Young H. Sohn

Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study

BACKGROUND Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinsons disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. METHODS LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinsons Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. FINDINGS 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012). INTERPRETATION The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. FUNDING Michael J Fox Foundation and National Institutes of Health.

A randomized trial of mesenchymal stem cells in multiple system atrophy

Neuroprotective or regenerative strategies are invaluable in multiple system atrophy (MSA) due to its rapid progression with fatal prognosis. We evaluated the efficacy of autologous mesenchymal stem cells (MSC) in patients with MSA‐cerebellar type (MSA‐C).

Surround inhibition in human motor system.

In sensory systems, a neural mechanism called surround inhibition (SI) sharpens sensation by creating an inhibitory zone around the central core of activation. In the motor system, the functional operation of SI remains to be demonstrated, although it has been hypothesized to contribute to the selection of voluntary movements. Here we test this hypothesis by using transcranial magnetic stimulation of the human motor cortex. The motor evoked potential of the little finger muscle is suppressed or unchanged during self-paced, voluntary movements of the index finger, mouth or leg, despite an increase in spinal excitability. This result indicates that motor excitability related to little finger movement is suppressed at the supraspinal level during these movements, and supports the idea that SI is an organizational principle of the motor system.

Arterial Pulsatility as an Index of Cerebral Microangiopathy in Diabetes

BACKGROUND AND PURPOSE This study was designed to evaluate cerebral hemodynamic changes related to diabetes mellitus (DM) with transcranial Doppler ultrasonography (TCD). METHODS We measured the flow velocities and the Gosling pulsatility index (PI) of the middle cerebral artery (MCA), extracranial internal carotid artery (ICA), and basilar artery (BA) in 56 stroke-free, normotensive patients with type 2 DM and 70 age- and gender-matched healthy volunteers. Patients were divided into 2 groups according to the presence of microvascular complications such as retinopathy, nephropathy, and neuropathy. RESULTS Patients showed slightly lower hematocrit and higher serum fibrinogen levels than control subjects, but other clinical profiles, including stroke risk factors except for diabetes, were comparable between patients and controls. The flow velocity of the ICA but not the MCA and BA in patients regardless of the complication was significantly higher than that in controls. The PIs of the MCA and ICA were significantly higher in patients with complication than those without complication, as well as in controls. The PI of the BA was also significantly higher, even in patients without complication, than in controls. The PIs of the MCA and ICA but not the BA were closely correlated with the duration of DM (r(2)=0.46 and 0.34, respectively). CONCLUSIONS This study defines TCD findings of diabetes-related cerebral hemodynamic changes and suggests that the PI reflects microangiopathic changes of cerebral vessels.

The pattern of cortical atrophy in patients with Parkinson's disease according to cognitive status.

Background: Cognitive dysfunction is common in Parkinsons disease (PD), and along with PD with dementia (PDD), the concept of mild cognitive impairment in PD (PD‐MCI) has been introduced. Methods: To identify structural candidates according to cognitive status in PD, we compared gray matter (GM) density across PD‐intact cognition (PD‐IC, n = 23), PD‐MCI (n = 27), and PDD (n = 18) using voxel‐based morphometry. Results: The demographic data among PD subjects were similar, however, general cognition and disease duration were more severe in PD‐MCI and PDD than in PD‐IC. Compared with controls, GM density was significantly decreased in the left occipital area in PD‐IC; the bilateral temporal, left prefrontal and insular, and right occipital areas in PD‐MCI; and in widespread brain areas in PDD. Compared with PD‐IC, patients with PD‐MCI had significantly decreased GM density in the right middle frontal area, and those with PDD had decreased GM density in the right parietal, middle frontal, insular, and lentiform areas. GM density in patients with PDD was significantly decreased in the bilateral middle temporal, right inferior temporal, and left middle and superior prefrontal areas. PDD patients with shorter disease duration before dementia (<5 year) showed greater GM atrophy in the posterior cingulate area than did those with longer disease duration (≥5 year). Conclusions: These data suggest that cortical atrophy in PD exhibits a greater extent with increasing levels of cognitive impairment, and different anatomical substrates would correspond to each cognitive status.

Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease

Mutations in five PARK genes (SNCA, PARKIN, DJ-1, PINK1, and LRRK2) are well-established genetic causes of Parkinson disease (PD). Recently, G2385R substitution in LRRK2 has been determined as a susceptibility allele in Asian PD. The objective of this study is to determine the frequency of mutations in these PARK genes in a Korean early-onset Parkinson disease (EOPD) cohort. The authors sequenced 35 exons in SNCA, PARKIN, DJ-1, PINK1, and LRRK2 in 72 unrelated EOPD (age-at-onset ≤50) recruited from ten movement disorders clinics in South Korea. Gene dosage change of the aforementioned genes was studied using multiple ligation-dependent probe amplification. We found four patients with PARKIN mutations, which were homozygous deletion of exon 4, compound heterozygous deletion of exon 2 and exon 4, heterozygous deletion of exon 4, and heterozygous nonsense mutation (Q40X). Four patients had PINK1 mutations; a compound heterozygous mutation (N367S and K520RfsX522) and three heterozygous mutations (G32R, R279H, and F385L). A missense mutation of SNCA (A53T) was found in a familial PD with autosomal dominant inheritance. Nine patients (12.5%) had heterozygous G2385R polymorphism of LRRK2, whereas none had G2019S mutation. However, no mutations were detected in DJ-1 and UCHL1 in our series. We identified genetic variants in PARKIN, PINK1, LRRK2, and SNCA as a cause or genetic risk factors for PD in 25% of Korean EOPD, and mutation of PARKIN was the most common genetic cause.

A comparative analysis of cognitive profiles and white matter alterations using voxel-based diffusion tensor imaging between patients with Parkinson's disease dementia and dementia with Lewy bodies

Background Despite clinical and neuropsychological similarities between Parkinsons disease dementia (PDD) and dementia with Lewy bodies (DLB), recent studies have demonstrated that structural and pathological changes are more severe in DLB than in PDD. Methods 19 patients with probable PDD and 18 patients with probable DLB who had a similar overall severity of dementia and demographic characteristics were examined by a standardised neuropsychological test and voxel-based analysis of fractional anisotropy (FA) using diffusion tensor imaging (DTI). Results The patients with DLB performed significantly worse in visual recognition memory, semantic fluency and ideomotor praxis than those with PDD (p<0.05). Compared with controls, the FA value in patients with PDD was significantly lower in bilateral frontal, left temporal and left parietal white matter. In patients with DLB, the pattern of FA reduction was similar to that of patients with PDD; however, white-matter abnormalities were more severe and extended into bilateral insular, bilateral posterior cingular and bilateral visual association regions. In a direct comparison between PDD and DLB, the FA value in patients with DLB was significantly decreased in bilateral posterior temporal, posterior cingular and bilateral visual association fibres extending into occipital areas. Conclusions Despite global similarities in cognitive performance and white-matter pathology between DLB and PDD patients, those with DLB had more severely impaired frontal and temporal area-associated cognitive subsets, and more severe white-matter pathology in temporal and visual association fibres. These data suggest that differences in the underlying nature of PDD and DLB may exist with global similarities in their cognitive performance and white-matter pathology.

Factors contributing to the development of restless legs syndrome in patients with Parkinson disease

Although restless legs syndrome (RLS) commonly accompanies Parkinson disease (PD), the mechanism of RLS development in PD is still unclear. We investigated the prevalence of RLS in Korean patients with PD, and the possible contributing factors to the development of RLS in those patients. Four hundred forty‐seven consecutive patients with PD were interviewed and examined. Among them, 73 patients (16.3%) were diagnosed with RLS. PD patients with RLS had a longer duration of PD symptoms, more severe PD disability, a greater degree of cognitive decline, and a longer duration of antiparkinson therapy than those without RLS. Multivariate logistic regression analysis revealed that the duration of antiparkinson therapy was the most significant factor contributing to the development of RLS in patients with PD. The present results support a higher prevalence of RLS in patients with PD and suggest that long‐term antiparkinson therapy, rather than PD itself, may contribute to the development of RLS.

Exploratory analysis of neuropsychological and neuroanatomical correlates of progressive mild cognitive impairment in Parkinson's disease

Background Parkinsons disease with mild cognitive impairment (PD-MCI) is a heterogeneous entity in terms of cognitive profiles and conversion to dementia. However, the risk factors for ongoing cognitive decline in patients with PD-MCI are not clearly defined. Methods 51 patients with PD-MCI were prospectively followed-up for a minimum of 2 years. Subjects were classified as MCI converters (n=15) or MCI non-converters (n=36) based on whether they were subsequently diagnosed with PD dementia. We explored cognitive profiles and neuroanatomical characteristics of PD-MCI converters using voxel based morphometry (VBM) of grey matter (GM) density and region of interest based volumetric analysis of the substantia innominata (SI). Results PD-MCI converters showed more severe cognitive deficits in frontal executive functions, immediate verbal memory and visual recognition memory compared with PD-MCI non-converters. VBM analysis revealed that PD-MCI converters had significantly lower GM density in the left prefrontal areas, left insular cortex and bilateral caudate nucleus compared with that in PD-MCI non-converters. The mean normalised SI volume was significantly smaller in both PD-MCI converters (1.19±0.35, p<0.001) and PD-MCI non-converters (1.52±0.27, p<0.001) compared with that in controls (1.87±0.19). PD-MCI converters had a significantly smaller normalised SI volume than PD-MCI non-converters (p<0.001). Conclusions Our data show that atrophy in the frontostriatal areas and cholinergic structures, as well as frontal lobe associated cognitive performance, may act as predictors of dementia in PD-MCI patients, suggesting distinctive patterns of cognitive profiles and a neuroanatomical basis for progressive PD-MCI.

Factors related to clinically probable REM sleep behavior disorder in Parkinson disease

Rapid eye movement sleep behavior disorder (RBD) is commonly accompanied in Parkinson disease (PD). However, the underlying mechanism linking RBD to PD remains unclear. We interviewed and examined 447 consecutive patients with PD to investigate factors associated with the presence of RBD in PD patients. Using the minimal diagnostic criteria for parasomnias provided in the International Classification of Sleep Disorders-Revised (ICSD-R), 164 patients (36.5%) were diagnosed with clinically probable RBD (cpRBD). PD patients with cpRBD were older, had a longer duration of PD, a more severe level of disability, a longer duration of antiparkinsonian medication, and a lower proportion of their Unified Parkinson Disease Rating Scale (UPDRS) scores accounted for by tremor than those without RBD. Multivariate and univariate logistic regression analyses revealed that patient age, PD symptom duration (and, accordingly, more severe motor disability), tremor score, and proportion of the UPDRS score accounted for by tremor were significant factors associated with the presence of RBD in PD patients. The results of the present study support previous observations that PD with RBD may result from a different underlying pattern of neurodegeneration than PD without RBD.