Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer's disease.

The aim of this exploratory investigation was to determine if genetic variation within amyloid precursor protein (APP) or its processing enzymes correlates with APP cleavage product levels: APPα, APPß or Aß42, in cerebrospinal fluid (CSF) of cognitively normal subjects or Alzheimer's disease (AD) patients. Cognitively normal control subjects (n = 170) and AD patients (n = 92) were genotyped for 19 putative regulatory tagging SNPs within 9 genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN and APH1B) involved in the APP processing pathway. SNP genotypes were tested for their association with CSF APPα, APPß, and Aß42, AD risk and age-at-onset while taking into account age, gender, race and APOE ε4. After adjusting for multiple comparisons, a significant association was found between ADAM10 SNP rs514049 and APPα levels. In controls, the rs514049 CC genotype had higher APPα levels than the CA, AA collapsed genotype, whereas the opposite effect was seen in AD patients. These results suggest that genetic variation within ADAM10, an APP processing gene, influences CSF APPα levels in an AD specific manner.

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease.

A number of distinct beta-amyloid (Abeta) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Abeta-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Abeta and amyloidogenic non-Abeta species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of Abeta and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Abeta1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Abeta, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Abeta toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Abeta the monkeys developed high titers not only against Abeta peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Abeta antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.

Cycad exposure and risk of dementia, MCI, and PDC in the Chamorro population of Guam.

OBJECTIVE: To study cycad-derived products as possible risk factors for dementia, mild cognitive impairment (MCI), and parkinsonism-dementia complex (PDC) on Guam. METHODS: Complete risk factor data from in-person interviews of 166 cases of Guam dementia, 50 cases of amnestic MCI, and 21 cases of PDC were compared with 1,581 controls in the base population regarding exposure to cycad-derived products from a traditional food (fadang), consumption of fruit bats, and use of cycad-derived topical medicine. RESULTS: Adjusted odds ratios (ORs) and 95% CIs for picking, processing, and eating fadang in young adulthood ranged from 1.42 (1.05 to 1.91) to 2.87 (1.48 to 5.56) and were consistently elevated and significant across all three diagnostic outcomes. Associations independent of exposure in young adulthood were for picking (OR 0.78, 95% CI 0.64 to 0.96) and processing (OR 0.77, 95% CI 0.63 to 0.94) fadang in childhood with Guam dementia. Men showed stronger and more consistent relations across exposure groups in young adulthood compared with women. No associations were found for consumption of fruit bats or exposure to cycad used as a topical medicine for any of the outcomes. Estimated adjusted population attributable risks suggest that exposure to eating fadang in young adulthood incurred the highest attributable risk percent. CONCLUSIONS: Environmental lifestyle and diet may contribute to the etiology of neurodegenerative diseases in the native population of Guam.

Neuromotor abnormalities and risk for psychosis in Alzheimer's disease.

BACKGROUND: Cross-sectional studies in Alzheimer's disease (AD) show a strong relationship between extrapyramidal motor signs and presence of psychosis, yet it remains unclear whether neuromotor abnormalities precede and therefore can predict development of psychosis in AD. OBJECTIVE: To identify cognitive and motor risk factors for the development of psychosis in patients with AD. METHODS: Baseline clinical motor ratings and instrumental measures of neuromuscular function were obtained from 54 nonpsychotic patients with AD who were evaluated annually for 2 years for the development of psychosis. Survival analyses were performed to identify incidence and risks associated with psychosis. RESULTS: The incidence of new onset psychosis in our sample was 32.5% in 2 years. Patients with abnormal agonist muscle burst amplitudes during rapid alternating movements of the hand were more likely to develop psychosis than those without (OR = 4.31; p = 0.007). Women with AD also had a higher risk of developing psychosis within 2 years than men (OR = 1.33; p = 0.01). CONCLUSIONS: Using simple noninvasive instrumental procedures for assessing neuromotor function, it may be possible to identify an individual's level of risk for developing psychosis during the course of AD.

Extrapyramidal signs and cognitive abilities in Alzheimer's disease.

OBJECTIVE: To evaluate whether the relationship between extrapyramidal signs (EPS) and cognitive disturbances in Alzheimer's disease (AD) is influenced by illness duration. METHODS: A multivariate regression analysis was used to study the relationships between EPS, illness duration and five cognitive ability areas based on the Mattis Dementia Rating Scale (DRS) in 89 clinically diagnosed AD patients with extrapyramidal motor involvement. RESULTS: Severity of EPS was statistically associated with performance on four cognitive ability areas from the DRS including: attention, initiation and perseveration, construction and memory. Age was a significant factor related to severity of EPS. However illness duration did not contribute to the strength of the association between EPS and cognitive disturbances in patients with AD. CONCLUSIONS: The findings of the present study support the notion that while neuropsychological and motor functions often coexist in patients with AD, their relationship seems to be unrelated to degenerative processes that accumulate throughout the illness.

Measuring cognitive change in a cohort of patients with Alzheimer's disease.

Annualized rates of cognitive change in Alzheimer's disease (AD), an important index of disease progression, show marked variability. To determine factors leading to such variability, we computed rates of change in a cohort of patients with AD tested annually with the Mini Mental State Examination (MMSE) and the more detailed Dementia Rating Scale (DRS). Estimates of rates of change (slopes) and intercepts were calculated using least squares and best linear unbiased predictors (BLUPs). Potential predictors of rates of change were examined using multivariate linear regression analysis. We found that the MMSE had more noise than the DRS. For the MMSE, slopes showed a moderate floor effect and a slight ceiling, depending on initial MMSE scores. These effects were less prominent for the DRS, for which slopes increased as intercepts decreased. In analyses of predictors of change, the MMSE was less useful than the DRS. In multiple linear regression models using DRS data, predictors showed statistically stronger effects and explained a greater extent of variation of slopes than did similar models using MMSE data. For example, among patients who died and underwent brain examination at autopsy, neuropathology of Lewy bodies plus AD (Lewy Body variant; LBV) was associated with significantly faster rates of cognitive decline compared to pure AD in analyses that used the DRS, but only trends were identified with the MMSE. The metric properties and longitudinal characteristics of cognitive tests and the statistical methods used to calculate change are key factors in obtaining reliable estimates of change in studying cohorts of patients with AD.

Amyloid-beta peptides interact with plasma proteins and erythrocytes: implications for their quantitation in plasma.

Amyloid beta peptides are bound rapidly in the plasma complicating an accurate assessment of their in vivo abundance by immunoassay procedures. The extent of Abeta immunoassay interference was used to estimate the Abeta binding capacity of purified plasma proteins, erythrocytes and whole plasma. Human serum albumin bound Abeta peptides rapidly with a 1:1 stoichiometry and at physiological concentrations was capable of binding over 95% of an input of 5 ng/ml Abeta. Purified alpha2-macroglobulin was able to bind Abeta peptides and at physiological concentration bound 73% of 5 ng/ml of Abeta. Erythrocytes also sequestered the Abeta peptides, showing a preference for binding Abeta 1-42. Incubation of 5 ng/ml of Abeta in plasma revealed that about 30% of the peptides were still detectable by immunoassay, presumably reflecting the binding of Abeta peptides with albumin and other plasma molecules. Thus, our studies reveal that both the soluble and formed elements of the blood are capable of sequestering Abeta peptides. To avoid underestimating plasma Abeta values, we employed an improved column chromatography method under denaturing conditions to liberate Abeta from its associations with plasma proteins. Quantification of Abeta 40 and 42 levels in plasma from both normal and AD individuals after chromatography showed a large overlap between AD and control groups, despite the very large pool of Abeta present in the AD brains. The potential origins of the plasma Abeta pool are discussed.

Quantifying drug-induced changes in parkinsonian rigidity using an instrumental measure of activated stiffness.

We review the literature on quantifying parkinsonian rigidity and present data from 124 subjects to demonstrate the clinical utility of activated stiffness to model rigidity. This method eliminates many of the confounding variables associated with the subjective assessment of rigidity. This 5-min computer-assisted procedure was highly reliable and sensitive to pharmacologic influences that produce and reduce parkinsonian rigidity.