Nupur Ghoshal

Core features of frontotemporal dementia recapitulated in progranulin knockout mice.

Frontotemporal dementia (FTD) is typified by behavioral and cognitive changes manifested as altered social comportment and impaired memory performance. To investigate the neurodegenerative consequences of progranulin gene (GRN) mutations, which cause an inherited form of FTD, we used previously generated progranulin knockout mice (Grn-/-). Specifically, we characterized two cohorts of early and later middle-aged wild type and knockout mice using a battery of tests to assess neurological integrity and behavioral phenotypes analogous to FTD. The Grn-/- mice exhibited reduced social engagement and learning and memory deficits. Immunohistochemical approaches were used to demonstrate the presence of lesions characteristic of frontotemporal lobar degeneration (FTLD) with GRN mutation including ubiquitination, microgliosis, and reactive astrocytosis, the pathological substrate of FTD. Importantly, Grn-/- mice also have decreased overall survival compared to Grn+/+ mice. These data suggest that the Grn-/- mouse reproduces some core features of FTD with respect to behavior, pathology, and survival. This murine model may serve as a valuable in vivo model of FTLD with GRN mutation through which molecular mechanisms underlying the disease can be further dissected.

Alzheimer disease identification using amyloid imaging and reserve variables: Proof of concept

Objective: Several factors may influence the relationship between Alzheimer disease (AD) lesions and the expression of dementia, including those related to brain and cognitive reserve. Other factors may confound the association between AD pathology and dementia. We tested whether factors thought to influence the association of AD pathology and dementia help to accurately identify dementia of the Alzheimer type (DAT) when considered together with amyloid imaging. Methods: Participants with normal cognition (n = 180) and with DAT (n = 25), aged 50 years or older, took part in clinical, neurologic, and psychometric assessments. PET with the Pittsburgh compound B (PiB) tracer was used to measure brain amyloid, yielding a mean cortical binding potential (MCBP) reflecting PiB uptake. Logistic regression was used to generate receiver operating characteristic curves, and the areas under those curves (AUC), to compare the predictive accuracy of using MCBP alone vs MCBP together with other variables selected using a stepwise selection procedure to identify participants with DAT vs normal cognition. Results: The AUC resulting from MCBP alone was 0.84 (95% confidence interval [CI] = 0.73–0.94; cross-validated AUC = 0.80, 95% CI = 0.68–0.92). The AUC for the predictive equation generated by a stepwise model including education, normalized whole brain volume, physical health rating, gender, and use of medications that may interfere with cognition was 0.94 (95% CI = 0.90–0.98; cross-validated AUC = 0.91, 95% CI = 0.85–0.96), an improvement (p = 0.025) over that yielded using MCBP alone. Conclusion: Results suggest that factors reported to influence associations between AD pathology and dementia can improve the predictive accuracy of amyloid imaging for the identification of symptomatic AD.

Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology

Objectives: We sought to identify demographic and clinical features that were associated with expression of symptoms in the presence of Alzheimer disease (AD) neuropathologic changes. Methods: We studied 82 asymptomatic (Clinical Dementia Rating global score = 0) and 824 symptomatic subjects (Clinical Dementia Rating score >0) with low to high AD neuropathologic changes at autopsy who were assessed at 1 of 34 National Institute on Aging–funded Alzheimer’s Disease Centers. All subjects underwent a clinical examination within 1 year of death. Logistic regression was used to evaluate factors associated with the odds of being asymptomatic vs symptomatic. Results: Asymptomatic subjects tended to have low neurofibrillary tangle scores but a wide range of neuritic plaque frequencies. There were, however, a few asymptomatic subjects with very high tangle and neuritic plaque burden, as well as symptomatic subjects with few changes. In the multivariable model, asymptomatic subjects were older (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 1.01–1.07), had lower clinical Hachinski Ischemic Score (OR = 0.82; 95% CI = 0.69–0.97), were less likely to have an APOE ε4 allele (OR = 0.36; 95% CI = 0.16–0.83), and had lower neurofibrillary tangle score (OR = 0.28; 95% CI = 0.17–0.45) compared with symptomatic subjects. Conclusions: Dissociating clinical symptoms from pathologic findings better allows for investigation of preclinical AD. Our results suggest that although the severity of the pathology, particularly neurofibrillary tangles, has a large role in determining the extent of symptoms, other factors, including age, APOE status, and comorbidities such as cerebrovascular disease also explain differences in clinical presentation.

Codistribution of Amyloid β Plaques and Spongiform Degeneration in Familial Creutzfeldt-Jakob Disease With the E200K-129M Haplotype

BACKGROUND Dominantly inherited Creutzfeldt-Jakob disease (CJD) represents 5% to 15% of all CJD cases. The E200K mutation in the prion protein (PrP) gene (PRNP) is the most frequent cause of familial CJD. Coexistent amyloid beta (Abeta) plaques have been reported in some transmissible spongiform encephalopathies but to date have not been reported in familial CJD with the E200K mutation. OBJECTIVE To characterize a family with CJD in which Abeta plaques codistribute with spongiform degeneration. DESIGN Clinicopathologic and molecular study of a family with CJD with the E200K-129M haplotype. SETTING Alzheimer disease research center. PARTICIPANTS Two generations of a family. MAIN OUTCOME MEASURES Clinical, biochemical, and neuropathologic observations in 2 generations of a family. RESULTS In this kindred, 3 autopsied cases showed pathologic changes typical for the E200K-129M haplotype, including spongiform degeneration, gliosis, neuronal loss, and PrP deposition. Moreover, 2 of these cases (ages 57 and 63 years) showed numerous Abeta plaques codistributed with spongiform degeneration. APOE genotyping in 2 cases revealed that Abeta plaques were present in the APOE epsilon4 carrier but not in the APOE epsilon4 noncarrier. Two additional cases exhibited incomplete penetrance, as they had no clinical evidence of CJD at death after age 80 years but had affected siblings and children. CONCLUSIONS To our knowledge, this is the first description of Abeta plaques in familial CJD with the E200K mutation. The codistribution of plaques and CJD-associated changes suggests that PrP plays a central role in Abeta formation and that Abeta pathology and prion disease likely in fluence each other. The kindred described herein provides support that PrP(E200K) may result in increased Abeta deposition.

Mood Changes in Cognitively Normal Older Adults are Linked to Alzheimer Disease Biomarker Levels.

OBJECTIVES To evaluate whether cerebrospinal fluid (CSF) and PET Pittsburgh Compound B (PiB) biomarkers of underlying Alzheimer disease (AD) pathology (β-amyloid42 [Aβ42], tau, phosphorylated tau181 [ptau181], tau/Aβ42, ptau181/Aβ42 and mean cortical binding potential [MCBP] for PET-PiB) predict changes in mood in cognitively normal older adults. SETTING Knight Alzheimers Disease Research Center (ADRC) at Washington University (WU). PARTICIPANTS Participants, 65 years of age or older, were enrolled from longitudinal studies at the WU Knight ADRC. MEASUREMENTS CSF, PET-PiB biomarkers, Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), Profile of Mood States-Short Form (POMS-SF), the Geriatric Depression Scale (GDS), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS Data from 118 participants at baseline and 66 participants at one-year follow-up were analyzed. CSF and PET biomarkers were not associated cross-sectionally with any mood disturbances at baseline (p > 0.05). Changes in mood as indicated by the total mood disturbance score on the POMS-SF, selected POMS-SF subscales, GDS, and NPI-Q scores from baseline to one-year follow-up were associated with (p < 0.05) CSF and PET-PiB biomarkers. There was no statistically significant decline in cognitive functioning. CONCLUSIONS Generally, higher values of CSF and PET-PiB biomarkers are associated with more changes in mood in cognitively normal older adults. Further work is needed to understand the temporal development of mood changes over several years during the phase of preclinical AD. Evaluating mood as a noncognitive outcome may provide further insight into the development of preclinical AD in cognitively normal older adults.

FUS A new actor on the frontotemporal lobar degeneration stage

Following hard on the heels of discoveries of pathogenic mutations in the TAR DNA-binding protein 43 gene ( TDP-43/TARDBP ) in familial amyotrophic lateral sclerosis (FALS)1,2 and, less frequently, in frontotemporal lobar degeneration (FTLD),3,4 mutations in the fused in sarcoma/translocation in liposarcoma gene ( FUS/TLS ) were recently identified as causing about 4% of FALS.5,6 Some FALS cases had previously been linked to chromosome 16, which prompted Vance et al.5 and Kwiatkowski et al.6 to target genes encoding DNA/RNA-binding proteins within the linkage region; this resulted in independent identification of 15 different FUS mutations in 26 unrelated persons with FALS. Most of the mutations clustered in the C-terminal region of the protein encoded by exons 14 and 15. Interestingly, most of the reported pathogenic mutations in TARDBP are also within the C-terminal, glycine-rich domain. This clustering in a highly conserved region indicates that this region has functional significance and may be related to its role in binding heterogeneous nuclear ribonucleoproteins. Neuropathologic studies of TDP-43 proteinopathy place most sporadic and familial cases of ALS within a spectrum of disorders which includes ALS, FTLD, and cases with clinical and neuropathologic features of both (ALS-FTLD).7,8 More than half …

Amyloid Imaging, Cerebrospinal Fluid Biomarkers Predict Driving Performance Among Cognitively Normal Individuals.

Postmortem brain studies of older drivers killed in car accidents indicate that many had Alzheimer disease (AD) neuropathologic changes. We examined whether AD biomarkers are related to driving performance among cognitively normal older adults. Individuals with normal cognition, aged 65+ years, and driving at least once per week, were recruited. Participants (N=129) took part in clinical assessments, a driving test, and positron emission tomography imaging with Pittsburgh compound B (PIB) and/or cerebrospinal fluid (CSF) collection. General linear models tested whether the number of driving errors differed as a function of each of the biomarker variables (mean cortical binding potential for PIB, and CSF A&bgr;42, tau, ptau181, tau/A&bgr;42, ptau181/A&bgr;42). Higher ratios of CSF tau/A&bgr;42, ptau181/A&bgr;42, and PIB mean cortical binding potential, were associated with more driving errors (P<0.05). Preclinical AD may have subtle cognitive and functional effects, which alone may go unnoticed. However, when combined, these changes may impact complex behaviors such as driving.

Preclinical Alzheimer's disease and longitudinal driving decline

Links between preclinical Alzheimers disease (AD) and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs.

Development and interval testing of a naturalistic driving methodology to evaluate driving behavior in clinical research.

Background: The number of older adults in the United States will double by 2056. Additionally, the number of licensed drivers will increase along with extended driving-life expectancy. Motor vehicle crashes are a leading cause of injury and death in older adults. Alzheimer’s disease (AD) also negatively impacts driving ability and increases crash risk. Conventional methods to evaluate driving ability are limited in predicting decline among older adults. Innovations in GPS hardware and software can monitor driving behavior in the actual environments people drive in. Commercial off-the-shelf (COTS) devices are affordable, easy to install and capture large volumes of data in real-time. However, adapting these methodologies for research can be challenging. This study sought to adapt a COTS device and determine an interval that produced accurate data on the actual route driven for use in future studies involving older adults with and without AD. Methods: Three subjects drove a single course in different vehicles at different intervals (30, 60 and 120 seconds), at different times of day, morning (9:00-11:59AM), afternoon (2:00-5:00PM) and night (7:00-10pm). The nine datasets were examined to determine the optimal collection interval. Results: Compared to the 120-second and 60-second intervals, the 30-second interval was optimal in capturing the actual route driven along with the lowest number of incorrect paths and affordability weighing considerations for data storage and curation. Discussion: Use of COTS devices offers minimal installation efforts, unobtrusive monitoring and discreet data extraction. However, these devices require strict protocols and controlled testing for adoption into research paradigms. After reliability and validity testing, these devices may provide valuable insight into daily driving behaviors and intraindividual change over time for populations of older adults with and without AD. Data can be aggregated over time to look at changes or adverse events and ascertain if decline in performance is occurring.

Whipple's disease masquerades as dementia with Lewy bodies.

B RIEF R EPORT Whipple’s Disease Masquerades as Dementia With Lewy Bodies Kyle Hurth, MD, PhD,* Rawan Tarawneh, MD, wz Nupur Ghoshal, MD, PhD, wz Tammie L.S. Benzinger, MD, PhD, wzy David B. Clifford, MD, y Michael Geschwind, MD, PhD,8 John C. Morris, MD, wz James E. Galvin, MD, z Robert E. Schmidt, MD, PhD,* and Nigel J. Cairns, PhD, FRCPath* wz (Alzheimer Dis Assoc Disord 2015;29:85–89) Key Words: Whipple’s disease, bacterial infection, dementia with Lewy bodies Received for publication March 25, 2013; accepted July 1, 2013. From the *Department of Pathology and Immunology, Division of Neuropathology; wCharles F. and Joanne Knight Alzheimer’s Disease Research Center; zDepartment of Neurology; yMallinck- rodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO; 8Department of Neurology, University of California, San Francisco, CA; and zComprehensive Center on Brain Aging, New York University Langone School of Medicine, New York, NY. K.H., R.T., and N.G. contributed equally. Supported by grants from the National Institute on Aging of the National Institutes of Health (P50-AG05681, P01-AG03991), the Hope Center for Neurological Disorders, the Buchanan Fund, the Charles F. & Joanne Knight Alzheimer’s Disease Research Center, and the Barnes- Jewish Hospital Foundation. A summary of these data were presented at the 2012 Annual Meeting of the American Association of Neuropathologists. N.G. has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by Elan/Janssen, Eli Lilly and Company, Wyeth, Pfizer, Novartis, and Bristol-Myers Squibb. T.L.S.B. declares an interest as a consultant for Biomedical Sys- tems, ICON Medical Imaging, Eli Lilly Advisory Board, and Avid Radiopharmaceuticals. D.B.C. serves on Data Safety Boards for Amgen, Biogen, GlaxoSmithKline, Millennium, Genzyme, Genentech, and Pfizer. He has been a consultant to Brinker, Biddle, Reath [Progressive Multifocal Leukoencephalopathy (PML) Consortium], Genentech, Genzyme, Bristol-Myers Squibb, Millen- nium, Biogen Idec, and Pfizer. He has received research support from the Alzheimer’s Association, Biogen Idec, Eli Lilly, Roche and Pfizer. He has received speaking fees from Biogen, University of Kentucky, ECTRIMS, and CMSC/ACTRIMS. J.C.M. declares an interest as a consultant for: Eisai, Elan/Janssen Alzheimer Immu- notherapy Program, GlaxoSmithKline, Novartis, Otsuka Pharma- ceuticals, Pfizer/Wyeth, Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, and Schering Plough; support form NIH/NIA; speaking fees: Dickinson address at Ohio Wesleyan, ABA Soriano Lectureship, Morrell Lecture (Chicago), Eisai (South Korea), Bial Neurology Forum (Portugal); royalties from: Black- well Medical, Taylor and Francis. J.E.G. serves on a scientific advisory board for the American Federation for Aging Research and on the Board of Directors and the Scientific Advisory Council for the Lewy Body Dementia Association; he serves on speakers’ bureaus for Pfizer Inc., Eisai Inc., Novartis, and Forest Labo- ratories Inc.; has served as a consultant for Novartis, Forest Lab- oratories Inc., Pfizer Inc., Eisai Inc., Janssen, and Medivation Inc.; he has received license fee payments for AD8 dementia screening test (copyrighted): license agreements between Washington Uni- versity and Pfizer Inc., Eisai Inc., and Novartis; and receives research support from Novartis, Eli Lilly and Company, Elan Corporation, Wyeth, Bristol-Myers Squibb, the NIH/NIA, and the Alzheimer Association. The remaining authors declare no conflicts of interest. Reprints: Nigel J. Cairns, PhD, FRCPath, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110 (e-mail: cairns@wustl.edu). Copyright r 2013 Wolters Kluwer Health, Inc. All rights reserved. Alzheimer Dis Assoc Disord CASE HISTORY Dr George Whipple first described the disease which bears his name in 1907. 1 He described a 36-year-old male physician who presented with a 5- to 6-year history of insidious symptoms including cough, recurrent attacks of arthritis, gradual weight loss, and asthenia. By the end of his life, skin changes, diarrhea, abdominal swelling, and mesenteric adenopathy were prominent. Pathologic examination showed macrophages and fat vacuoles in the small bowel and inflammation and macrophages within pleura, peritoneum, and the aortic valve. Silver staining demonstrated rod- shaped structures. Electron microscopy has revealed that these aggregates consist of networks of membranous structures and bacillary bodies of the bacterium Tropheryma whipplei. 2,3 Bacterial DNA sequencing and antibodies to T. whipplei may now be used to confirm the diagnosis. We report a 49-year-old white man with a 4-year history of progressive cognitive and behavioral impairment, parkinsonism, cognitive fluctuation, altered sleep-wake cycles, myoclonus, visual hallucinations, and subsequent death. His past medical history included hypertension, chronic obstructive pulmonary disease, smoking, alcohol use, and cadaveric growth hormone replacement for delayed puberty as a child. There was no family history of dementia or movement disorder. He worked as a painter and was frequently exposed to solvents. He was in his usual state of health until approximately 2 years before initial evaluation. At that time, behavioral disturbances were noted by the family from whom he was estranged. He was described as depressed and severely withdrawn. Approximately 12 to 16 months into his course, he became forgetful of recent events and conversations and repeated himself. He had increasingly odd behavior including sleeping during the day and being awake at night, wandering outside inappropriately dressed, and confabulating. His cognition fluctuated from staring spells to deep sleep from which he was difficult to arouse. At other times he was alert and fully oriented without recollection of prior events. He began to have well-formed visual hallucinations that he described as “brightly-colored pets” or “small people” and occur- red during periods of lucidity. Eighteen months after onset, he was evaluated at an outside hospital for pneumonia, confusion, and agitation. He had notable parkinsonism and myoclonus of the left upper extremity. Imaging and diagnostic studies were unrevealing. Valproic acid partially improved his myoclonic movements. He was also treated with intravenous thiamine given his prior alcohol use and presentation concerning for Wernicke-Korsakoff syndrome. Small doses of risperidone and olanzapine produced generalized rigidity and drowsiness. He had one unexplained syncopal episode during his admission. Between episodes, he was alert and fully oriented and was discharged to a skilled nursing facility. Sporadic Creutzfeldt-Jakob disease was considered because of the rapid cognitive decline and a history of treatment with cadaveric growth hormone extract led to the suspicion of iatrogenic Creutzfeldt-Jakob disease. However, the absence of periodic sharp wave complexes in the context of mildly left predominant Volume 29, Number 1, January–March 2015 www.alzheimerjournal.com |