Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease.
OBJECTIVE
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.


METHODS
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describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013.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
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.
The Edmond J. Safra Program in Parkinson's Disease, University Health Network, Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Lorraine V
LV
Kalia
The Edmond J. Safra Program in Parkinson's Disease, University Health Network, Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Anthony E
AE
Lang
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Lili-Naz
LN
Hazrati
Mayo Clinic, Jacksonville, Florida.
Shinsuke
S
Fujioka
Mayo Clinic, Jacksonville, Florida.
Zbigniew K
ZK
Wszolek
Mayo Clinic, Jacksonville, Florida.
Dennis W
DW
Dickson
Mayo Clinic, Jacksonville, Florida.
Owen A
OA
Ross
University of Pennsylvania, Philadelphia.
Vivianna M
VM
Van Deerlin
University of Pennsylvania, Philadelphia.
John Q
JQ
Trojanowski
University of Pennsylvania, Philadelphia.
Howard I
HI
Hurtig
Columbia University, New York, New York.
Roy N
RN
Alcalay
Columbia University, New York, New York.
Karen S
KS
Marder
Columbia University, New York, New York.
Lorraine N
LN
Clark
Hospital Clínic de Barcelona, Universitat de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain.
Carles
C
Gaig
Hospital Clínic de Barcelona, Universitat de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain.
Eduardo
E
Tolosa
Hospital Universitario Donostia, CIBERNED, San Sebastián, Spain.
Javier
J
Ruiz-Martínez
Hospital Universitario Donostia, CIBERNED, San Sebastián, Spain.
Jose F
JF
Marti-Masso
Bellvitge University Hospital, L' Hospitalet de Llobregat, Barcelona, Spain.
Isidre
I
Ferrer
Hospital Universitario Donostia, CIBERNED, San Sebastián, Spain.
Adolfo
A
López de Munain
Veterans Affairs Medical Center, San Francisco, California.
Samuel M
SM
Goldman
The Parkinson's Institute, Sunnyvale, California.
Birgitt
B
Schüle
The Parkinson's Institute, Sunnyvale, California.
J William
JW
Langston
St Olavs Hospital, Trondheim, Norway.
Jan O
JO
Aasly
University of Turin, Turin, Italy.
Maria T
MT
Giordana
Erasmus MC, Rotterdam, the Netherlands.
Vincenzo
V
Bonifati
Skåne University Hospital and Lund University, Lund, Sweden.
Andreas
A
Puschmann
Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy.
Margherita
M
Canesi
Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy.
Gianni
G
Pezzoli
Centre Hospitalier Universitaire La Timone, Marseille, France.
Andre
A
Maues De Paula
Sagamihara National Hospital, Kanagawa, Japan.
Kazuko
K
Hasegawa
Sorbonne 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.
Charles
C
Duyckaerts
Sorbonne 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.
Alexis
A
Brice
University of British Columbia, Vancouver, British Columbia, Canada.
A Jon
AJ
Stoessl
The Edmond J. Safra Program in Parkinson's Disease, University Health Network, Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Connie
C
Marras
D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016631:Lewy Bodies / Q000473:pathology*; D008297:Male; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012720:Severity of Illness Index; D013223:Statistics as Topic
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases