Clinical Correlations With Lewy Body Pathology in LRRK2-Related Parkinson Disease | Dementia and Cognitive Impairment | JAMA Neurology | JAMA Network
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Case Report/Case Series
January 2015

Clinical Correlations With Lewy Body Pathology in LRRK2-Related Parkinson Disease

Author Affiliations
  • 1The Edmond J. Safra Program in Parkinson’s Disease, University Health Network, Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 2Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  • 3Mayo Clinic, Jacksonville, Florida
  • 4University of Pennsylvania, Philadelphia
  • 5Columbia University, New York, New York
  • 6Hospital Clínic de Barcelona, Universitat de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain
  • 7Hospital Universitario Donostia, CIBERNED, San Sebastián, Spain
  • 8Bellvitge University Hospital, L’ Hospitalet de Llobregat, Barcelona, Spain
  • 9Veterans Affairs Medical Center, San Francisco, California
  • 10The Parkinson’s Institute, Sunnyvale, California
  • 11St Olavs Hospital, Trondheim, Norway
  • 12University of Turin, Turin, Italy
  • 13Erasmus MC, Rotterdam, the Netherlands
  • 14Skåne University Hospital and Lund University, Lund, Sweden
  • 15Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy
  • 16Centre Hospitalier Universitaire La Timone, Marseille, France
  • 17Sagamihara National Hospital, Kanagawa, Japan
  • 18Sorbonne Université, Pierre and Marie Curie University, Institut du Cerveau et de la Moelle Epinière, Institut National de la Santé et de la Recherche Médicale, Centre national de la recherche scientique, Paris, France
  • 19University of British Columbia, Vancouver, British Columbia, Canada
JAMA Neurol. 2015;72(1):100-105. doi:10.1001/jamaneurol.2014.2704

Importance  Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of genetic Parkinson disease (PD) known to date. The clinical features of manifesting LRRK2 mutation carriers are generally indistinguishable from those of patients with sporadic PD. However, some PD cases associated with LRRK2 mutations lack Lewy bodies (LBs), a neuropathological hallmark of PD. We investigated whether the presence or absence of LBs correlates with different clinical features in LRRK2-related PD.

Observations  We describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013. Among the different mutations, the LRRK2 p.G2019S mutation was most frequently associated with LB pathology. Nonmotor features of cognitive impairment/dementia, anxiety, and orthostatic hypotension were correlated with the presence of LBs. In contrast, a primarily motor phenotype was associated with a lack of LBs.

Conclusions and Relevance  To our knowledge, this is the first report of clinicopathological correlations in a series of LRRK2-related PD cases. Findings from this selected group of patients with PD demonstrated that parkinsonian motor features can occur in the absence of LBs. However, LB pathology in LRRK2-related PD may be a marker for a broader parkinsonian symptom complex including cognitive impairment.