The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: A cross-sectional PET study

Shu Ying Liu, Daryl J. Wile, Jessie Fanglu Fu, Jason Valerio, Elham Shahinfard, Siobhan McCormick, Rostom Mabrouk, Nasim Vafai, Jess McKenzie, Nicole Neilson, Alexandra Perez-Soriano, Julieta E. Arena, Mariya Cherkasova, Piu Chan, Jing Zhang, Cyrus P. Zabetian, Jan O. Aasly, Zbigniew K Wszolek, Martin J. McKeown, Michael J. AdamThomas J. Ruth, Michael Schulzer, Vesna Sossi, A. Jon Stoessl

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalThe Lancet Neurology
DOIs
StateAccepted/In press - Jan 1 2018

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Cholinergic Agents
Parkinson Disease
Cross-Sectional Studies
Acetylcholinesterase
Mutation
Hydrolysis
Thalamus
Movement Disorders
Corpus Striatum
Propionates
National Institutes of Health (U.S.)
Brain
Norway
Canada
Linear Models
Dopamine
Regression Analysis
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease : A cross-sectional PET study. / Liu, Shu Ying; Wile, Daryl J.; Fu, Jessie Fanglu; Valerio, Jason; Shahinfard, Elham; McCormick, Siobhan; Mabrouk, Rostom; Vafai, Nasim; McKenzie, Jess; Neilson, Nicole; Perez-Soriano, Alexandra; Arena, Julieta E.; Cherkasova, Mariya; Chan, Piu; Zhang, Jing; Zabetian, Cyrus P.; Aasly, Jan O.; Wszolek, Zbigniew K; McKeown, Martin J.; Adam, Michael J.; Ruth, Thomas J.; Schulzer, Michael; Sossi, Vesna; Stoessl, A. Jon.

In: The Lancet Neurology, 01.01.2018.

Research output: Contribution to journalArticle

Liu, SY, Wile, DJ, Fu, JF, Valerio, J, Shahinfard, E, McCormick, S, Mabrouk, R, Vafai, N, McKenzie, J, Neilson, N, Perez-Soriano, A, Arena, JE, Cherkasova, M, Chan, P, Zhang, J, Zabetian, CP, Aasly, JO, Wszolek, ZK, McKeown, MJ, Adam, MJ, Ruth, TJ, Schulzer, M, Sossi, V & Stoessl, AJ 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. https://doi.org/10.1016/S1474-4422(18)30032-2
Liu, Shu Ying ; Wile, Daryl J. ; Fu, Jessie Fanglu ; Valerio, Jason ; Shahinfard, Elham ; McCormick, Siobhan ; Mabrouk, Rostom ; Vafai, Nasim ; McKenzie, Jess ; Neilson, Nicole ; Perez-Soriano, Alexandra ; Arena, Julieta E. ; Cherkasova, Mariya ; Chan, Piu ; Zhang, Jing ; Zabetian, Cyrus P. ; Aasly, Jan O. ; Wszolek, Zbigniew K ; McKeown, Martin J. ; Adam, Michael J. ; Ruth, Thomas J. ; Schulzer, Michael ; Sossi, Vesna ; Stoessl, A. Jon. / The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease : A cross-sectional PET study. In: The Lancet Neurology. 2018.
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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.",
author = "Liu, {Shu Ying} and Wile, {Daryl J.} and Fu, {Jessie Fanglu} and Jason Valerio and Elham Shahinfard and Siobhan McCormick and Rostom Mabrouk and Nasim Vafai and Jess McKenzie and Nicole Neilson and Alexandra Perez-Soriano and Arena, {Julieta E.} and Mariya Cherkasova and Piu Chan and Jing Zhang and Zabetian, {Cyrus P.} and Aasly, {Jan O.} and Wszolek, {Zbigniew K} and McKeown, {Martin J.} and Adam, {Michael J.} and Ruth, {Thomas J.} and Michael Schulzer and Vesna Sossi and Stoessl, {A. Jon}",
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TY - JOUR

T1 - The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease

T2 - 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

PY - 2018/1/1

Y1 - 2018/1/1

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.

AB - 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.

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