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The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: a cross-sectional PET study.
Lancet Neurol 2018; 17(4):309-316LN

Abstract

BACKGROUND

Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinson's disease.

METHODS

Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinson's disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N-11C-methyl-piperidin-4-yl propionate to scan for acetylcholinesterase activity. The primary outcome measure was rate of acetylcholinesterase hydrolysis, calculated using the striatal input method. We compared acetylcholinesterase hydrolysis rates between groups using ANCOVA, with adjustment for age based on the results of linear regression analysis.

FINDINGS

We recruited 14 patients with LRRK2 Parkinson's disease, 16 LRRK2 mutation carriers without Parkinson's disease, eight patients with idiopathic Parkinson's disease, and 11 healthy controls. We noted significant between-group differences in rates of acetylcholinesterase hydrolysis in cortical regions (average cortex p=0·009, default mode network-related regions p=0·006, limbic network-related regions p=0·020) and the thalamus (p=0·008). LRRK2 mutation carriers without Parkinson's disease had increased acetylcholinesterase hydrolysis rates compared with healthy controls in the cortex (average cortex, p=0·046). Patients with LRRK2 Parkinson's disease had significantly higher acetylcholinesterase activity in some cortical regions (average cortex p=0·043, default mode network-related regions p=0·021) and the thalamus (thalamus p=0·004) compared with individuals with idiopathic disease. Acetylcholinesterase hydrolysis rates in healthy controls were correlated inversely with age.

INTERPRETATION

LRRK2 mutations are associated with significantly increased cholinergic activity in the brain in mutation carriers without Parkinson's disease compared with healthy controls and in LRRK2 mutation carriers with Parkinson's disease compared with individuals with idiopathic disease. Changes in cholinergic activity might represent early and sustained attempts to compensate for LRRK2-related dysfunction, or alteration of acetylcholinesterase in non-neuronal cells.

FUNDING

Michael J Fox Foundation, National Institutes of Health, and Pacific Alzheimer Research Foundation.

Authors+Show Affiliations

Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada; Department of Neurobiology, Neurology, and Geriatrics, Xuanwu Hospital Capital Medical University, Beijing, China.University of British Columbia-Okanagan Southern Medical Program, Kelowna, BC, Canada.Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada.Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada.Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada.Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada.Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada.Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada.Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada.Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada.Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada.Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada.Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada.Department of Neurobiology, Neurology, and Geriatrics, Xuanwu Hospital Capital Medical University, Beijing, China.Department of Pathology, University of Washington, Seattle, WA, USA.Veterans Affairs Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA, USA.Norwegian University of Science and Technology, Trondheim, Norway.Mayo Clinic, Jacksonville, FL, USA.Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada.Department of Chemistry, University of British Columbia, Vancouver, BC, Canada.TRIUMF (Tri-University Meson Facility), Vancouver, BC, Canada.Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada.Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada.Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada. Electronic address: jstoessl@mail.ubc.ca.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29456161

Citation

Liu, Shu-Ying, et al. "The Effect of LRRK2 Mutations On the Cholinergic System in Manifest and Premanifest Stages of Parkinson's Disease: a Cross-sectional PET Study." The Lancet. Neurology, vol. 17, no. 4, 2018, pp. 309-316.
Liu SY, Wile DJ, Fu JF, et al. The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: a cross-sectional PET study. Lancet Neurol. 2018;17(4):309-316.
Liu, S. Y., Wile, D. J., Fu, J. F., Valerio, J., Shahinfard, E., McCormick, S., ... Stoessl, A. J. (2018). The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: a cross-sectional PET study. The Lancet. Neurology, 17(4), pp. 309-316. doi:10.1016/S1474-4422(18)30032-2.
Liu SY, et al. The Effect of LRRK2 Mutations On the Cholinergic System in Manifest and Premanifest Stages of Parkinson's Disease: a Cross-sectional PET Study. Lancet Neurol. 2018;17(4):309-316. PubMed PMID: 29456161.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: a cross-sectional PET study. AU - Liu,Shu-Ying, AU - Wile,Daryl J, AU - Fu,Jessie Fanglu, AU - Valerio,Jason, AU - Shahinfard,Elham, AU - McCormick,Siobhan, AU - Mabrouk,Rostom, AU - Vafai,Nasim, AU - McKenzie,Jess, AU - Neilson,Nicole, AU - Perez-Soriano,Alexandra, AU - Arena,Julieta E, AU - Cherkasova,Mariya, AU - Chan,Piu, AU - Zhang,Jing, AU - Zabetian,Cyrus P, AU - Aasly,Jan O, AU - Wszolek,Zbigniew K, AU - McKeown,Martin J, AU - Adam,Michael J, AU - Ruth,Thomas J, AU - Schulzer,Michael, AU - Sossi,Vesna, AU - Stoessl,A Jon, Y1 - 2018/02/16/ PY - 2017/06/02/received PY - 2017/12/27/revised PY - 2018/01/16/accepted PY - 2018/2/20/pubmed PY - 2019/2/28/medline PY - 2018/2/20/entrez SP - 309 EP - 316 JF - The Lancet. Neurology JO - Lancet Neurol VL - 17 IS - 4 N2 - BACKGROUND: Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinson's disease. METHODS: Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinson's disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N-11C-methyl-piperidin-4-yl propionate to scan for acetylcholinesterase activity. The primary outcome measure was rate of acetylcholinesterase hydrolysis, calculated using the striatal input method. We compared acetylcholinesterase hydrolysis rates between groups using ANCOVA, with adjustment for age based on the results of linear regression analysis. FINDINGS: We recruited 14 patients with LRRK2 Parkinson's disease, 16 LRRK2 mutation carriers without Parkinson's disease, eight patients with idiopathic Parkinson's disease, and 11 healthy controls. We noted significant between-group differences in rates of acetylcholinesterase hydrolysis in cortical regions (average cortex p=0·009, default mode network-related regions p=0·006, limbic network-related regions p=0·020) and the thalamus (p=0·008). LRRK2 mutation carriers without Parkinson's disease had increased acetylcholinesterase hydrolysis rates compared with healthy controls in the cortex (average cortex, p=0·046). Patients with LRRK2 Parkinson's disease had significantly higher acetylcholinesterase activity in some cortical regions (average cortex p=0·043, default mode network-related regions p=0·021) and the thalamus (thalamus p=0·004) compared with individuals with idiopathic disease. Acetylcholinesterase hydrolysis rates in healthy controls were correlated inversely with age. INTERPRETATION: LRRK2 mutations are associated with significantly increased cholinergic activity in the brain in mutation carriers without Parkinson's disease compared with healthy controls and in LRRK2 mutation carriers with Parkinson's disease compared with individuals with idiopathic disease. Changes in cholinergic activity might represent early and sustained attempts to compensate for LRRK2-related dysfunction, or alteration of acetylcholinesterase in non-neuronal cells. FUNDING: Michael J Fox Foundation, National Institutes of Health, and Pacific Alzheimer Research Foundation. SN - 1474-4465 UR - https://www.unboundmedicine.com/medline/citation/29456161/The_effect_of_LRRK2_mutations_on_the_cholinergic_system_in_manifest_and_premanifest_stages_of_Parkinson's_disease:_a_cross_sectional_PET_study_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1474-4422(18)30032-2 DB - PRIME DP - Unbound Medicine ER -