods. Materials and Methods Forty data sets from 39 patients (mean age ± standard deviation [SD], 67 years ± 8), including 16 male patients and 23 female patients (mean age, 66 years ± 6 and 68 years ± 9, respectively), who underwent simultaneous amyloid (fluorine 18 [18F]-florbetaben) PET/MRI examinations were acquired from March 2016 through October 2017 and retrospectively analyzed. One hundredth of the raw list-mode PET data were randomly chosen to simulate a low-dose (1%) acquisition. Convolutional neural networks were implemented with low-dose PET and multiple MR images (PET-plus-MR model) or with low-dose PET alone (PET-only) as inputs to predict full-dose PET images. Quality of the synthesized images was evaluated while Bland-Altman plots assessed the agreement of regional standard uptake value ratios (SUVRs) between image types. Two readers scored image quality on a five-point scale (5 = excellent) and determined amyloid status (positive or negative). Statistical analyses were carried out to assess the difference of image quality metrics and reader agreement and to determine confidence intervals (CIs) for reading results. Results The synthesized images (especially from the PET-plus-MR model) showed marked improvement on all quality metrics compared with the low-dose image. All PET-plus-MR images scored 3 or higher, with proportions of images rated greater than 3 similar to those for the full-dose images (-10% difference [eight of 80 readings], 95% CI: -15%, -5%). Accuracy for amyloid status was high (71 of 80 readings [89%]) and similar to intrareader reproducibility of full-dose images (73 of 80 [91%]). The PET-plus-MR model also had the smallest mean and variance for SUVR difference to full-dose images. Conclusion Simultaneously acquired MRI and ultra-low-dose PET data can be used to synthesize full-dose-like amyloid PET images. © RSNA, 2018 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2018180940

  View details for PubMedID 30526350

• Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study: A Randomized Clinical Trial. JAMA neurology Sha, S. J., Deutsch, G. K., Tian, L., Richardson, K., Coburn, M., Gaudioso, J. L., Marcal, T., Solomon, E., Boumis, A., Bet, A., Mennes, M., van Oort, E., Beckmann, C. F., Braithwaite, S. P., Jackson, S., Nikolich, K., Stephens, D., Kerchner, G. A., Wyss-Coray, T. 2018

  Abstract

  Young mouse plasma restores memory in aged mice, but, to our knowledge, the effects are unknown in patients with Alzheimer disease (AD).To assess the safety, tolerability, and feasibility of infusions of young fresh frozen plasma (yFFP) from donors age 18 to 30 years in patients with AD.The Plasma for Alzheimer Symptom Amelioration (PLASMA) study randomized 9 patients under a double-blind crossover protocol to receive 4 once-weekly infusions of either 1 unit (approximately 250 mL) of yFFP from male donors or 250 mL of saline, followed by a 6-week washout and crossover to 4 once-weekly infusions of an alternate treatment. Patients and informants were masked to treatment and subjective measurements. After an open-label amendment, 9 patients received 4 weekly yFFP infusions only and their subjective measurements were unmasked. Patients were enrolled solely at Stanford University, a tertiary academic medical center, from September 2014 to December 2016, when enrollment reached its target. Eighteen consecutive patients with probable mild to moderate AD dementia, a Mini-Mental State Examination (score of 12 to 24 inclusive), and an age of 50 to 90 years were enrolled. Thirty-one patients were screened and 13 were excluded: 11 failed the inclusion criteria and 2 declined to participate.One unit of yFFP from male donors/placebo infused once weekly for 4 weeks.The primary outcomes were the safety, tolerability, and feasibility of 4 weekly yFFP infusions. Safety end point analyses included all patients who received the study drug/placebo.There was no difference in the age (mean [SD], 74.17 [7.96] years), sex (12 women [67%]), or baseline Mini-Mental State Examination score (mean [SD], 19.39 [3.24]) between the crossover (n = 9) and open-label groups (n = 9). There were no related serious adverse events. One patient discontinued participation because of urticaria and another because of an unrelated stroke. There was no statistically significant difference between the plasma (17 [94.4%]) and placebo (9 [100.0%]) cohorts for other adverse events, which were mild to moderate in severity. The most common adverse events in the plasma group included hypertension (3 [16.7%]), dizziness (2 [11.1%]), sinus bradycardia (3 [16.7%]), headache (3 [16.7%]), and sinus tachycardia (3 [16.7%]). The mean visit adherence (n = 18) was 86% (interquartile range, 87%-100%) and adherence, accounting for a reduction in the total visit requirement due to early patient discontinuation, was 96% (interquartile range, 89%-100%).The yFFP treatment was safe, well tolerated, and feasible. The study's limitations were the small sample size, short duration, and change in study design. The results warrant further exploration in larger, double-blinded placebo-controlled clinical trials.ClinicalTrials.gov Identifier: NCT02256306.

  View details for DOI 10.1001/jamaneurol.2018.3288

  View details for PubMedID 30383097

• An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations. Alzheimer's & dementia (New York, N. Y.) Sha, S. J., Miller, Z. A., Min, S., Zhou, Y., Brown, J., Mitic, L. L., Karydas, A., Koestler, M., Tsai, R., Corbetta-Rastelli, C., Lin, S., Hare, E., Fields, S., Fleischmann, K. E., Powers, R., Fitch, R., Martens, L. H., Shamloo, M., Fagan, A. M., Farese, R. V., Pearlman, R., Seeley, W., Miller, B. L., Gan, L., Boxer, A. L. 2017; 3 (4): 507–12

  Abstract

  Introduction: Frontotemporal lobar degeneration-causing mutations in the progranulin (GRN) gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration-approved blood-brain barrier-penetrant calcium channel blocker, increased PGRN levels in PGRN-deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human GRN mutation carriers.Methods: We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight GRN mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints.Results: There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of -5.2±10.9% in plasma and -10.2±7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8-week period.Discussion: While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.

  View details for DOI 10.1016/j.trci.2017.08.002

  View details for PubMedID 29124108

• Egocentric and allocentric visuospatial working memory in premotor Huntington's disease: A double dissociation with caudate and hippocampal volumes. Neuropsychologia Possin, K. L., Kim, H., Geschwind, M. D., Moskowitz, T., Johnson, E. T., Sha, S. J., Apple, A., Xu, D., Miller, B. L., Finkbeiner, S., Hess, C. P., Kramer, J. H. 2017; 101: 57-64

  Abstract

  Our brains represent spatial information in egocentric (self-based) or allocentric (landmark-based) coordinates. Rodent studies have demonstrated a critical role for the caudate in egocentric navigation and the hippocampus in allocentric navigation. We administered tests of egocentric and allocentric working memory to individuals with premotor Huntington's disease (pmHD), which is associated with early caudate nucleus atrophy, and controls. Each test had 80 trials during which subjects were asked to remember 2 locations over 1-sec delays. The only difference between these otherwise identical tests was that locations could only be coded in self-based or landmark-based coordinates. We applied a multiatlas-based segmentation algorithm and computed point-wise Jacobian determinants to measure regional variations in caudate and hippocampal volumes from 3T MRI. As predicted, the pmHD patients were significantly more impaired on egocentric working memory. Only egocentric accuracy correlated with caudate volumes, specifically the dorsolateral caudate head, right more than left, a region that receives dense efferents from dorsolateral prefrontal cortex. In contrast, only allocentric accuracy correlated with hippocampal volumes, specifically intermediate and posterior regions that connect strongly with parahippocampal and posterior parietal cortices. These results indicate that the distinction between egocentric and allocentric navigation applies to working memory. The dorsolateral caudate is important for egocentric working memory, which can explain the disproportionate impairment in pmHD. Allocentric working memory, in contrast, relies on the hippocampus and is relatively spared in pmHD.

  View details for DOI 10.1016/j.neuropsychologia.2017.04.022

  View details for PubMedID 28427989

• Early-onset Alzheimer's disease versus frontotemporal dementia: resolution with genetic diagnoses? Neurocase Sha, S. J., Khazenzon, A. M., Ghosh, P. M., Rankin, K. P., Pribadi, M., Coppola, G., Geschwind, D. H., Rabinovici, G. D., Miller, B. L., Lee, S. E. 2016; 22 (2): 161-167

  Abstract

  We report a diagnostically challenging case of a 64-year-old man with a history of remote head trauma who developed mild behavioral changes and dyscalculia. He was diagnosed with clinical Alzheimer's disease (AD), with additional features consistent with behavioral variant frontotemporal dementia. Structural magnetic resonance imaging revealed atrophy in bilateral frontal and parietal cortices and hippocampi on visual inspection and left frontal pole and bilateral anterior temporal encephalomalacia, suspected to be due to head trauma. Consistent with the diagnosis of Alzheimer's pathology, positron emission tomography (PET) with Pittsburgh compound B suggested the presence of beta-amyloid. Fluorodeoxyglucose PET demonstrated hypometabolism in bilateral frontal and temporoparietal cortices. Voxel-based morphometry showed atrophy predominant in ventral frontal regions (bilateral orbitofrontal cortex, pregenual anterior cingulate/medial superior frontal gyrus), bilateral mid cingulate, bilateral lateral temporal cortex, and posterior insula. Bilateral caudate, thalamus, hippocampi, and cerebellum were prominently atrophied. Unexpectedly, a pathologic hexanucleotide repeat expansion in C9ORF72 was identified in this patient. This report underscores the clinical variability in C9ORF72 expansion carriers and the need to consider mixed pathologies, particularly when imaging studies are inconsistent with a single syndrome or pathology.

  View details for DOI 10.1080/13554794.2015.1080283

  View details for PubMedID 26304661

• Frontotemporal Dementia and Psychiatric Illness: Emerging Clinical and Biological Links in Gene Carriers AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Block, N. R., Sha, S. J., Karydas, A. M., Fong, J. C., De May, M. G., Miller, B. L., Rosen, H. J. 2016; 24 (2): 107-116

  Abstract

  To describe psychiatric presentations in individuals with genetic mutations causing frontotemporal dementia (FTD).Case descriptions from five carriers of FTD-related gene mutations with symptoms associated with non-neurodegenerative psychiatric disease.A comprehensive research program investigating genetic and non-genetic FTD at the University of California, San Francisco Memory and Aging Center.Three proband and two non-proband gene carriers.Medical history and neurological examination, neuropsychological testing, magnetic resonance and/or positron emission tomography imaging, and a genetic analysis to screen for dementia-related mutations. Genetic status was unknown at the time of initial evaluation.The chosen cases are illustrative of the variety of presentations of psychiatric symptoms in FTD gene carriers. In some cases, a non-neurodegenerative psychiatric illness was diagnosed based on specific symptoms, but the diagnosis may have been inappropriate based on the overall syndrome. In other cases, symptoms closely resembling those seen in non-neurodegenerative psychiatric illness did occur, in some cases immediately preceding the development of dementia, and in other cases developing a decade prior to dementia symptoms.Psychiatric symptoms in FTD gene carriers can be very similar to those seen in non-neurodegenerative psychiatric illness. Psychiatric symptoms with atypical features (e.g., late-life onset, insidiously worsening course) should prompt careful assessment for neurodegenerative disease. Guidelines for such an assessment should be established.

  View details for DOI 10.1016/j.jagp.2015.04.007

  View details for Web of Science ID 000370787800002

  View details for PubMedID 26324540

  View details for PubMedCentralID PMC4686378

• Predicting amyloid status in corticobasal syndrome using modified clinical criteria, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. Alzheimer's research & therapy Sha, S. J., Ghosh, P. M., Lee, S. E., Corbetta-Rastelli, C., Jagust, W. J., Kornak, J., Rankin, K. P., Grinberg, L. T., Vinters, H. V., Mendez, M. F., Dickson, D. W., Seeley, W. W., Gorno-Tempini, M., Kramer, J., Miller, B. L., Boxer, A. L., Rabinovici, G. D. 2015; 7 (1): 8-?

  Abstract

  Group comparisons demonstrate greater visuospatial and memory deficits and temporoparietal-predominant degeneration on neuroimaging in patients with corticobasal syndrome (CBS) found to have Alzheimer's disease (AD) pathology versus those with underlying frontotemporal lobar degeneration (FTLD). The value of these features in predicting underlying AD pathology in individual patients is unknown. The goal of this study is to evaluate the utility of modified clinical criteria and visual interpretations of magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) for predicting amyloid deposition (as a surrogate of Alzheimer's disease neuropathology) in patients presenting with CBS.In total, 25 patients meeting CBS core criteria underwent amyloid (Pittsburgh compound B; PIB) PET scans. Clinical records, MRI, and FDG scans were reviewed blinded to PIB results. Modified clinical criteria were used to classify CBS patients as temporoparietal variant CBS (tpvCBS) or frontal variant CBS (fvCBS). MRI and FDG-PET were classified based on the predominant atrophy/hypometabolism pattern (frontal or temporoparietal).A total of 9 out of 13 patients classified as tpvCBS were PIB+, compared to 2out of 12 patients classified as fvCBS (P < 0.01, sensitivity 82%, specificity 71% for PIB+ status). Visual MRI reads had 73% sensitivity and 46% specificity for PIB+ status with moderate intra-rater reliability (Cohen's kappa = 0.42). Visual FDG reads had higher sensitivity (91%) for PIB+ status with perfect intra-rater reliability (kappa = 1.00), though specificity was low (50%). PIB results were confirmed in all 8 patients with available histopathology (3 PIB+ with confirmed AD, 5 PIB- with FTLD).Splitting CBS patients into frontal or temporoparietal clinical variants can help predict the likelihood of underlying AD, but criteria require further refinement. Temporoparietal-predominant neuroimaging patterns are sensitive but not specific for AD.

  View details for DOI 10.1186/s13195-014-0093-y

  View details for PubMedID 25733984

  View details for PubMedCentralID PMC4346122

• Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion BRAIN Lee, S. E., Khazenzon, A. M., Trujillo, A. J., Guo, C. C., Yokoyama, J. S., Sha, S. J., Takada, L. T., Karydas, A. M., Block, N. R., Coppola, G., Pribadi, M., Geschwind, D. H., Rademakers, R., Fong, J. C., Weiner, M. W., Boxer, A. L., Kramer, J. H., Rosen, H. J., Miller, B. L., Seeley, W. W. 2014; 137: 3047-3060

  Abstract

  Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 ± 7.7 years, four females) and 14 non-carriers (age 60.8 ± 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task-free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topographically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with early-stage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting early-stage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.

  View details for DOI 10.1093/brain/awu248

  View details for Web of Science ID 000346760900026

  View details for PubMedID 25273996

• Quantitative 7T Phase Imaging in Premanifest Huntington Disease AMERICAN JOURNAL OF NEURORADIOLOGY Apple, A. C., Possin, K. L., Satris, G., JOHNSON, E., Lupo, J. M., Jakary, A., Wong, K., Kelley, D. A., Kang, G. A., SHA, S. J., Kramer, J. H., Geschwind, M. D., Nelson, S. J., Hess, C. P. 2014; 35 (9): 1707-1713

  Abstract

  In vivo MR imaging and postmortem neuropathologic studies have demonstrated elevated iron concentration and atrophy within the striatum of patients with Huntington disease, implicating neuronal loss and iron accumulation in the pathogenesis of this neurodegenerative disorder. We used 7T MR imaging to determine whether quantitative phase, a measurement that reflects both iron content and tissue microstructure, is altered in subjects with premanifest Huntington disease.Local field shift, calculated from 7T MR phase images, was quantified in 13 subjects with premanifest Huntington disease and 13 age- and sex-matched controls. All participants underwent 3T and 7T MR imaging, including volumetric T1 and 7T gradient recalled-echo sequences. Local field shift maps were created from 7T phase data and registered to caudate ROIs automatically parcellated from the 3T T1 images. Huntington disease-specific disease burden and neurocognitive and motor evaluations were also performed and compared with local field shift.Subjects with premanifest Huntington disease had smaller caudate volume and higher local field shift than controls. A significant correlation between these measurements was not detected, and prediction accuracy for disease state improved with inclusion of both variables. A positive correlation between local field shift and genetic disease burden was also found, and there was a trend toward significant correlations between local field shift and neurocognitive tests of working memory and executive function.Subjects with premanifest Huntington disease exhibit differences in 7T MR imaging phase within the caudate nuclei that correlate with genetic disease burden and trend with neurocognitive assessments. Ultra-high-field MR imaging of quantitative phase may be a useful approach for monitoring neurodegeneration in premanifest Huntington disease.

  View details for DOI 10.3174/ajnr.A3932

  View details for Web of Science ID 000341639900011

  View details for PubMedID 24742810

• Executive Functions in Premanifest Huntington's Disease MOVEMENT DISORDERS You, S. C., Geschwind, M. D., Sha, S. J., Apple, A., Satris, G., Wood, K. A., Johnson, E. T., Gooblar, J., Feuerstein, J. S., Finkbeiner, S., Kang, G. A., Miller, B. L., Hess, C. P., Kramer, J. H., Possin, K. L. 2014; 29 (3): 405-409

  Abstract

  We investigated the viability of psychometrically robust executive function measures as markers for premanifest Huntington's disease (HD).Fifteen premanifest HD subjects and 42 controls were compared on the NIH EXAMINER executive function battery. This battery yields an overall executive composite score, plus working memory, cognitive control, and fluency scores that are measured on psychometrically matched scales. The scores were correlated with two disease markers, disease burden and striatal volumes, in the premanifest HD subjects.The premanifest HD subjects scored significantly lower on the working memory score. The executive composite positively correlated with striatal volumes, and the working memory score negatively correlated with disease burden. The cognitive control and fluency scores did not differ between the groups or correlate significantly with the disease markers.The NIH EXAMINER executive composite and working memory scores are sensitive markers of cognitive dysfunction, striatal volume, and disease burden in premanifest HD.

  View details for DOI 10.1002/mds.25762

  View details for Web of Science ID 000332823000022

  View details for PubMedID 24375511

  View details for PubMedCentralID PMC4029327

• Interrater reliability of the new criteria for behavioral variant frontotemporal dementia NEUROLOGY LaMarre, A. K., Rascovsky, K., Bostrom, A., Toofanian, P., Wilkins, S., Sha, S. J., Perry, D. C., Miller, Z. A., Naasan, G., Laforce, R. J., Hagen, J., Takada, L. T., Tartaglia, M. C., Kang, G., Galasko, D., Salmon, D. P., Farias, S. T., Kaur, B., Olichney, J. M., Park, L. Q., Mendez, M. F., Tsai, P., Teng, E., Dickerson, B. C., Domoto-Reilly, K., McGinnis, S., Miller, B. L., Kramer, J. H. 2013; 80 (21): 1973-1977

  Abstract

  To evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD).Twenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by κ statistics for multiple raters with categorical ratings.The mean κ value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD ("almost perfect agreement"). Interrater reliability for 4 of the 6 core features had "substantial" agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; κ = 0.61-0.80), whereas 2 had "moderate" agreement (apathy/inertia, neuropsychological; κ = 0.41-0.6). Clinician years of experience did not significantly influence rater accuracy.The FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important.

  View details for Web of Science ID 000319332900015

  View details for PubMedID 23635967

• Frontotemporal dementia due to C9ORF72 mutations Clinical and imaging features NEUROLOGY Sha, S. J., Takada, L. T., Rankin, K. P., Yokoyama, J. S., Rutherford, N. J., Fong, J. C., Khan, B., Karydas, A., Baker, M. C., DeJesus-Hernandez, M., Pribadi, M., Coppola, G., Geschwind, D. H., Rademakers, R., Lee, S. E., Seeley, W., Miller, B. L., Boxer, A. L. 2012; 79 (10): 1002-1011

  Abstract

  To describe the phenotype of patients with C9FTD/ALS (C9ORF72) hexanucleotide repeat expansion.A total of 648 patients with frontotemporal dementia (FTD)-related clinical diagnoses and Alzheimer disease (AD) dementia were tested for C9ORF72 expansion and 31 carried expanded repeats (C9+). Clinical and neuroimaging data were compared between C9+ (15 behavioral variant FTD [bvFTD], 11 FTD-motor neuron disease [MND], 5 amyotrophic lateral sclerosis [ALS]) and sporadic noncarriers (48 bvFTD, 19 FTD-MND, 6 ALS).All C9+ patients displayed clinical syndromes of bvFTD, ALS, or FTD-MND. At first evaluation, C9+ bvFTD patients had more delusions and greater impairment of working memory, but milder eating dysregulation compared to bvFTD noncarriers. C9+FTD-MND patients had a trend for longer survival and had an earlier age at onset than FTD-MND noncarriers. Voxel-based morphometry demonstrated more thalamic atrophy in FTD and FTD-MND carriers than in noncarriers.Patients with the C9ORF72 hexanucleotide repeat expansion develop bvFTD, ALS, or FTD-MND with similar clinical and imaging features to sporadic cases. Other FTD spectrum diagnoses and AD dementia appear rare or absent among C9+ individuals. Longer survival in C9+ FTD-MND suggests slower disease progression and thalamic atrophy represents a novel and unexpected feature.

  View details for Web of Science ID 000308674000015

  View details for PubMedID 22875087

  View details for PubMedCentralID PMC3430713

• Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Khan, B. K., Yokoyama, J. S., Takada, L. T., Sha, S. J., Rutherford, N. J., Fong, J. C., Karydas, A. M., Wu, T., Ketelle, R. S., Baker, M. C., Hernandez, M., Coppola, G., Geschwind, D. H., Rademakers, R., Lee, S. E., Rosen, H. J., Rabinovici, G. D., Seeley, W. W., Rankin, K. P., Boxer, A. L., Miller, B. L. 2012; 83 (4): 358-364

  Abstract

  Some patients meeting behavioural variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy and have thus been referred to as bvFTD 'phenocopies' or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have demonstrated no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions are described.384 patients with an FTD clinical spectrum and Alzheimer's disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns, assessed using voxel based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls.Both patients were aged 48 years at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over 7 years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over 2 years, her neuropsychological and functional scores as well as brain atrophy remained stable.C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.

  View details for DOI 10.1136/jnnp-2011-301883

  View details for Web of Science ID 000301296600003

  View details for PubMedID 22399793

• Neuropsychiatric features of C9orf72-associated behavioral variant frontotemporal dementia and frontotemporal dementia with motor neuron disease ALZHEIMERS RESEARCH & THERAPY Takada, L. T., Sha, S. J. 2012; 4 (5)

  Abstract

  Earlier reports of chromosome 9p-linked frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS) kindreds observed psychosis as a prominent feature in some patients. Since the discovery of chromosome 9 open reading frame 72 (C9orf72) hexanucleotide expansions as a cause of FTD and ALS, research groups and consortia around the world have reported their respective observations of the clinical features associated with this mutation. We reviewed the recent literature on C9orf72-associated FTD and ALS with focus on the neuropsychiatric features associated with this mutation, as well as the experience at University of California, San Francisco. The results and methodologies varied greatly across studies, making comparison of results challenging. Four reports found that psychotic features (particularly delusions) were frequent among mutation carriers, particularly when present early during the disease course, suggesting that this symptom category may be a marker for the mutation. Disinhibition and apathy were the most commonly reported early behavioral symptoms, but these may not be helpful in distinguishing carriers and noncarriers because of the symptoms' frequency in sporadic behavioral variant FTD. Other neuropsychiatric features were reported in different frequencies across studies, suggesting either a similar behavioral phenotype in carriers and noncarriers or reflecting the heterogeneity in clinical presentation of behavioral variant FTD due to C9orf72 expansions. Further studies with larger cohorts will be necessary to determine the neuropsychiatric presentation associated with this mutation.

  View details for DOI 10.1186/alzrt141

  View details for Web of Science ID 000315195500004

  View details for PubMedID 23034079

• Treatment implications of C9ORF72 ALZHEIMERS RESEARCH & THERAPY Sha, S. J., Boxer, A. 2012; 4 (6)

  Abstract

  Frontotemporal dementia (FTD) is a common dementia syndrome in patients under the age of 65 years with many features overlapping with amyotrophic lateral sclerosis (ALS). The link between FTD and ALS has been strengthened by the discovery that a hexanucleotide repeat expansion in a non-coding region of the C9ORF72 gene causes both familial and sporadic types of these two diseases. As we begin to understand the pathophysiological mechanisms by which this mutation leads to FTD and ALS (c9FTD/ALS), new targets for disease-modifying therapies will likely be unveiled. Putative C9ORF72 expansion pathogenic mechanisms include loss of C9ORF72 protein function, sequestration of nucleic acid binding proteins due to expanded hexanucleotide repeats, or a combination of the two. New animal models and other research tools informed by work in other repeat expansion neurodegenerative diseases such as the spinocerebellar ataxias will help to elucidate the mechanisms of C9ORF72-mediated disease. Similarly, re-examining previous studies of drugs developed to treat ALS in light of this new mutation may identify novel FTD treatments. Ultimately, research consortiums incorporating animal models and well-characterized clinical populations will be necessary to fully understand the natural history of the c9FTD/ALS clinical phenotypes and identify biomarkers and therapeutic agents that can cure the most common form of genetically determined FTD and ALS.

  View details for DOI 10.1186/alzrt149

  View details for Web of Science ID 000315195900003

  View details for PubMedID 23186535

• Are frontotemporal lobar degeneration, progressive supranuclear palsy and corticobasal degeneration distinct diseases? NATURE CLINICAL PRACTICE NEUROLOGY Sha, r. S., Hou, C., Viskontas, I. V., Miller, B. L. 2006; 2 (12): 658-665

  Abstract

  New findings relating to the clinical, genetic and molecular bases of neurodegenerative disorders have led to a shift away from traditional nomenclatures of clinical syndromes. Historically, frontotemporal lobar degeneration (FTLD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) were classified on the basis of distinct clinical and pathological features. In recent years, however, advances in molecular and genetic research have led clinicians to suggest that the similar etiologies of the three disorders warrant their amalgamation into a single disorder with three subtypes. In this Review, we consider the utility and validity of combining FTLD, CBD and PSP. The earliest reports of these disorders demonstrate their distinctiveness, whereas recent findings challenge traditional nomenclatures by showing etiological overlap. For example, tau inclusions have been confirmed in patients with CBD and those with PSP, and in some patients with FTLD, implying that all three disorders are 'tauopathies'. Furthermore, most patients with progressive nonfluent aphasia, a subtype of FTLD, show PSP or CBD post-mortem. Even tau-related cases of FTLD, CBD and PSP are distinguishable on the basis of other criteria, however, and many FTLD cases do not show tau pathology. We argue, therefore, that FTLD, CBD and PSP should be considered as pathologically similar but distinct syndromes. New research criteria for CBD and PSP should note that progressive nonfluent aphasia is often a precursor of these conditions.

  View details for DOI 10.1038/ncpneuro0357

  View details for Web of Science ID 000242169100009

  View details for PubMedID 17117169

• Distinctive neuropsychological patterns in frontotemporal dementia, semantic dementia, and Alzheimer disease. Cognitive and behavioral neurology Kramer, J. H., Jurik, J., Sha, S. J., Rankin, K. P., Rosen, H. J., Johnson, J. K., Miller, B. L. 2003; 16 (4): 211-218

  Abstract

  To assess the ability of a brief neuropsychological bedside screening battery to discriminate between Alzheimer disease, frontotemporal dementia, and semantic dementia.Subjects were 21 patients with frontotemporal dementia, 14 patients with semantic dementia, and 30 patients with Alzheimer disease comparable in terms of Mini Mental Status Examination score, age, and education. Frontotemporal dementia and semantic dementia diagnoses were made clinically using the consensus criteria of Neary et al. 1 Subjects were administered a brief neuropsychological screening assessing episodic memory, working memory, executive function, naming, spatial ability, abstract reasoning, and calculations.Both the Alzheimer disease and semantic dementia groups were significantly impaired relative to the frontotemporal dementia group on verbal memory, whereas only the Alzheimer disease group was impaired on visual memory. Frontotemporal dementia patients performed significantly worse on backward digit span and made significantly more executive errors than Alzheimer disease and semantic dementia patients. Semantic dementia patients were more impaired than Alzheimer disease and frontotemporal dementia patients on confrontation naming. Discriminant function analyses identified the 5 most discriminating variables that correctly classified 89.2% of cases.Frontotemporal dementia, semantic dementia, and Alzheimer disease are associated with distinct neuropsychological profiles that classify these dementia syndromes with considerable success. The neuropsychological profiles highlight the distinctiveness between the 3 syndromes, are consistent with the known loci of neuropathology in these conditions, and can potentially serve as an adjunct to the current clinical criteria.

  View details for PubMedID 14665820