title: Intact working memory in non-manifesting LRRK2 carriers--an fMRI study.
abstract: Cognitive impairments are prevalent in patients with Parkinson's disease. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of genetic Parkinsonism. Non-manifesting carriers of the G2019S mutation in the LRRK2 gene were found to have lower executive functions as measured by the Stroop task. This exploratory study aimed to assess whether the cognitive impairment in non-manifesting carriers is specific for executive functions or includes other cognitive domains such as working memory. We recruited 77 non-manifesting first-degree relatives of Parkinson's disease patients (38 carriers). A block-design fMRI N-back task, with 0-back, 2-back and 3-back conditions, was used in order to assess working memory. Participants were well matched on the Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test, Unified Parkinson's Disease Rating Scale part III, digit span, age, gender and Beck Depression Inventory. The task achieved the overall expected effect in both groups with longer reaction times and lower accuracy rates with increasing task demands. However, no whole-brain or region-of-interest between-groups differences were found on any of the task conditions. These results indicate that non-manifesting carriers of the G2019S mutation in the LRRK2 gene have a specific cognitive profile with executive functions, as assessed by the Stroop task, demonstrating significant impairment but with working memory, as assessed with the N-back task, remaining relatively intact. These finding shed light on the pre-motor cognitive changes in this unique 'at risk' population and should enable more focused cognitive assessments of these cohorts.
authors.affiliation: Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv, 64239, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Functional Brain Center, Wohl Institute for Advanced Imaging, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Avner
authors.initials: A
authors.lastname: Thaler
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Rick C
authors.initials: RC
authors.lastname: Helmich
authors.affiliation: Functional Brain Center, Wohl Institute for Advanced Imaging, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Or-Borichev
authors.affiliation: Department of Neurology, Catharina Hospital, Eindhoven, The Netherlands.
authors.forename: Bart F L
authors.initials: BF
authors.lastname: van Nuenen
authors.affiliation: Functional Brain Center, Wohl Institute for Advanced Imaging, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Shapira-Lichter
authors.affiliation: Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv, 64239, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tanya
authors.initials: T
authors.lastname: Gurevich
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Genetic Institute, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Orr-Urtreger
authors.affiliation: Columbia University Medical Center, Columbia University, New-York, NY, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Marder
authors.affiliation: Beth Israel Medical Center, New York, NY, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Bressman
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Bastiaan R
authors.initials: BR
authors.lastname: Bloem
authors.affiliation: Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv, 64239, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Sieratzki Chair in Neurology, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Giladi
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Functional Brain Center, Wohl Institute for Advanced Imaging, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.|Sagol School for Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Talma
authors.initials: T
authors.lastname: Hendler
authors.affiliation: Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv, 64239, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Mirelman
mesh_terms: D000328:Adult; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D056344:Executive Function / Q000502:physiology*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D057190:Stroop Test
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: G2019S; LRRK2; N-back; fMRI; working memory