Neural correlates of executive functions in healthy G2019S LRRK2 mutation carriers.
BACKGROUND
The G2019S mutation in the leucine rich repeat kinase 2 (LRRK2) gene is prevalent among Ashkenazi Jewish patients with Parkinson's disease (PD). Cognitive deficits are common in early stage PD. We aimed to characterize the effect of the G2019S mutation on neural mechanisms of executive function processing by testing whether healthy mutation carriers who are an "at risk" population for the future development of PD differed from non-carriers on an functional magnetic resonance imaging (fMRI) Stroop interference task.


METHODS
Cognitive performance and task related cerebral activity were measured in 40 healthy first-degree relatives of Ashkenazi PD patients (19 carriers and 21 non-carriers of the G2019S mutation). Both regional differences in neural activity and seed region driven functional connectivity methods were performed using fMRI.


RESULTS
Compared to non-carriers, mutation carriers had greater baseline deactivation and increased task related activity in the right inferior parietal lobe, right precuneus and right fusiform gyrus. Whole brain functional connectivity analysis revealed stronger coupling between these regions and both basal ganglia structures as well as cortical regions in the carrier group. Non-manifesting G2019S mutation carriers and non-carriers performed similarly on the task and on all other assessed measures, so behavioral differences in task performance and baseline cognitive functions cannot explain the observed imaging differences.


CONCLUSIONS
G2019S carriers, at risk for developing PD, had similar behavioral performance as non-carriers during the Stroop task, but increased activity in brain regions that have previously been found to be part of the ventral attention system together with stronger coupling between task related areas and structures that make up the ventral and dorsal attention system as well as the basal ganglia-thalamocortical network. This suggests a neural compensatory mechanism that enables intact cognitive performance in asymptomatic mutation carriers.
Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: avnerth@gmail.com.
Avner
A
Thaler
Anat
A
Mirelman
Rick C
RC
Helmich
Bart F L
BF
van Nuenen
Keren
K
Rosenberg-Katz
Tanya
T
Gurevich
Avi
A
Orr-Urtreger
Karen
K
Marder
Susan
S
Bressman
Bastiaan R
BR
Bloem
Nir
N
Giladi
Talma
T
Hendler
D000328:Adult; D000368:Aged; D056344:Executive Function / Q000502:physiology*; D005260:Female; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D013647:Task Performance and Analysis
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
Executive functions; LRRK2; Parkinson's disease; Stroop task