A cognitive fMRI study in non-manifesting LRRK2 and GBA carriers

Abstract

Mutations in the GBA and LRRK2 genes account for one-third of the prevalence of Parkinson’s disease (PD) in Ashkenazi Jews. Non-manifesting carriers (NMC) of these mutations represent a population at risk for future development of PD. PD patient who carry mutations in the GBA gene demonstrates more significant cognitive decline compared to idiopathic PD patients. We assessed cognitive domains using fMRI among NMC of both LRRK2 and GBA mutations to better understand pre-motor cognitive functions in these populations. Twenty-one LRRK2-NMC, 10 GBA-NMC, and 22 non-manifesting non-carriers (NMNC) who participated in this study were evaluated using the standard questionnaires and scanned while performing two separate cognitive tasks; a Stroop interference task and an N-Back working memory task. Cerebral activation patterns were assessed using both whole brain and predefined region of interest (ROI) analysis. Subjects were well matched in all demographic and clinical characteristics. On the Stroop task, in spite of similar behavior, GBA-NMC demonstrated increased task-related activity in the right medial frontal gyrus and reduced task-related activity in the left lingual gyrus compared to both LRRK2-NMC and NMNC. In addition, GBA-NMC had higher activation patterns in the incongruent task compared to NMNC in the left medial frontal gyrus and bilateral precentral gyrus. No whole-brain differences were noted between groups on the N-Back task. Paired cognitive and task-related performance between GBA-NMC, LRRK2-NMC, and NMNC could indicate that the higher activation patterns in the incongruent Stroop condition among GBA-NMC compared to LRRK2-NMC and NMNC may represent a compensatory mechanism that enables adequate cognitive performance.

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Acknowledgments

We thank the participants of this project for their participation and the Michael J Fox Foundation for Parkinson’s research for their support.

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Correspondence to Avner Thaler.

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Conflict of interest

Avner Thaler: reports receiving a travel grant from the 14th and 16th MDS congress. Tanya Gurevich: reports receiving funding for travel and speaker honoraria from the National Parkinson Foundation, Solvay pharmaceuticals, TEVA, RAFA, Medtronic, Novartis, Medison, Allergan, GlaxoSmithKline, Perrigo, and Intecpharma. Avi Orr-Urtreger: reports receiving research support from the Israeli Science Foundation Legacy Heritage Fund, the Chief Scientist Department of Health, Israel, the ALS Association USA, and the Kahn Foundation Israel. Karen Marder: reports receiving research support through Columbia University from the Parkinson Disease Foundation, MJFF, Huntington Disease Society of America, Parkinson Study Group, CHDI, and being a section editor for Current Neurology and Neuroscience. Susan Bressman: reports being on the scientific advisory board of Bachmann Strauss Dystonia and Parkinson’s Foundation, MJFF and Dystonia Medical Research Foundation. Nir Giladi: reports serving on the advisory boards o, Teva-Lundbeck, NeuroDerm, Intec Pharma, Lysosomal Therapeutics, Dexel Ltd and Chairing the Data monitoring safety committee of Teva LTD and Pharma2B. Received funding for travel and honoraria from Teva-Lundbeck, UCB, NeuroDerm. Serves on the editorial board of Journal of Parkinson’s Disease. Being a consultant for, NeuroDerm, Intec Pharma and Lysosomal Therapeutic Inc. Received grants from the NPF, Israeli Science Foundation, NIH, MJFF, and FP7 of the EU.

Funding

This work was supported by the Michael J Fox Foundation for Parkinson research and the Netherlands Organization for Scientific Research (NWO; VIDI Grant No. 016.076.352 to B.R.B.).

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N. Bregman and A. Thaler contributed equally to this work.

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Bregman, N., Thaler, A., Mirelman, A. et al. A cognitive fMRI study in non-manifesting LRRK2 and GBA carriers. Brain Struct Funct 222, 1207–1218 (2017). https://doi.org/10.1007/s00429-016-1271-4

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Keywords

  • GBA
  • LRRK2
  • fMRI
  • Stroop
  • N-Back