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Open Access 01-08-2020 | Positron Emission Tomography | Original Communication

Imaging dopamine function and microglia in asymptomatic LRRK2 mutation carriers

Authors: Morten Gersel Stokholm, Alicia Garrido, Eduardo Tolosa, Mónica Serradell, Alex Iranzo, Karen Østergaard, Per Borghammer, Arne Møller, Peter Parbo, Kristian Stær, David J. Brooks, Maria José Martí, Nicola Pavese

Published in: Journal of Neurology | Issue 8/2020

Abstract

Neuroinflammation (microglial activation) and subclinical nigrostriatal dysfunction have been reported in subjects at risk of Parkinsonism. Eight non-manifesting carriers (NMCs) of LRRK2 G2019S mutation had ¹¹C-PK11195 and ¹⁸F-DOPA PET to assess microglial activation and striatal dopamine system integrity, respectively. Comparisons were made with healthy controls. Five LRRK2-NMCs had subclinical reductions of putaminal ¹⁸F-DOPA uptake. Three of them had significantly raised nigral ¹¹C-PK11195 binding bilaterally. These findings indicate that nigrostriatal dysfunction and neuroinflammation occur in LRRK2-NMCs. Studies in larger cohorts with appropriate follow-up are needed to elucidate the significance of neuroinflammation in the premotor phase of LRRK2-PD.

Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW, L.C. International (2008) LC International, Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case–control study. Lancet Neurol 7(7):583–590CrossRef

Marder K, Wang Y, Alcalay RN, Mejia-Santana H, Tang MX, Lee A, Raymond D, Mirelman A, Saunders-Pullman R, Clark L, Ozelius L, Orr-Urtreger A, Giladi N, Bressman S, L.A.J. Consortium (2015) Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium. Neurology 85(1):89–95CrossRef

Kalia LV, Lang AE, Hazrati LN, Fujioka S, Wszolek ZK, Dickson DW, Ross OA, Van Deerlin VM, Trojanowski JQ, Hurtig HI, Alcalay RN, Marder KS, Clark LN, Gaig C, Tolosa E, Ruiz-Martinez J, Marti-Masso JF, Ferrer I, Lopez de Munain A, Goldman SM, Schule B, Langston JW, Aasly JO, Giordana MT, Bonifati V, Puschmann A, Canesi M, Pezzoli G, Maues De Paula A, Hasegawa K, Duyckaerts C, Brice A, Stoessl AJ, Marras C (2015) Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol 72(1):100–105CrossRef

Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science 353(6301):777–783CrossRef

Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, Eggert K, Oertel W, Banati RB, Brooks DJ (2006) In vivo imaging of microglial activation with [¹¹C](R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol Dis 21(2):404–412CrossRef

Stokholm MG, Iranzo A, Ostergaard K, Serradell M, Otto M, Svendsen KB, Garrido A, Vilas D, Borghammer P, Santamaria J, Moller A, Gaig C, Brooks DJ, Tolosa E, Pavese N (2017) Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case–control study. Lancet Neurol 16(10):789–796CrossRef

Iranzo A, Tolosa E, Gelpi E et al (2013) Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study. Lancet Neurol 12(5):443–453CrossRef

Parbo P, Ismail R, Hansen KV, Amidi A, Marup FH, Gottrup H, Braendgaard H, Eriksson BO, Eskildsen SF, Lund TE, Tietze A, Edison P, Pavese N, Stokholm MG, Borghammer P, Hinz R, Aanerud J, Brooks DJ (2017) Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer's disease. Brain 140(7):2002–2011CrossRef

Wile DJ, Agarwal PA, Schulzer M, Mak E, Dinelle K, Shahinfard E, Vafai N, Hasegawa K, Zhang J, McKenzie J, Neilson N, Strongosky A, Uitti RJ, Guttman M, Zabetian CP, Ding YS, Adam M, Aasly J, Wszolek ZK, Farrer M, Sossi V, Stoessl AJ (2017) Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies. Lancet Neurol 16(5):351–359CrossRef

10.

Salat D, Noyce AJ, Schrag A, Tolosa E (2016) Challenges of modifying disease progression in prediagnostic Parkinson's disease. Lancet Neurol 15(6):637–648CrossRef

11.

Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M, Van den Haute C, Melki R, Baekelandt V (2015) alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522(7556):340–344CrossRef

12.

Schneider SA, Alcalay RN (2017) Neuropathology of genetic synucleinopathies with parkinsonism: review of the literature. Mov Disord 32(11):1504–1523CrossRef

13.

Venneti S, Lopresti BJ, Wiley CA (2006) The peripheral benzodiazepine receptor (translocator protein 18 kDa) in microglia: from pathology to imaging. Prog Neurobiol 80(6):308–322CrossRef

Title: Imaging dopamine function and microglia in asymptomatic LRRK2 mutation carriers
Authors: Morten Gersel Stokholm
Alicia Garrido
Eduardo Tolosa
Mónica Serradell
Alex Iranzo
Karen Østergaard
Per Borghammer
Arne Møller
Peter Parbo
Kristian Stær
David J. Brooks
Maria José Martí
Nicola Pavese
Publication date: 01-08-2020
Publisher: Springer Berlin Heidelberg
Keywords: Positron Emission Tomography
Parkinson's Disease
Movement Disorder
Published in: Journal of Neurology / Issue 8/2020
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-020-09830-3

At a glance: The STEP trials

Springer Medicine

Imaging dopamine function and microglia in asymptomatic LRRK2 mutation carriers

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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