Faculty Bibliography

Parkinson disease (PD) is the most common neurodegenerative movement disorder, affecting 1 in 100 individuals over the age of 60. Dementia in the setting of PD (PDD) may be among the most debilitating symptoms associated with disease progression. Estimates of cognitive decline and dementia in PD suggest that up to 14% per year of patients over age 65 with PD will develop some cognitive impairment. Unfortunately, PDD is not well characterized and the relationship of PDD to Alzheimer disease remains unclear. PDD has been proposed as part of a spectrum with dementia with Lewy bodies, and PDD and dementia with Lewy bodies frequently coexist with Alzheimer disease. It is uncertain, however, whether there is a meaningful distinction between the different disorders. It has also been difficult to gain understanding of the interaction of motor and non-motor symptoms that affect quality of life in PD and confound cognitive and psychomotor performance. This review will examine the clinical, cognitive, neuropsychiatric features of cognitive deficits associated with PD, discuss their pathologic basis and propose avenues for future research

Parkinson's disease (PD) is the most common movement disorder. Major disease symptoms are due to the loss of dopaminergic (DA) neurons in substantia nigra (SN). The pathologic hallmark of PD is Lewy bodies (LBs) in the SN and the major protein in LBs is alpha-synuclein (AS). A plethora of evidence points towards the culpability of AS in the pathogenesis of PD including: (1) linkage of AS mutations to familial forms of PD, (2) triplication of the AS locus causing PD, and (3) overexpression of AS in transgenic mice and Drosophila leads to PD-like phenotypes. Studies of purified AS have revealed its ability to interact with diverse molecules including monoamines. Monoamine metabolism is associated with oxidative stress conditions that may contribute to DA-AS interactions promoting aggregation and neuronal damage. However, in order to explain the selective vulnerability of DA neurons there needs to be a link between DA metabolism and AS aggregation. Since only the DA neurons contain significant amounts of DA, this has been hypothesized to account for the selective vulnerability of SN neurons. However, DA itself may not be toxic at physiologic relevant doses, so it is probable that other DA metabolites may play a major role in AS aggregation. In this review, we discuss the role of the DA metabolite 3,4-dihydroxyphenylacetaldehyde to provide a plausible link between DA production and metabolism, AS aggregation and the pathogenesis of PD

Alzheimer disease research has focused on detecting the earliest signs of cognitive decline and efforts are ongoing to develop biomarkers and cognitive measures that reliably distinguish between nondemented and demented individuals. However, little is known about factors that may directly or indirectly influence screening behavior of older community-dwelling adults. We describe an iterative process for the development and formative evaluation of a questionnaire about dementia knowledge and screening behaviors in older adults to understand the psychosocial factors underlying intention to obtain dementia screening to profile individuals manifesting intention to undergo dementia screening compared to those who will not. The Behavioral Model of Health Services Use was used as a conceptual framework for a questionnaire with constructs from the Health Belief Model, Theory of Reasoned Action and Self-Efficacy. After pretesting, we used a random dialing strategy to test our questionnaire on a final sample of 1024 older Missourians. Internal consistency and construct validity were examined. Pretesting identified several potential problems that were improved with rewording. Cronbach alpha was greater than 0.6 (range 0.62 to 0.92) in all but one construct testing dementia knowledge, suggesting good to excellent internal consistency. Convergent (construct) validity was assessed using confirmatory factor analysis. All constructs but 3 demonstrated good validity. Addressing these issues will allow researchers to identify unique characteristics based on age, race, sex, socioeconomic differences and geographic location, and characterize barriers to screening programs to more effectively develop targeted community-based interventions

LY450139 dihydrate, a gamma-secretase inhibitor, was studied in a randomized, controlled trial of 70 patients with Alzheimer disease. Subjects were given 30 mg for 1 week followed by 40 mg for 5 weeks. Treatment was well tolerated. Abeta(1-40) in plasma decreased by 38.2%; in CSF, Abeta(1-40) decreased by 4.42 +/- 9.55% (p = not significant). Higher drug doses may result in additional decreases in plasma Abeta concentrations and a measurable decrease in CSF Abeta

Parkinson's disease (PD) is characterized by the polymerization of wild-type (WT) or mutant alpha-synuclein (AS) into aggregates and fibrils, which are observed as Lewy bodies (LBs) and Lewy neurites (LNs) in PD patients. However, inability to demonstrate aggregation in many cell culture systems is a major drawback for effective in vitro modeling of AS aggregation. Utilizing PCR-based cloning approach, we generated A30P, A53T, and the recently reported E46K encoding mutation in the KTKEGV repeat region of AS gene. While cloning E46K mutant, a glycine deletion mutation (E46KDeltaG) adjacent to the intended lysine mutation was serendipitously generated. Expression of mutant constructs and green fluorescent protein (GFP)-tagged mutant constructs in catecholaminergic SH-SY5Y (5Y) cells revealed 40% of AS-E46KDeltaG and 18% of AS-E46K transfected cells formed aggregates as compared to 12% in AS-A53T, 6% in AS-WT, and 2% in AS-A30P transfected cells. Western blot analysis demonstrated the formation of high molecular weight AS aggregates. Electron microscopic analysis of 5Y cells expressing the E46K and E46KDeltaG mutants demonstrated two distinct kinds of inclusions: Type I, which showed dense granular profile; and Type II, which were largely membranous vacuolar inclusions without granular material. These two inclusions are reminiscent of Lewy bodies and pale bodies observed in PD postmortem brain samples. Our results demonstrate that mutations in 4th KTKEGV repeat lead to higher propensity of aggregation of AS compared to other mutants