Rare Variants in PLXNA4 and Parkinson's Disease.

Approximately 20% of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset familial PD followed by frequency assessment in 975 PD cases and 1014 ethnically-matched controls and linkage analysis to identify potentially causal variants. Based on the predicted penetrance and the frequencies, a variant in PLXNA4 proved to be the best candidate and PLXNA4 was screened for additional variants in 862 PD cases and 940 controls, revealing an excess of rare non-synonymous coding variants in PLXNA4 in individuals with PD. Although we cannot conclude that the variant in PLXNA4 is indeed the causative variant, these findings are interesting in the light of a surfacing role of axonal guidance mechanisms in neurodegenerative disorders but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance

Loss of thalamic serotonin transporters in early drug-naïve Parkinson’s disease patients is associated with tremor: an [123I]β-CIT SPECT study

In vitro studies revealed serotonin transporter (5-HTT) decline in Parkinson’s disease (PD). Yet, few studies investigated thalamic 5-HTT in vivo and its effect on PD heterogeneity. We analyzed thalamic [123I]β-CIT binding (mainly reflecting 5-HTT binding) in 32 drug-naïve PD patients and 13 controls with SPECT. Twenty-six patients were examined twice (17 months apart). Based on UPDRS scores, we identified subgroups of patients with moderate/severe tremor (PDT) and without tremor (PDWT) at the time of clinical diagnosis. Additionally, depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at baseline. Mean thalamic specific to non-specific [123I]β-CIT binding ratio was lower in patients when compared to controls, and further decreased during follow-up. At baseline, average thalamic ratio was significantly lower in the PDT than in the PDWT subgroup. No correlation was found between BDI scores and thalamic binding ratios. Our findings show decline of [123I]β-CIT binding to thalamic 5-HTT in PD and its possible contribution to tremor onset

A medial to lateral shift in pre-movement cortical activity in hemi-Parkinson's disease

Objective: Recent evidence suggests that cortical activity associated with voluntary movement is relatively shifted from medial to lateral premotor areas in Parkinson's disease. This shift occurs bilaterally even for unilateral responses. It is not clear whether the shift in processing reflects an overall change in movement strategy, thereby involving alternate cortical areas, or reflects a compensatory change whereby, given the appropriate conditions, less impaired cortical areas are able to provide a similar function in compensation for those areas which are more impaired. This issue was examined in patients with hemi-Parkinson's disease, in whom basal ganglia impairment is most pronounced in one hemisphere. Methods: Fourteen patients with hemi-Parkinson's disease and 15 age-matched control subjects performed a Go/NoGo finger movement task and the contingent negative variation (CNV) was recorded from 21 scalp positions. Results and conclusions: Maximal CNV amplitudes were found over central medial regions for control subjects, but were shifted more frontally for Parkinson's disease patients, reduced in amplitude over the midline and lateralized towards the side ipsilateral to the greatest basal ganglia impairment. This shift in cortical activity from medial to lateral areas in Parkinson's disease patients appears to reflect a compensatory mechanism operating predominantly on the side of greatest basal ganglia impairment. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved

[123I]beta-CIT SPECT distinguishes vascular parkinsonism from Parkinson's disease.

We investigated whether [(123)I]-beta-CIT and single-photon emission computed tomography (SPECT) imaging distinguishes patients with clinically suspected vascular parkinsonism (VP) from patients with idiopathic Parkinson's disease (PD). [(123)I]beta-CIT SPECT is a sensitive marker of dopaminergic degeneration, and the degree of striatal binding reduction in PD correlates with disease severity. Thirteen patients who fulfilled rigid clinical criteria for VP (mean +/- S.D.: age, 76.5 +/- 5.3 years; disease duration, 3.6 +/- 2.8 years), 20 PD patients (age, 66.2 +/- 9.5 years; disease duration, 4.3 +/- 2.7 years), and 30 healthy persons (age, 44.6 +/- 19.2 years) underwent [(123)I]beta-CIT SPECT imaging. Age-corrected striatal beta-CIT binding was reduced on average by 40.8% in PD but was near normal in the VP group (mean reduction, 1.2%). This difference was statistically significant (Z = 4.68; P < 0.001). The left-right asymmetry of striatal beta-CIT binding was significantly increased in the PD group compared with normal controls and the VP group (F(2) = 17.4, P <0.001). Moreover, putamen-caudate nucleus ratios were significantly reduced in PD compared with both VP patients and healthy controls (F(2) = 65.5, P < 0.001). Whole striatal beta-CIT binding was more than one standard deviation above the mean PD values in all but one of the individual VP patients. Our findings suggest that the presynaptic dopaminergic deficits seen in PD are absent in most patients with VP. [(123)I]beta-CIT SPECT imaging may be useful to help distinguish between PD and VP patients during life

The role of SCARB2 as susceptibility factor in Parkinson's disease

Background Genetic variation in the glucocerebrosidase (GBA) gene is strongly associated with Parkinson's disease (PD). Transport of glucocerebrosidase to the lysosome involves the protein encoded by the SCARB2 gene. An association between the common SNP rs6812193, upstream of SCARB2, and PD has been reported previously. The role of exonic variants in the SCARB2 gene in PD has not been examined. Methods We studied the role of exonic variants in SCARB2 and tried to replicate the association between the SNP rs6812193 and PD in a German and Austrian sample. Screening of all SCARB2 exons by high-resolution melting curve analysis was performed in 376 German PD patients. The SNP rs6812193 was analyzed in 984 PD patients and 1014 general population controls. Results We identified no novel exonic variants in SCARB2 but confirmed the association between SNP rs6812193 and PD (OR, 0.86; P=.02). (c) 2013 Movement Disorder Societ