Parkinson Disease: Wider C

Wider C, Wszolek ZK. · Department of Neurology, Cannaday Building 2E, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA. · Lancet Neurol. · Pubmed #19081502 No free full text.

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Wider C, Wszolek ZK. · Department of Neurology, Mayo Clinic, Jacksonville, Fla. 32224, USA. · Neurodegener Dis. · Pubmed #18322368 No free full text.

Abstract: Genetic studies have led to major discoveries in the pathogenesis of various neurodegenerative diseases. Ubiquitin-positive familial frontotemporal dementia was recently found to be caused by mutations in the progranulin gene (PGRN), and the major constituent of the inclusions, TDP-43, was subsequently identified. The tau gene (MAPT) causes frontotemporal dementia with parkinsonism linked to chromosome 17. In Parkinson disease, LRRK2 mutations have emerged as a major cause of both familial and sporadic forms, adding to the previously known genes SNCA,PRKN,DJ1 and PINK1. Several genes have been implicated in Alzheimer disease, including the APP gene and the PSEN genes. Recently, variants in the sortilin-related receptor 1 gene, SORL1, were associated with Alzheimer disease.

Wider C, Wszolek ZK. · Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA. · Parkinsonism Relat Disord. · Pubmed #18267241 No free full text.

Abstract: Our knowledge regarding the genetics of Parkinson's disease (PD) and parkinsonism has evolved dramatically during the past decade, with the discovery of numerous loci and genes. The LRRK2 gene has emerged as the most commonly involved in both familial and sporadic PD. Several variants in LRRK2 and SNCA have been associated with an increased risk of sporadic PD. PRKN, PINK1 and DJ1 mutations cause early-onset recessively inherited PD. Autosomal dominant dementia and parkinsonism is caused by mutations in the MAPT gene, and in the most recently discovered PGRN gene.

Wider C, Burkhard PR, Sajadi A, Vingerhoets FJ. · Service de neurologie, CHUV, 1011 Lausanne. · Rev Med Suisse. · Pubmed #16734187 No free full text.

Abstract: Neurodegenerative disorders represent a major and growing cause of morbidity and mortality in our populations, and a therapeutic challenge for the years to come. This paper reviews the mechanisms implicated in neuronal death, focusing on the model of Parkinson's disease. Available data are critically presented, and oriented in a therapeutic perspective. Neuroprotective strategies are mentioned, along with stem cell transplantation, growth factor production and gene therapy.

Wider C, Russmann H, Villemure JG, Robert B, Bogousslavsky J, Burkhard PR, Vingerhoets FJ. · Department of Neurology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland. · Arch Neurol. · Pubmed #16831963 links to  free full text

Abstract: BACKGROUND: Long-duration response (LDR) to levodopa is supposed to decrease with Parkinson disease (PD) progression, but direct observation of this response in advanced PD has never been performed. OBJECTIVE: To study the LDR to levodopa in patients with advanced PD treated with subthalamic deep brain stimulation (DBS). DESIGN AND SETTING: We studied 30 consecutive patients with PD who underwent subthalamic DBS. One group had no antiparkinsonian treatment since surgery (no-levodopa group), whereas medical treatment had to be reinitiated in the other group (levodopa group). MAIN OUTCOME MEASURE: Motor subscale score of the Unified Parkinson's Disease Rating Scale. RESULTS: Compared with preoperative assessment, evaluation 6 months postoperatively with DBS turned off for 3 hours found a worsening of the motor subscale score of the Unified Parkinson's Disease Rating Scale in the no-levodopa group. This worsening being absent in the levodopa group, it probably reflected the loss of the LDR to levodopa in the no-levodopa group. When DBS was turned on, postoperative motor subscale scores of the Unifid Parkinson's Disease Rating Scale in both groups were similar to preoperative scores while receiving medication, suggesting that subthalamic DBS compensated for the short-duration response and LDR to levodopa. CONCLUSIONS: Our results suggest that the LDR to levodopa remains significant even in advanced PD, and that subthalamic DBS compensates for the short-duration response and LDR to levodopa.

Vilariño-Güell C, Wider C, Soto-Ortolaza AI, Cobb SA, Kachergus JM, Keeling BH, Dachsel JC, Hulihan MM, Dickson DW, Wszolek ZK, Uitti RJ, Graff-Radford NR, Boeve BF, Josephs KA, Miller B, Boylan KB, Gwinn K, Adler CH, Aasly JO, Hentati F, Destée A, Krygowska-Wajs A, Chartier-Harlin MC, Ross OA, Rademakers R, Farrer MJ. · Molecular Genetics Laboratory and Core, Morris K. Udall Parkinson's Disease Research Center of Excellence, Mayo Clinic, Department of Neuroscience, 4500 San Pablo Road, Jacksonville, FL 32224, USA. · Neurology. · Pubmed #19506225 No free full text.

Abstract: OBJECTIVE: Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration. METHODS: In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS. RESULTS: This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case-control series did not identify any variants segregating with disease or associated with increased disease risk. CONCLUSIONS: This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis.

Wider C, Skipper L, Solida A, Brown L, Farrer M, Dickson D, Wszolek ZK, Vingerhoets FJ. · Department of Neurology, CHUV, Lausanne, Switzerland. · Parkinsonism Relat Disord. · Pubmed #18342564 No free full text.

Abstract: AIM: To describe a large family with autosomal dominant parkinsonism. BACKGROUND: Seven genes are directly implicated in autosomally inherited parkinsonism. However, there are several multigenerational large families known with no identifiable mutation. MATERIAL AND METHODS: Family members were evaluated clinically, by history and chart review. Genetic investigation included SCA2, SCA3, UCHL1, SNCA, LRRK2, PINK1, PRKN, PGRN, FMR1 premutation, and MAPT. The proband underwent brain fluorodopa PET (FD-PET) scan, and one autopsy was available. RESULTS: Eleven patients had a diagnosis of Parkinson's disease (PD), nine women. Mean age of onset was 52 with tremor-predominant dopa-responsive parkinsonism. Disease progression was slow but severe motor fluctuations occurred. One patient required subthalamic nucleus deep-brain stimulation with a good motor outcome. One patient had mental retardation, schizophrenia and became demented, and another patient was demented. Three patients and also two unaffected subjects had mild learning difficulties. All genetic tests yielded negative results. FD-PET showed marked asymmetric striatal tracer uptake deficiency, consistent with PD. Pathological examination demonstrated no Lewy bodies and immunostaining was negative for alpha-synuclein. CONCLUSION: Apart from a younger age of onset and a female predominance, the phenotype was indistinguishable from sporadic tremor-predominant PD, including FD-PET scan results. As known genetic causes of autosomal dominant PD were excluded, this family harbors a novel genetic defect.

Wider C, Pollo C, Bloch J, Burkhard PR, Vingerhoets FJ. · Department of Neurology, CHUV, Rue du Bugnon, 1011 Lausanne, Switzerland. · Parkinsonism Relat Disord. · Pubmed #17822940 No free full text.

Abstract: OBJECTIVE: To describe the long-term outcome in 50 consecutive advanced Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS). METHOD: Assessments were carried out at baseline, 6 months, 2 years, and 5 years postoperatively. RESULTS: Compared to baseline scores without medication, we found a highly significant improvement of UPDRS III with stimulation, maintained at 5 years (p<0.001). This improvement, however, tended to diminish over time. Dyskinesia and off periods were also improved (p<0.0001 for both). Seventeen patients died during follow-up, who tended to be older at surgery (p<0.01). CONCLUSIONS: STN-DBS is an effective treatment for advanced PD patients, and the beneficial effect is maintained at 5 years. However, worsening occurs over time due to disease progression.

Salarian A, Russmann H, Wider C, Burkhard PR, Vingerhoets FJ, Aminian K. · Laboratory of Movement Analysis and Measurement, Swiss Federal Institute of Technology, Lausanne (EPFL), 1015, Switzerland. · IEEE Trans Biomed Eng. · Pubmed #17278588 No free full text.

Abstract: An ambulatory system for quantification of tremor and bradykinesia in patients with Parkinson's disease (PD) is presented. To record movements of the upper extremities, a sensing units which included miniature gyroscopes, has been fixed to each of the forearms. An algorithm to detect and quantify tremor and another algorithm to quantify bradykinesia have been proposed and validated. Two clinical studies have been performed. In the first study, 10 PD patients and 10 control subjects participated in a 45-min protocol of 17 typical daily activities. The algorithm for tremor detection showed an overall sensitivity of 99.5% and a specificity of 94.2% in comparison to a video reference. The estimated tremor amplitude showed a high correlation to the Unified Parkinson's Disease Rating Scale (UPDRS) tremor subscore (e.g., r = 0.87, p < 0.001 for the roll axis). There was a high and significant correlation between the estimated bradykinesia related parameters estimated for the whole period of measurement and respective UPDRS subscore (e.g., r = -0.83, p < 0.001 for the roll axis). In the second study, movements of upper extremities of 11 PD patients were recorded for periods of 3-5 hr. The patients were moving freely during the measurements. The effects of selection of window size used to calculate tremor and bradykinesia related parameters on the correlation between UPDRS and these parameters were studied. By selecting a window similar to the period of the first study, similar correlations were obtained. Moreover, one of the bradykinesia related parameters showed significant correlation (r = -0.74, p < 0.01) to UPDRS with window sizes as short as 5 min. Our study provides evidence that objective, accurate and simultaneous assessment of tremor and bradykinesia can be achieved in free moving PD patients during their daily activities.

Wider C, Ghika J, Bogousslavsky J, Vingerhoets F. · Department of Neurology, University Hospital, Lausanne, Switzerland. · Mov Disord. · Pubmed #15300666 No free full text.

Abstract: Craniocervical muscles are the most frequently involved in dystonia, which can be either focal of segmental. While often experiencing an increase in dystonia with voluntary motor activity, many patients report temporary relief with geste antagoniste. We describe a patient who presented a peculiar craniocervical segmental dystonia, triggered by putting on glasses with a ribbon.