Adler, Charles H.

The objective is to examine the risk of dementia in subjects with essential tremor (ET) involved in the Arizona Study of Aging and Neurodegenerative Disorders. All subjects were free of a neurodegenerative diagnosis at baseline and had annual motor, general neurological, and neuropsychological assessments. Subjects with ET were compared with controls for the risk of dementia. There were 83 subjects with ET and 424 subjects without tremor. Mean age at study entry was 80±5.9 for ET and 76±8.5 for controls. Median tremor duration was 5.2 years at study entry. Followup was a median of 5.4 years (range 0.9 to 12.1). The hazard ratio for the association between ET and dementia was 0.79 (95% CI 0.33 to 1.85). The hazard ratio for the association between tremor onset at age 65 or over, versus onset before age 65, was 2.1 (95% CI 0.24 to 18) and the hazard ratio for the association between tremor duration greater than 5 years, versus less than 5 years, was 0.46 (95% CI 0.08 to 2.6). We conclude that all elderly ET was not associated with an increased risk of dementia but that a subset of subjects with older age onset/shorter duration tremor may be at higher risk.

ABSTRACTThe recent formalization of clinical criteria for Parkinson's disease with dementia (PDD) codifies many studies on this topic, including those assessing biological correlates. These studies show that the emergence of PDD occurs on the background of severe dopamine deficits with, the main pathological drivers of cognitive decline being a synergistic effect between alpha‐synuclein and Alzheimer's disease pathology. The presence of these pathologies correlates with a marked loss of limbic and cortically projecting dopamine, noradrenaline, serotonin, and acetylcholine neurons, although the exact timing of these relationships remains to be determined. Genetic factors, such as triplications in the α‐synuclein gene, lead to a clear increased risk of PDD, whereas others, such as parkin mutations, are associated with a reduced risk of PDD. The very recent formalization of clinical criteria for PD with mild cognitive impairment (PD‐MCI) allows only speculation on its biological and genetic bases. Critical assessment of animal models shows that chronic low‐dose MPTP treatment in primates recapitulates PD‐MCI over time, enhancing the current biological concept of PD‐MCI as having enhanced dopamine deficiency in frontostriatal pathways as well as involvement of other neurotransmitter systems. Data from other animal models support multiple transmitter involvement in cognitive impairment in PD. Whereas dopamine dysfunction has been highlighted because of its obvious role in PD, the role of the other neurotransmitter systems, neurodegenerative pathologies, and genetic factors in PD‐MCI remains to be fully elucidated. © 2014 International Parkinson and Movement Disorder Society

ABSTRACT There has been controversy as to whether there is an underlying neurodegenerative process of the cerebellum in essential tremor (ET). The aim of this study was to examine whether ET is associated with Purkinje cell (PC) loss. Prospectively categorized ET and control subjects who were longitudinally examined in the Arizona Study for Aging and Neurodegenerative Disorders and came to autopsy between 1998 and 2013 underwent standardized neuropathological assessment of the brain. PC linear density of the cerebellar hemisphere was calculated in a blinded manner. There were 56 ET cases and 62 age‐matched controls free of dementia and other neurodegenerative disorders included in the study. Mean PC linear density was 3.80 ± 0.81 cells per mm for tremor cases and 3.82 ± 0.91 cells per mm for controls ( Δ 0.02; 95% confidence interval [CI]: −0.30‐0.34). PC counts were not associated with tremor duration (r = 0.06; 95% CI: −0.21‐0.32). These data demonstrate that ET is not associated with cerebellar PC loss. © 2014 International Parkinson and Movement Disorder Society

ABSTRACT Parkinson's disease (PD) biomarkers are needed to enhance therapeutics research and to understand PD pathogenesis. Methods that simultaneously measure hundreds of small molecular‐weight compounds—metabolomic analysis–“fingerprint” disease‐specific alterations in individual compounds or metabolic pathways. Beyond a nontargeted search for PD biomarkers, we hypothesized that PD cerebrospinal fluid would show increased formation of the excitotoxin 3‐hydroxykynurenine and diminished concentration of the antioxidant glutathione. Cerebrospinal fluid was collected at <4 hours postmortem from 48 pathologically‐verified PD subjects and 57 comparably‐aged controls. Assays involved ultra‐high‐performance liquid and gas chromatography linked to mass spectrometry. We used univariate techniques to determine fold‐changes in concentrations of biochemicals; false‐discovery rates were calculated to exclude spurious findings. Data was modeled using a Support Vector Machine for analyzing compounds selected by Welch's t test. Classification accuracy was determined by cross‐validation. Of 243 structurally‐identified biochemicals,19 compounds differentiated PD from controls at a 20% false‐discovery level. In PD, mean 3‐hydroxykynurenine concentration was increased by one‐third, and mean oxidized glutathione was decreased by 40% (for each, P < .01). Four of the 19 compounds differentiating PD from controls were N‐acetylated amino acids, suggesting a generalized alteration in N‐acetylation activity. The Support Vector Machine classification model distinguished between groups at 83% sensitivity and 91% specificity for the learning data, and at 65% and 79% from cross‐validation. In this study, the first for metabolomic profiling of PD cerebrospinal fluid, we found several novel biomarkers and offer new directions for recognizing disease‐specific biochemical indicators. The findings support involvement of excitotoxicity and oxidative stress in the pathogenesis of PD. © 2013 International Parkinson and Movement Disorder Society

Identifying biomarkers that distinguish Parkinson's disease (PD) from normal control (NC) individuals has the potential to increase diagnostic sensitivity for the detection of early-stage PD. A previous proteomic study identified potential biomarkers in postmortem ventricular cerebrospinal fluid (V-CSF) from neuropathologically diagnosed PD subjects lacking Alzheimer's disease (AD) neuropathology. In the present study, we assessed these biomarkers as well as p-tau 181 , Aβ42, and S100B by ELISA in PD (n = 43) and NC (n = 49) cases. The p-tau 181 /Aβ42 ratio and ApoA-1 showed statistically significant differences between groups. Multiple regression analysis demonstrated that p-tau 181 /Aβ42 had a significant odds ratio: OR = 1.42 (95% confidence interval [CI], 1.12–1.84), P = 0.006. Among the molecules investigated, intriguing correlations were observed that require further investigation. Our results suggest coexistent AD CSF biomarkers within the PD group notwithstanding that it was selected to minimize AD neuropathological lesions.