Mechanisms of Hybrid Oligomer Formation in the Pathogenesis of Combined Alzheimer's and Parkinson's Diseases

Background: Misfolding and pathological aggregation of neuronal proteins has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are frequent neurodegenerative diseases of the aging population. While progressive accumulation of amyloid b protein (Ab) oligomers has been identified as one of the central toxic events in AD, accumulation of a-synuclein (a-syn) resulting in the formation of oligomers and protofibrils has been linked to PD and Lewy body Disease (LBD). We have recently shown that Ab promotes a-syn aggregation and toxic conversion in vivo, suggesting that abnormal interactions between misfolded proteins might contribute to disease pathogenesis. However the molecular characteristics and consequences of these interactions are not completely clear. Methodology/Principal Findings: In order to understand the molecular mechanisms involved in potential Ab/a-syn interactions, immunoblot, molecular modeling, and in vitro studies with a-syn and Ab were performed. We showed in vivo in the brains of patients with AD/PD and in transgenic mice, Ab and a-synuclein co-immunoprecipitate and form complexes. Molecular modeling and simulations showed that Ab binds a-syn monomers, homodimers, and trimers, forming hybrid ringlike pentamers. Interactions occurred between the N-terminus of Ab and the N-terminus and C-terminus of a-syn. Interacting a-syn and Ab dimers that dock on the membrane incorporated additional a-syn molecules, leading to th

Donepezil for cognitive impairment in Parkinson's disease: a randomised controlled study

Objective: To study the safety and efficacy of the cholinesterase inhibitor donepezil in patients with Parkinson's disease (PD) and cognitive impairment. Methods: This was a double blind, randomised and placebo controlled, crossover study in which 14 patients with PD and cognitive impairment received donepezil (5 or 10 mg per day) or matching placebo during two sequential periods lasting 10 weeks each. The primary outcome measures were the mini mental state examination (MMSE) score, the clinician's interview based impression of change plus caregiver input (CIBIC+) score, and the motor subscale of the unified Parkinson's disease rating scale (UPDRS). Results: Two patients on donepezil (14%) dropped out after one and four weeks of the first treatment period because of peripheral cholinergic side effects, otherwise the adverse effects were few and not severe. Carryover or residual effects were not observed. Parkinsonism did not increase during donepezil treatment. After 10 weeks of treatment, the mean MMSE score was increased by 2.1(SD 2.7) points on donepezil and 0.3 (SD 3.2) points on placebo, and the CIBIC+ score was 3.3 (SD 0.9) on donepezil and 4.1 (SD 0.8) on placebo. Statistical analysis of the repeated measurements and crossover study design showed significant effects of donepezil compared with placebo for MMSE (p=0.013) and CIBIC+ (p=0.034). Five (42%) patients on donepezil and two (17%) on placebo were rated as improved on the basis of the CIBIC+ score. Conclusions: Donepezil improves cognition, and seems to be well tolerated and not to worsen parkinsonism in patients with cognitive impairment

Causal inference with recurrent and competing events

Many research questions concern treatment effects on outcomes that can recur several times in the same individual. For example, medical researchers are interested in treatment effects on hospitalizations in heart failure patients and sports injuries in athletes. Competing events, such as death, complicate causal inference in studies of recurrent events because once a competing event occurs, an individual cannot have more recurrent events. Several statistical estimands have been studied in recurrent event settings, with and without competing events. However, the causal interpretations of these estimands, and the conditions that are required to identify these estimands from observed data, have yet to be formalized. Here we use a formal framework for causal inference to formulate several causal estimands in recurrent event settings, with and without competing events. When competing events exist, we clarify when commonly used classical statistical estimands can be interpreted as causal quantities from the causal mediation literature, such as (controlled) direct effects and total effects. Furthermore, we show that recent results on interventionist mediation estimands allow us to define new causal estimands with recurrent and competing events that may be of particular clinical relevance in many subject matter settings. We use causal directed acyclic graphs and single world intervention graphs to illustrate how to reason about identification conditions for the various causal estimands based on subject matter knowledge. Furthermore, using results on counting processes, we show that our causal estimands and their identification conditions, which are articulated in discrete time, converge to classical continuous time counterparts in the limit of fine discretizations of time. We propose estimators and establish their consistency for the various identifying functionals. Finally, we use the proposed estimators to compute the effect of blood pressure lowering treatment on the recurrence of acute kidney injury using data from the Systolic Blood Pressure Intervention Trial.BIOSTA

Mapping Cortical Atrophy in Parkinson's Disease Patients with Dementia

BACKGROUND: Cognitive impairment is very common in patients with Parkinson's disease (PD). Brain changes accompanying cognitive decline in PD are still not fully established. METHODS: We applied cortical pattern matching and cortical thickness analyses to the three-dimensional T1-weighted brain MRI scans of 14 age-matched cognitively normal elderly (NC), 12 cognitively normal PD (PDC), and 11 PD dementia (PDD) subjects. We used linear regression models to investigate the effect of diagnosis on cortical thickness. All maps were adjusted for multiple comparisons using permutation testing with a threshold p < 0.01. RESULTS: PDD showed significantly thinner bilateral sensorimotor, perisylvian, lateral parietal, as well as right posterior cingulate, parieto-occipital, inferior temporal and lateral frontal cortices relative to NC (left p(corrected) = 0.06, right p(corrected) = 0.009). PDD showed significantly thinner bilateral sensorimotor, right frontal and right parietal-occipital cortices relative to PDC (right p(corrected) = 0.05). The absolute difference in cortical thickness between PDD and the other diagnostic groups ranged from 3% to 19%. CONCLUSION: Our data shows that cognitive decline in PD is associated with cortical atrophy. PDD subjects have the most widespread gray matter atrophy suggesting more cortical involvement as PD patients progress to dementia

Ethanolic Extract of Garcinia mangostana l. pericarp as Preservative in Antacid suspension

Objective. The study was conducted to determine the preservative activity of ethanolic extract of mangosteen (Garcinia mangostana L.) pericarp and its compatibility in an antacid suspension.&#x0D; Methods. The extract was subjected to phytochemical screening and was used as preservative in a formulated antacid suspension. Compatibility with the active pharmaceutical ingredient (API) and excipients were analyzed using fourier transform-infrared spectroscopy. Preservative activity of the formulation against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa was assessed using the United States Pharmacopoeia (USP) antimicrobial effectiveness test, with methylparaben as positive control and suspension without preservative as negative control.&#x0D; Results. The extract exhibited pharmaceutical compatibility with API and excipients. The formulation revealed comparable reduction in microbial count of E. coli, S. aureus, and P. aeruginosa with positive control at Day 14 (p=0.916, 0.624, 0.335). At Day 28, comparable activity with positive control was only observed against E. coli and S. aureus (p=0.999, 0.854). However, it displayed significant increase in activity against P. aeruginosa (p=0.010) at Day 28. These activities may be attributed to glycosides and reducing substances present in the extract.&#x0D; Conclusion. The ethanolic extract from Garcinia mangostana L. pericarp acted as a preservative in the formulation of an antacid suspension. It conformed to the USP criteria for antimicrobial effectiveness test on bacteria.</jats:p

Mild cognitive impairment in Parkinson disease: A multicenter pooled analysis

Background: In studies of mild cognitive impairment (MCI) in Parkinson disease (PD), patients without dementia have reported variable prevalences and profiles of MCI, likely to be due to methodologic differences between the studies.Objective: The objective of this study was to determine frequency and the profile of MCI in a large, multicenter cohort of well-defined patients with PD using a standardized analytic method and a common definition of MCI.Methods: A total of 1,346 patients with PD from 8 different cohorts were included. Standardized analysis of verbal memory, visuospatial, and attentional/executive abilities was performed. Subjects were classified as having MCI if their age-and education-corrected z score on one or more cognitive domains was at least 1.5 standard deviations below the mean of either control subjects or normative data.Results: A total of 25.8% of subjects (95% confidence interval [CI] 23.5-28.2) were classified as having MCI. Memory impairment was most common (13.3%; 11.6-15.3), followed by visuospatial (11.0%; 9.4-13.0) and attention/executive ability impairment (10.1%; 8.6-11.9). Regarding cognitive profiles, 11.3% (9.7-13.1) were classified as nonamnestic single-domain MCI, 8.9% (7.0-9.9) as amnestic single-domain, 4.8% (3.8-6.1) as amnestic multiple-domain, and 1.3% (0.9-2.1) as nonamnestic multiple-domain MCI. Having MCI was associated with older age at assessment and at disease onset, male gender, depression, more severe motor symptoms, and advanced disease stage.Conclusions: MCI is common in patients with PD without dementia, affecting a range of cognitive domains, including memory, visual-spatial, and attention/executive abilities. Future studies of patients with PD with MCI need to determine risk factors for ongoing cognitive decline and assess interventions at a predementia stage. Neurology (R) 2010;75:1062-106