Faculty Bibliography

The Clinical Dementia Rating (CDR) is a common rating system used in clinical trials and longitudinal research projects to rate the presence and severity of cognitive problems in Alzheimer disease and related disorders. The interview process requires training and can be time-consuming. Here, we describe the validity, reliability, and discriminative ability of a computer-generated CDR using a personal digital assistant format. This project used clinical data from 138 archival and live evaluations (patient and informant interviews) collected for research purposes at Washington University to develop and test a software-based system for the administration and automatic scoring of the CDR. The system was programmed for use on a hand-held computer via the Palm Operating System. We developed domain-specific algorithms to quantify and translate clinical scoring decisions for the 3 cognitive (Memory, Orientation, Judgment and Problem Solving) and the 3 functional (Community Affairs, Home and Hobbies, Personal Care) domains of the CDR. An acceptable set of algorithms were developed using data from 104 research cases, reflecting a range of impairment levels (CDR 0 to 3) and expert scoring decisions. These algorithms were then tested for accuracy in a validation sample of 34 cases. The computer-generated CDR has excellent internal consistency (Cronbach's alpha ranging from 0.94 to 0.98) and interrater reliability (intraclass correlation coefficient ranging from 0.88 to 0.96). The computer-generated CDR showed excellent discrimination between demented and nondemented cases (Area under the curve=0.95; 95% confidence interval, 0.84-1.1). The computer-generated CDR using a Palm Operating System is easy to use, valid, and reliable. The level of agreement compares favorably to published interrater reliability data for the CDR. Software-based administration and automatic scoring of the CDR is a viable alternative to paper-based methods and may be useful in research and clinical settings, especially where electronic data management and reliability in scoring are critical

OBJECTIVE: To re-examine proposed models of cognitive test performance that concluded separate factor structures were required for people with Alzheimer disease (AD) and older adults without dementia. METHODS: Five models of cognitive test performance were compared using multistep confirmatory factor analysis in 115 individuals with autopsy-confirmed AD and 191 research participants without clinical dementia from longitudinal studies at the Washington University AD Research Center. The models were then cross-validated using independent samples of 323 people with clinically diagnosed dementia of the Alzheimer type and 212 cognitively healthy older adults. RESULTS: After controlling for Alzheimer-specific changes in episodic memory, performance on the battery of tests used here was best represented in people both with and without dementia by a single model of one general factor and three specific factors (verbal memory, visuospatial ability, and working memory). Performance by people with dementia was lower on the general factor than it was by those without dementia. Larger variances associated with the specific factors in the group with dementia indicated greater individual differences in the pattern of cognitive deficits in the stage of AD. CONCLUSIONS: A hybrid model of general and specific cognitive domains simplifies cognitive research by allowing direct comparison of normal aging and Alzheimer disease performance. The presence of a general factor maximizes detection of the dementia, whereas the specific factors reveal the heterogeneity of dementia's associated cognitive deficits

BACKGROUND: There is little information about how receptive older adults are to discuss memory problems with healthcare providers. Here we test the psychosocial factors explaining older adults' intention to undergo screening for Alzheimer disease (AD). METHODS: A population-based, random-digit dialing strategy surveyed 1,039 older adults. The Behavioral Model of Health Services Use was used as a conceptual framework for a questionnaire testing constructs from several behavioral theories. Structural equation modeling assessed the relationship of latent variables to each construct with goodness-of-fit indices. RESULTS: The study had an 82% response rate and 72% completer rate. The respondents' mean age was 62.7 +/- 10.2 years (range, 50 to 97 years). The sample was 67% women, 86% were white, and less than 40% had personal experience with AD. Respondents were nondemented (Short Blessed scores, 1.7 +/- 2.2). Predictors of intention to screen included perceived benefits (gamma = .35), knowledge of dementia (gamma = .26), self-efficacy (gamma = .23), preventive health behaviors (gamma = .17), and perceived susceptibility (gamma = .14). Knowledge was positively correlated with perceived benefits (phi = .29) and susceptibility (phi = .20). Preventive behaviors (phi = .20) were positively correlated with perceived benefits. Self-efficacy correlated positively with preventive behaviors (phi = .24) and perceived benefits (phi = .37) and negatively with perceived susceptibility (phi = -.11). Goodness-of-fit indices suggested a good fit of this model (root mean square error of approximation, .037; comparative fit index, 0.98; relative fit index; .96). DISCUSSION: Older adults who have knowledge of dementia and perceive benefit from diagnosis and treatment are more likely to exhibit willingness and confidence to be tested for cognitive problems. Individuals with high self-efficacy, perceived susceptibility, and positive preventive health behaviors are also more likely to exhibit intention. These constructs can now be used to develop interventions to evaluate cognitive health in the elderly

OBJECTIVE: To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. DESIGN: Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. SETTING: Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. MAIN OUTCOME MEASURES: Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. RESULTS: Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. CONCLUSIONS: LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322

Aggregation of amyloid-beta protein (Abeta) is a key pathogenic event in Alzheimer's disease (AD). Curcumin, a constituent of the Indian spice Turmeric is structurally similar to Congo Red and has been demonstrated to bind Abeta amyloid and prevent further oligomerization of Abeta monomers onto growing amyloid beta-sheets. Reasoning that oligomerization kinetics and mechanism of amyloid formation are similar in Parkinson's disease (PD) and AD, we investigated the effect of curcumin on alpha-synuclein (AS) protein aggregation. In vitro model of AS aggregation was developed by treatment of purified AS protein (wild-type) with 1 mM Fe3+ (Fenton reaction). It was observed that the addition of curcumin inhibited aggregation in a dose-dependent manner and increased AS solubility. The aggregation-inhibiting effect of curcumin was next investigated in cell culture utilizing catecholaminergic SH-SY5Y cell line. A model system was developed in which the red fluorescent protein (DsRed2) was fused with A53T mutant of AS and its aggregation examined under different concentrations of curcumin. To estimate aggregation in an unbiased manner, a protocol was developed in which the images were captured automatically through a high-throughput cell-based screening microscope. The obtained images were processed automatically for aggregates within a defined dimension of 1-6 microm. Greater than 32% decrease in mutant alpha-synuclein aggregation was observed within 48 h subsequent to curcumin addition. Our data suggest that curcumin inhibits AS oligomerization into higher molecular weight aggregates and therefore should be further explored as a potential therapeutic compound for PD and related disorders

Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopamine (DA) neurons and the presence of alpha-synuclein (AS) aggregates as Lewy bodies (LBs) in the remaining substantia nigra (SN) neurons. A continuing puzzle in studying PD pathogenesis is that although AS is expressed throughout the brain, LBs and selective dopaminergic cell loss lead to characteristic clinical signs of PD, suggesting that there is a link between AS aggregation and DA metabolism. One potential candidate for this link is the monoamine oxidase (MAO) metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as neither DA nor DA metabolites other than DOPAL are toxic to SN neurons at physiological concentrations. We tested DOPAL-induced AS aggregation in a cell-free system, in vitro in DA neuron cultures and in vivo with stereotactic injections into the SN of Sprague-Dawley rats by Western blots, fluorescent confocal microscopy and immunohistochemistry. We demonstrate that DOPAL in physiologically relevant concentrations, triggers AS aggregation in the cell-free system, and in cell cultures resulting in the formation of potentially toxic AS oligomers and aggregates. Furthermore, DOPAL injection into the SN of Sprague-Dawley rats resulted in DA neuron loss and the accumulation of high molecular weight oligomers of AS detected by Western blot. Our findings support the hypothesis that DA metabolism via DOPAL can cause both DA neuron loss and AS aggregation observed in PD

Deficits in attention are present early in the course of Alzheimer disease (AD). Acetylcholine receptors are appealing molecular targets for intervention as cholinergic pathways are involved in the neurobiology of attention. For this reason, measures of attention were included in 2 independent, multicenter, randomized, parallel, controlled trials in subjects with AD comparing the effects of galantamine, an acetylcholinesterase inhibitor and postulated nicotinic receptor modulator, and donepezil, an acetylcholinesterase inhibitor. The attention battery of the Cognitive Drug Research computerized assessment system was used in both trials. Small magnitude, positive signals were observed for simple and choice reaction times for both compounds. Attention task performance tended to improve early for galantamine-treated subjects. A consistent temporal pattern of improvement was not observed in donepezil-treated subjects. Quantitative findings appeared more pronounced in subjects with moderate AD. Galantamine's proposed action as a nicotinic receptor modulator may bear on these findings. Improved attention may have positive effects on cognitive and functional outcomes for AD patients, although this hypothesis requires further study and validation

Lewy body dementia (LBD) is the second most common dementia after Alzheimer's disease (AD). LBD is characterized clinically by visual hallucinations, extrapyramidal symptoms, cognitive fluctuations and neuroleptic sensitivity. LBD and AD share many common features in pathology, genetics and biochemical alterations; however, correct clinical distinction between these disorders has prognostic and therapeutic implications. There are currently no definitive radiological or biological markers for LBD, but studies suggest that premorbid differences in cognitive domains and personality traits, differences in clinical presentation, and alterations in autonomic function and sleep may improve diagnosis. Cholinergic dysfunction plays a major role in both AD and LBD; however, dysfunction is greater in LBD. This may account for the more prominent hallucinations, and offers the possibility of a greater response to cholinesterase inhibitors in LBD. The treatment of LBD is symptomatic and is based on a limited number of clinical trials and extension of results from trials in AD. Current research is focused on the role of synuclein aggregation with possible roles for synuclein-derived peptides as aggregation inhibitors. Other approaches target amyloid, neuroinflammation, oxidative injury, proteolysis, lipid peroxidation and immunotherapies with variable results. Improved understanding of disease mechanisms may open new therapeutic avenues for LBD in the future