Sandra A. Jacobson

The Montreal Cognitive Assessment and the Mini-Mental State Examination as Screening Instruments for Cognitive Impairment: Item Analyses and Threshold Scores

Aims: To perform an item analysis of the Montreal Cognitive Assessment (MoCA) versus the Mini-Mental State Examination (MMSE) in the prediction of cognitive impairment, and to examine the characteristics of different MoCA threshold scores. Methods: 135 subjects enrolled in a longitudinal clinicopathologic study were administered the MoCA by a single physician and the MMSE by a trained research assistant. Subjects were classified as cognitively impaired or cognitively normal based on independent neuropsychological testing. Results: 89 subjects were found to be cognitively normal, and 46 cognitively impaired (20 with dementia, 26 with mild cognitive impairment). The MoCA was superior in both sensitivity and specificity to the MMSE, although not all MoCA tasks were of equal predictive value. A MoCA threshold score of 26 had a sensitivity of 98% and a specificity of 52% in this population. In a population with a 20% prevalence of cognitive impairment, a threshold of 24 was optimal (negative predictive value 96%, positive predictive value 47%). Conclusion: This analysis suggests the potential for creating an abbreviated MoCA. For screening in primary care, the MoCA threshold of 26 appears optimal. For testing in a memory disorders clinic, a lower threshold has better predictive value.

Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain‐only donations and currently has banked more than 1600 brains. More than 430 whole‐body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimers disease, Parkinsons disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimers Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinsons Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinsons Research. The Program has made rapid autopsy a priority, with a 3.0‐hour median post‐mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant‐funded projects.

Frequency of Alzheimer's Disease Pathology at Autopsy in Patients with Clinical Normal Pressure Hydrocephalus

Normal pressure hydrocephalus (NPH) is considered to be potentially treatable with the placement of a cerebrospinal fluid (CSF) shunt. However, the procedure has been reported to have variable success, particularly with respect to improving the cognitive impairment in NPH. The presence of neurologic comorbidities, particularly Alzheimers disease (AD), may contribute to shunt responsiveness. Uncovering the extent to which AD and NPH co‐occur has implications for diagnosis and treatment of NPH. Autopsy studies of patients with NPH during their lifetime would elucidate the frequency of such comorbidities.

Essential tremor is not associated with cerebellar Purkinje cell loss

There has been controversy as to whether there is an underlying neurodegenerative process of the cerebellum in essential tremor (ET). The aim of this study was to examine whether ET is associated with Purkinje cell (PC) loss. Prospectively categorized ET and control subjects who were longitudinally examined in the Arizona Study for Aging and Neurodegenerative Disorders and came to autopsy between 1998 and 2013 underwent standardized neuropathological assessment of the brain. PC linear density of the cerebellar hemisphere was calculated in a blinded manner. There were 56 ET cases and 62 age‐matched controls free of dementia and other neurodegenerative disorders included in the study. Mean PC linear density was 3.80 ± 0.81 cells per mm for tremor cases and 3.82 ± 0.91 cells per mm for controls (Δ 0.02; 95% confidence interval [CI]: −0.30‐0.34). PC counts were not associated with tremor duration (r = 0.06; 95% CI: −0.21‐0.32). These data demonstrate that ET is not associated with cerebellar PC loss.

REM sleep behavior disorder and neuropathology in Parkinson's disease

Rapid eye movement (REM) sleep behavior disorder (RBD) in Parkinsons disease (PD) is associated with differences in clinical phenotype, including dementia, autonomic loss, and gait dysfunction. The pathological basis for this remains unclear.

Positron Emission Tomography and Neuropathologic Estimates of Fibrillar Amyloid-β in a Patient With Down Syndrome and Alzheimer Disease

BACKGROUND Down syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-β (Aβ) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aβ in the living human brain and to provide a close correlation with subsequent Aβ neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aβ in patients with Down syndrome remains to be determined. OBJECTIVES To characterize PET estimates of fibrillar Aβ burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death. Design/ METHODS With the familys informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patients diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patients diagnosis or PET measurements. RESULTS Visual ratings and automated analyses of the PET image revealed a heavy fibrillar Aβ burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan. CONCLUSIONS Florbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aβ burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aβ and to evaluate investigational Aβ-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease.

Clinicopathological outcomes of prospectively followed normal elderly brain bank volunteers

Existing reports on the frequencies of neurodegenerative diseases are typically based on clinical diagnoses. We sought to determine these frequencies in a prospectively assessed, community-based autopsy series. Included subjects had normal cognitive and movement disorder assessments at study entry. Of the 119 cases meeting these criteria, 52% were women; the median age of study entry was 83.5 years (range, 67-99 years), and the median duration from the first visit until death was 4.3 years (range, 0-10 years). At autopsy, clinicopathological diagnoses were made in 30 cases (25%). These diagnoses included 20 with Alzheimer disease (AD) (17%), 7 with vascular dementia (6%), 4 with progressive supranuclear palsy (3%), 3 with Parkinson disease and 1 each with dementia with Lewy bodies, corticobasal degeneration, or multiple system atrophy (0.8% each). Of the 87 subjects still clinically normal at death (73%), 33 had extensive AD pathology (preclinical AD) (38%), 17 had incidental Lewy bodies (20%), and 4 had incidental pathology consistent with progressive supranuclear palsy (5%). The diagnoses were not mutually exclusive. Although limited by a relatively small sample size, the neuropathological outcome of these initially normal elderly subjects represents a rough estimate of the incidence of these neurodegenerative conditions over a defined time period.

Receptor for advanced glycation end products: its role in Alzheimer's disease and other neurological diseases

The receptor for advanced glycation end products (RAGE) has been demonstrated to play a central role in the pathogenic mechanisms of a growing number of important neurological diseases, including Alzheimers disease (AD) and stroke. Two functional types of RAGE have been associated with neurological diseases: cell membrane-bound (full length) and soluble. In general, ligand binding to full-length RAGE initiates sustained cellular activation and receptor-dependent signaling resulting in inflammation and cellular stress, and is ultimately associated with increased RAGE expression. By comparison, soluble forms of RAGE, generated either by alternative splicing or by proteolysis, can reduce the severity of the consequence of ligand-membrane RAGE interactions by preventing ligands from binding to the full-length RAGE. This can inhibit the neurotoxic or proinflammatory responses involved in disease states. This article reviews the pathobiology of RAGE, with emphasis on soluble forms of RAGE, and discusses its relevance to AD and to other neurological diseases, as well as how manipulation of the different forms of RAGE is becoming a powerful therapeutic strategy.

Donepezil: potential neuroprotective and disease-modifying effects

Background: There is substantial evidence from preclinical studies that cholinesterase inhibitors affect basic processes that have been implicated in Alzheimers disease (AD) pathogenesis, suggesting that these drugs should have both disease-modifying and neuroprotective effects in humans. The evidence seems to be strongest in relation to donepezil, which is the focus of this review. Objective: To summarize the preclinical literature regarding the effects of donepezil on cellular and molecular processes underlying AD. Second, to suggest reasons for the apparent disparity between robust preclinical effects and modest clinical effects of this drug and others in its class. Methods: Articles retrieved from PubMed searches were critically reviewed and selected for relevance to the current topic. Results/conclusion: Donepezil has numerous cellular and molecular effects that should influence AD progression.

Florbetapir PET, FDG PET, and MRI in Down syndrome individuals with and without Alzheimer's dementia

Down syndrome (DS) is associated with amyloid b (Ab) deposition.