The Neurodegenerative Diseases Research Unit (NDRU) focuses on atypical parkinsonism syndromes to unravel molecular genetic mechanisms involved in the pathophysiology and to discover targets for rational therapeutic development. Over the last year we have undertaken several ambitious projects. In collaboration with the Johns Hopkins Pathology department, we performed exome sequencing of a pathologically confirmed cohort of dementia with Lewy bodies (DLB) patients. Our study found that 25% of cases carried either a high risk variant or causative mutation in one of three genes (GBA, PSEN1, APP). Further we confirmed that the APOE e4 allele significantly increases risk for disease and decreases survival. Taken together, these results highlight that genetic factors are playing a prominent role in the pathobiology of DLB, and strongly support the notion that DLB occurs along a spectrum between Parkinson disease and Alzheimer dementia. As part of a multi-center, international collaboration we performed a genome-wide association study in multiple system atrophy (MSA). This study found several interesting genetic loci that could reveal important insights into the disease etiology. Follow up replication studies of larger cohorts will have to be performed to confirm their role in MSA. Ongoing projects in our laboratory include: (1) genotype-phenotype analyses of pathologically confirmed atypical parkinsonism cohorts using custom-designed genotyping chips; (2) a genome-wide association study in DLB; (3) candidate gene analyses in MSA and DLB; and (4) a natural history study of atypical parkinsonism syndromes. In summary, we have successfully applied modern genomic approaches. The projects highlighted above have already identified several genetic variants that are implicated in the pathobiology of DLB and MSA. Additional follow-up studies are required for replication, fine-mapping and a more refined dissection of genetic factors involved in atypical parkinsonism syndromes.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
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
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
Geiger, Joshua T; Arthur, Karissa C; Dawson, Ted M et al. (2016) C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies. Neurodegener Dis 16:370-2
Federoff, M; Price, T R; Sailer, A et al. (2016) Genome-wide estimate of the heritability of Multiple System Atrophy. Parkinsonism Relat Disord 22:35-41
Geiger, Joshua T; Ding, Jinhui; Crain, Barbara et al. (2016) Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies. Neurobiol Dis 94:55-62
Scholz, Sonja W; Bras, Jose (2015) Genetics Underlying Atypical Parkinsonism and Related Neurodegenerative Disorders. Int J Mol Sci 16:24629-55
Scholz, Sonja W; Jeon, Beom S (2015) GBA mutations and Parkinson disease: when genotype meets phenotype. Neurology 84:866-7