The Neurodegenerative Diseases Research Unit (NDRU) focuses on atypical parkinsonism syndromes to unravel molecular genetic mechanisms involved in the pathophysiology, to study molecular relationships to more common neurodegenerative diseases and to discover targets for rational therapeutic development. Over the last year, we have undertaken several ambitious projects. 1. As part of a large consortium effort, we have been involved in the development of a genotyping array called the NeuroChip. This genotyping platform is designed for rapid, affordable, comprehensive and high-throughput genotyping of genetic mutations and risk variants associated with neurological diseases, including atypical parkinsonism syndromes. We have optimized, annotated and validated the content of the NeuroChip (Blauwendraat et al, Neurobiology of Aging, 2017). This platform will be useful for molecular diagnostics and genetic research. 2. We performed NeuroChip genotyping in cohorts with neurodegenerative dementias, including Alzheimers disease, Lewy body dementia and progressive supranuclear palsy. We applied machine learning to pathologically confirmed cohorts diagnosed with these dementia syndromes. When we tested the derived algorithms in additional cohorts, we found that our models can successfully discriminate patients from control subjects based on genetic data. This highlights the potential ability of using machine learning as ancillary diagnostic tools. Such research could improve early diagnosis of neurodegenerative dementias. 3. We performed NeuroChip genotyping on diverse neurodegenerative diseases from brain banks across North America and collaborating sites in Europe. Evaluations of genotype-phenotype correlations are currently ongoing. 4. We are part of an ambitious intramural genome sequencing project that will generate a unique resource for genetic research in non-Alzheimer dementias. Specifically, this project will produce genome sequence data of 2000 Lewy body dementia cases, 2000 frontotemporal dementia cases and 1500 neurologically healthy controls. The overall aim of this ongoing project is to expand genetic discovery efforts to non-Alzheimer dementias. All data will be made publicly available to the research community.

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Nicolas, Aude (see original citation for additional authors) (2018) Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron 97:1268-1283.e6
Guerreiro, Rita; Ross, Owen A; Kun-Rodrigues, Celia et al. (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64-74
Blauwendraat, Cornelis; Reed, Xylena; Kia, Demis A et al. (2018) Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease. JAMA Neurol :
Blauwendraat, Cornelis; Kia, Demis A; Pihlstrøm, Lasse et al. (2018) Insufficient evidence for pathogenicity of SNCA His50Gln (H50Q) in Parkinson's disease. Neurobiol Aging 64:159.e5-159.e8
Chen, Xi; Scholz, Sonja W (2018) Identification of new ?-synuclein regulator by nontraditional drug development pipeline. Mov Disord 33:402
Geiger, Joshua T; Schindler, Alice B; Blauwendraat, Cornelis et al. (2017) TUBB2B Mutation in an Adult Patient with Myoclonus-Dystonia. Case Rep Neurol 9:216-221
Blauwendraat, Cornelis; Faghri, Faraz; Pihlstrom, Lasse et al. (2017) NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases. Neurobiol Aging 57:247.e9-247.e13
Scholz, Sonja W (2017) Restless legs syndrome: is it all in the genes? Lancet Neurol 16:859-860
Blauwendraat, Cornelis; Nalls, Mike A; Federoff, Monica et al. (2017) ADORA1 mutations are not a common cause of Parkinson's disease and dementia with Lewy bodies. Mov Disord 32:298-299
Scholz, Sonja W; Houlden, Henry (2017) Author response: A genome-wide association study in multiple system atrophy. Neurology 88:1296-1297

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