Faculty Bibliography

The cellular mechanisms underlying neuronal loss and neurodegeneration have been an area of interest in the last decade. Although neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and Huntington disease each have distinct clinical symptoms and pathologies, they all share common mechanisms such as protein aggregation, oxidative injury, inflammation, apoptosis, and mitochondrial injury that contribute to neuronal loss. Although cerebrovascular disease has different causes from the neurodegenerative disorders, many of the same common disease mechanisms come into play following a stroke. Novel therapies that target each of these mechanisms may be effective in decreasing the risk of disease, abating symptoms, or slowing down their progression. Although most of these therapies are experimental, and require further investigation, a few seem to offer promise

BACKGROUND: Cognitive fluctuations are spontaneous alterations in cognition, attention, and arousal. Fluctuations are a core feature of dementia with Lewy bodies, but the impact of fluctuations in healthy brain aging and Alzheimer disease (AD) are unknown. METHODS: Research participants (n = 511, age 78.1 +/- 8 years, education 14.9 +/- 3 years) enrolled in a longitudinal study of memory and aging at the Washington University Alzheimer Disease Research Center were assessed for the presence and severity of dementia with the Clinical Dementia Rating (CDR) and a neuropsychological test battery. Informant assessments of fluctuations with the Mayo Fluctuations Questionnaire and daytime level of alertness with the Mayo Sleep Questionnaire were completed. RESULTS: After controlling for age and alertness level, participants with cognitive fluctuations (3 or 4 individual symptoms) were 4.6 times more likely to have dementia (95% confidence interval: 2.05, 10.40). Participants who presented with disorganized, illogical thinking were 7.8 times more likely to be rated CDR >0. The risk of being rated CDR 0.5 among those with fluctuations was 13.4 times higher than among those without fluctuations. The risk of being rated CDR 1 increased 34-fold among participants with fluctuations. Compared with participants without fluctuations, the presence of cognitive fluctuations corresponds to a decrease in performance across individual neuropsychological tests as well as composite scores. CONCLUSIONS: Cognitive fluctuations occur in Alzheimer disease and, when present, significantly affect both clinical rating of dementia severity and neuropsychological performance. Assessment of fluctuations should be considered in the evaluation of patients for cognitive disorders

OBJECTIVE: To compare longitudinal changes in the hippocampal structure in subjects with very mild dementia of the Alzheimer type (DAT) treated with donepezil hydrochloride, untreated subjects with very mild DAT, and controls without dementia. DESIGN: MPRAGE sequences were collected approximately 2 years apart on two 1.5-T magnetic resonance imaging systems, yielding 2 cohorts. Large-deformation high-dimensional brain mapping was used to compute deformation of hippocampal subfields. SETTING: A dementia clinic at Washington University School of Medicine. Patients or Other PARTICIPANTS: Subjects came from 2 sources: 18 untreated subjects with DAT and 26 controls were drawn from a previous longitudinal study; 18 treated subjects with DAT were studied prospectively, and 44 controls were drawn from a longitudinal study from the same period. Intervention Patients were prescribed donepezil by their physician. MAIN OUTCOME MEASURES: Hippocampal volume loss and surface deformation. RESULTS: There was no significant cohort effect at baseline; therefore, the 2 groups of control subjects were combined. The potential confounding effect of cohort/scanner was dealt with by including it as a covariate in statistical tests. There was no significant group effect in the rate of change of hippocampal volume or subfield deformation. Further exploration showed that compared with the untreated subjects with DAT, the treated subjects with DAT did not differ in the rate of change in any of the hippocampal measures. They also did not differ from the controls, while the untreated subjects with DAT differed from the controls in the rates of change of hippocampal volume and CA1 and subiculum subfield deformations. CONCLUSIONS: Treatment with donepezil did not alter the progression of hippocampal deformation in subjects with DAT in this study. Small sample size may have contributed to this outcome

BACKGROUND: Detection of the earliest cognitive changes signifying Alzheimer disease is difficult. OBJECTIVE: To model the cognitive decline in preclinical Alzheimer disease. DESIGN: Longitudinal archival study comparing individuals who became demented during follow-up and people who remained nondemented on each of 4 cognitive factors: global, verbal memory, visuospatial, and working memory. SETTING: Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri. PARTICIPANTS: One hundred thirty-four individuals who became demented during follow-up and 310 who remained nondemented. MAIN OUTCOME MEASURES: Inflection point in longitudinal cognitive performance. RESULTS: The best-fitting model for each of the 4 factors in the stable group was linear, with a very slight downward trend on all but the Visuospatial factor. In contrast, a piecewise model with accelerated slope after a sharp inflection point provided the best fit for the group that progressed. The optimal inflection point for all 4 factors was prior to diagnosis of dementia: Global, 2 years; Verbal and Working Memory, 1 year; and Visuospatial, 3 years. These results were also obtained when data were limited to the subset (n = 44) with autopsy-confirmed Alzheimer disease. CONCLUSIONS: There is a sharp inflection point followed by accelerating decline in multiple domains of cognition, not just memory, in the preclinical period in Alzheimer disease when there is insufficient cognitive decline to warrant clinical diagnosis using conventional criteria. Early change was seen in tests of visuospatial ability, most of which were speeded. Research into early detection of cognitive disorders using only episodic memory tasks may not be sensitive to all of the early manifestations of disease

BACKGROUND: Inadequate recruitment into Alzheimer disease clinical trials is an important threat to the validity and generalizability of the studies. The majority of dementia patients are first evaluated by community-based physicians; however, physician perceptions of clinical research are largely unknown. METHODS: A survey was distributed to 3123 physicians in 3 states; 370 were returned. Survey items assessed attitudes, perceived benefits of and barriers to referral to clinical research, and physicians use of the internet for medical information. RESULTS: The mean age of the respondents was 50.6+/-10.8 years; 70% were male, 78% white, 61% were primary care providers; 63% used the internet > or =3 times/week. No demographic or medical specialty differences existed between those who were likely (n=193) and unlikely (n=162) to refer patients to clinical trials. Differences were discovered in perceived benefits reported by physicians who were more likely to refer, whereas differences in perceived barriers existed in primary care compared with specialists. Referral to clinical trials is predicted by close proximity to a research center [odds ratio (OR): 4.0; 95% confidence interval (CI), 1.1-15.6] and availability of internet information regarding diagnostic evaluation (OR: 2.3; 95% CI, 1.1-4.7). Primary barriers included concerns about exposure of patients to uncomfortable procedures (OR: 4.7; 95% CI, 1.2-18.7) and lack of time to discuss research participation (OR: 6.8; 95% CI, 1.4-32.3). CONCLUSIONS: Proximity to a research center and availability of diagnostic clinical tools are strong predictors of clinical trial referral. Concern over risks to patients and lack of time are strong barriers. These results suggest that dementia outreach education targeted to physicians should emphasize the importance of clinical trials with a focus on discussing research participation in a time-efficient manner and increasing awareness of risk reduction and the safety of research protocols. Providing easy access to up-to-date, user-friendly educational materials on dementia diagnosis and research via the internet are likely to improve referrals of patients to Alzheimer disease clinical trials from community physicians

STUDY OBJECTIVES: Parkinson disease (PD) is the second most common neurodegenerative disorder in the United States. It is associated with motor deficits, sleep disturbances, and cognitive impairment. The pathology associated with PD and the effects of sleep deprivation impinge, in part, upon common molecular pathways suggesting that sleep loss may be particularly deleterious to the degenerating brain. Thus we investigated the long-term consequences of sleep deprivation on shortterm memory using a Drosophila model of Parkinson disease. PARTICIPANTS: Transgenic strains of Drosophila melanogaster. DESIGN: Using the GAL4-UAS system, human alpha-synuclein was expressed throughout the nervous system of adult flies. Alpha-synuclein expressing flies (alpha S flies) and the corresponding genetic background controls were sleep deprived for 12 h at age 16 days and allowed to recover undisturbed for at least 3 days. Short-term memory was evaluated using aversive phototaxis suppression. Dopaminergic systems were assessed using mRNA profiling and immunohistochemistry. MEASURMENTS AND RESULTS: When sleep deprived at an intermediate stage of the pathology, alpha S flies showed persistent short-term memory deficits that lasted > or = 3 days. Cognitive deficits were not observed in younger alpha S flies nor in genetic background controls. Long-term impairments were not associated with accelerated loss of dopaminergic neurons. However mRNA expression of the dopamine receptors dDA1 and DAMB were significantly increased in sleep deprived alpha S flies. Blocking D1-like receptors during sleep deprivation prevented persistent shortterm memory deficits. Importantly, feeding flies the polyphenolic compound curcumin blocked long-term learning deficits. CONCLUSIONS: These data emphasize the importance of sleep in a degenerating/reorganizing brain and shows that pathological processes induced by sleep deprivation can be dissected at the molecular and cellular level using Drosophila genetics