Faculty Bibliography

Alzheimer's disease (AD) is the most common and most studied cause of dementia. Significant advances have been made since the first set of clinical criteria for AD were put forth in 1984 that are now captured in the new criteria for AD published in 2011. Key features include recognition of a broad AD spectrum (from preclinical to mild cognitive impairment to AD dementia) and requirement of AD biomarkers for diagnosis. Correctly diagnosing dementia type is increasingly important in an era when potential disease-modifying agents are soon to be marketed. The typical AD dementia syndrome has at its core, an amnestic syndrome of the hippocampal type, followed by associated deficits in word-finding, spatial cognition, executive functions and neuropsychiatric changes. Atypical presentations of AD have also been identified that are presumed to have a different disease course. It can be difficult to distinguish between the various dementia syndromes given the overlap in many common clinical features across the dementias. The clinical difficulty in diagnosis may reflect the underlying pathology, as AD often co-occurs with other pathologies at autopsy, such as cerebrovascular disease or Lewy bodies. Neuropsychological evaluation has provided clinicians and researchers with profiles of cognitive strengths and weaknesses that help to define the dementias. There is yet no single behavioral marker that can reliably discriminate AD from the other dementias. The combined investigation of cognitive and neurobehavioral symptoms coupled with imaging markers could provide a more accurate approach for differentiating between AD and other major dementia syndromes in the future

AIMS: Cognitive impairment and dementia are common features of Parkinson's disease (PD). Patients with Parkinson's disease dementia (PDD) often have significant cholinergic defects, which may be treated with cholinesterase inhibitors (ChEIs). The objective of this review was to consider available efficacy, tolerability, and safety data from studies of ChEIs in PDD. DISCUSSIONS: A literature search resulted in the identification of 20 relevant publications. Of these, the treatment of PD patients with rivastigmine, donepezil, or galantamine was the focus of six, eleven, and two studies respectively, while one study reported use of both tacrine and donepezil. The majority of studies were small (<40 patients), with the exception of two large randomized controlled trials (RCTs) that are the main focus of this review. In the smaller studies, treatment benefits were reported on a range of outcome measures, though results were extremely variable. While the full results of a large RCT of donepezil in patients with PDD are not yet available, significant treatment differences were reported on the CIBIC-plus at the highest treatment dose. A trend toward improvement was also observed in treated patients on the ADAS-cog. The second large RCT found significant improvements in rivastigmine-treated patients compared with placebo on both the ADAS-cog (P < 0.001) and the ADCS-CGIC (P < 0.007), as well as on all secondary efficacy outcomes. Consequently, rivastigmine is now widely approved for the symptomatic treatment of mild to moderate PDD. CONCLUSIONS: Taken together, these studies suggest that ChEIs are efficacious in the treatment of PDD

BACKGROUND:Lowering cholesterol is associated with reduced CNS amyloid deposition and increased dietary cholesterol increases amyloid accumulation in animal studies. Epidemiologic data suggest that use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may decrease the risk of Alzheimer disease (AD) and a single-site trial suggested possible benefit in cognition with statin treatment in AD, supporting the hypothesis that statin therapy is useful in the treatment of AD. OBJECTIVE:To determine if the lipid-lowering agent simvastatin slows the progression of symptoms in AD. METHODS:This randomized, double-blind, placebo-controlled trial of simvastatin was conducted in individuals with mild to moderate AD and normal lipid levels. Participants were randomly assigned to receive simvastatin, 20 mg/day, for 6 weeks then 40 mg per day for the remainder of 18 months or identical placebo. The primary outcome was the rate of change in the Alzheimer's Disease Assessment Scale-cognitive portion (ADAS-Cog). Secondary outcomes measured clinical global change, cognition, function, and behavior. RESULTS:A total of 406 individuals were randomized: 204 to simvastatin and 202 to placebo. Simvastatin lowered lipid levels but had no effect on change in ADAS-Cog score or the secondary outcome measures. There was no evidence of increased adverse events with simvastatin treatment. CONCLUSION/CONCLUSIONS:Simvastatin had no benefit on the progression of symptoms in individuals with mild to moderate AD despite significant lowering of cholesterol. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class I evidence that simvastatin 40 mg/day does not slow decline on the ADAS-Cog.

Despite the potential of the internet for informing clinical practice, little is know about physicians' use of and attitudes about internet use for dementia care. We surveyed 373 physicians to inform development of on-line dementia education resources. Two thirds reported using internet-based resources in their clinical practices at least three times per week; 61% participated in on-line continuing medical education. Three fourths agreed that internet-based resources are helpful in clinical care but most expressed mixed views about quality of available information. Respondents reported limited awareness and use of dementia-specific internet resources, but expressed an interest in such information regarding screening, treatment, community resources, and patient education. National Institute on Aging-funded Alzheimer's Disease Centers are in a unique position to disseminate on-line resources for physicians on dementia diagnosis, treatment, and care. Our study suggests that such a resource would be well received and utilized by physicians

OBJECTIVE: Clinicopathologic phenotypes of dementia with Lewy bodies (DLB) and Alzheimer disease (AD) often overlap, making discrimination difficult. We performed resting state blood oxygen level-dependent (BOLD) functional connectivity MRI (fcMRI) to determine whether there were differences between AD and DLB. METHODS: Participants (n = 88) enrolled in a longitudinal study of memory and aging underwent 3-T fcMRI. Clinical diagnoses of probable DLB (n = 15) were made according to published criteria. Cognitively normal control participants (n = 38) were selected for the absence of cerebral amyloid burden as imaged with Pittsburgh compound B (PiB). Probable AD cases (n = 35) met published criteria and had appreciable amyloid deposits with PiB imaging. Functional images were collected using a gradient spin-echo sequence sensitive to BOLD contrast (T2* weighting). Correlation maps selected a seed region in the combined bilateral precuneus. RESULTS: Participants with DLB had a functional connectivity pattern for the precuneus seed region that was distinct from AD; both the DLB and AD groups had functional connectivity patterns that differed from the cognitively normal group. In the DLB group, we found increased connectivity between the precuneus and regions in the dorsal attention network and the putamen. In contrast, we found decreased connectivity between the precuneus and other task-negative default regions and visual cortices. There was also a reversal of connectivity in the right hippocampus. CONCLUSIONS: Changes in functional connectivity in DLB indicate patterns of activation that are distinct from those seen in AD and may improve discrimination of DLB from AD and cognitively normal individuals. Since patterns of connectivity differ between AD and DLB groups, measurements of BOLD functional connectivity can shed further light on neuroanatomic connections that distinguish DLB from AD

ACADEMIC EMERGENCY MEDICINE 2011; 18:374-384 (c) 2011 by the Society for Academic Emergency Medicine ABSTRACT: Background: Cognitive dysfunction, including dementia and delirium, is prevalent in geriatric emergency department (ED) patients, but often remains undetected. One barrier to reliable identification of acutely or chronically impaired cognitive function is the lack of an acceptable screening tool. While multiple brief screening instruments have been derived, ED validation trials have not previously demonstrated tools that are appropriately sensitive for clinical use. Objectives: The primary objective was to evaluate and compare the Ottawa 3DY (O3DY), Brief Alzheimer's Screen (BAS), Short Blessed Test (SBT), and caregiver-completed AD8 (cAD8) diagnostic test performance for cognitive dysfunction in geriatric ED patients using the Mini Mental Status Exam (MMSE) as the criterion standard. A secondary objective was to assess the diagnostic accuracy for the cAD8 (which is an informant-based instrument) when used in combination with the other performance-based screening tools. Methods: In an observational cross-sectional cohort study at one urban academic university-affiliated medical center, trained research assistants (RAs) collected patients' responses on the Confusion Assessment Method for the Intensive Care Unit, BAS, and SBT. When available, reliable caregivers completed the cAD8. The MMSE was then obtained. The O3DY was reconstructed from elements of the MMSE and the BAS. Consenting subjects were non-critically ill, English-speaking adults over age 65 years, who had not received potentially sedating medications prior to or during cognitive testing. Using an MMSE score of </=23 as the criterion standard for cognitive dysfunction, the sensitivity, specificity, likelihood ratios, and receiver operating characteristic (ROC) area under the curve (AUC) were computed. Venn diagrams were constructed to quantitatively compare the degree of overlap among positive test results between the performance-based instruments. Results: The prevalence of cognitive dysfunction for the 163 patients enrolled with complete data collection was 37%, including 5.5% with delirium. Dementia was self-reported in 3%. Caregivers were available to complete the cAD8 for 56% of patients. The SBT, BAS, and O3DY each demonstrated 95% sensitivity, compared with 83% sensitivity for the cAD8. The SBT had a superior specificity of 65%. No combination of instruments with the cAD8 significantly improved diagnostic accuracy. The SBT provided the optimal overlap with the MMSE. Conclusions: The SBT, BAS, and O3DY are three brief performance-based screening instruments to identify geriatric patients with cognitive dysfunction more rapidly than the MMSE. Among these three instruments, the SBT provides the best diagnostic test characteristics and overlap with MMSE results. The addition of the cAD8 to the other instruments does not enhance diagnostic accuracy

Disease-modifying approaches for Alzheimer's disease (AD) might be most effective when initiated very early in the course, before the pathologic burden and neuronal and synaptic degeneration make it unlikely that halting disease progression would have a significant impact on patient outcomes. Biomarkers of disease may provide important avenues of research to enhance the diagnosis of individuals with early AD and could assist in the identification of those individuals at risk for developing AD. However, for such biomarkers to become clinically useful, long-term follow-up studies are necessary to evaluate the relevance of cross-sectional biomarker changes to the longitudinal course of the disease. The objective of this article is to review recent progress in AD biomarkers for the early diagnosis, classification, progression and prediction of AD and their usefulness in new treatment trials

The AD8 questionnaire developed by Washington University in St Louis is a screening tool with 8 questions to reliably differentiate nondemented from demented individuals even at the very mild stage. We recruited 239 participants, including 114 cognitively normal, 73 very mild dementia, and 52 mild dementia to validate its application in Taiwanese. The cut-off value of AD8 was 2 in discriminating cognitively normal from demented individuals with the area under curve (AUC) = 0.961, sensitivity = 97.6%, specificity = 78.1%, positive likelihood ratio (PLR) = 4.5, and negative likelihood ratio (NLR) = 0.03. The cut-off value also was 2 in discriminating nondemented from very mild dementia with the AUC = 0.948, sensitivity = 95.9%, specificity = 78.1%, PLR = 4.4, and NLR = 0.05. The Chinese AD8 is effective in discriminating individuals with dementia, even at its mildest stages from those without dementia with properties identical to the original English version. The cAD8 is a quick dementia screening tool that can be applied across cultures

PURPOSE: Patients with Lewy body dementia (LBD) may present a unique set of symptoms and challenges to family caregivers compared with other types of dementia. Prominent difficulties include motor impairment, activities of daily living (ADLs) disability, recurrent behavioral and emotional problems (BEPs), and diagnostic difficulties. These problems are likely to affect caregivers' subjective burden. DESIGN AND METHODS: The present study used data from an Internet survey conducted by the Lewy Body Dementia Association. Respondents were 611 people who indicated that they were currently involved in the care of their relative with LBD. Subjective burden was assessed with a 12-item short version of the Zarit Burden Interview. RESULTS: A factor analysis revealed 3 dimensions of burden: role strain, personal strain, and worry about performance. Multiple regressions were used to examine predictors of these dimensions. BEPs, ADL disability, isolation, caregiver age, and patient gender were significant predictors of specific factors. Falls, formal service use, difficulty finding a physician, and evaluation of the physician had no significant associations with burden. IMPLICATIONS: These findings highlight burden experiences by caregivers of patients with LBD and the impact of BEPs, ADL assistance, and awareness about LBD on subjective burden

Misfolded proteins are at the core of many neurodegenerative diseases, nearly all of them associated with cognitive impairment. For example Creutzfeldt-Jacob disease is associated with aggregation of prion protein, ( 1,2) Lewy body dementia and Parkinson disease with alpha-synuclein ( 3,4)