PET in LRRK2 mutations

Comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation

John R. Adams, Hinke Van Netten, Michael Schulzer, Edwin Mak, Jessamyn Mckenzie, Audrey Strongosky, Vesna Sossi, Thomas J. Ruth, Chong S. Lee, Matthew Farrer, Thomas Gasser, Ryan J. Uitti, Donald B. Calne, Zbigniew K Wszolek, A. Jon Stoessl

Research output: Contribution to journalArticle

202 Citations (Scopus)

Abstract

Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: 18F-6-fluoro-L-dopa ( 18F-dopa) to assess dopamine (DA) synthesis and storage, 11C-(±)α-dihydrotetrabenazine ( 11C-DTBZ) for the vesicular monoamine transporter, and 11C-d-threo-methylphenidate ( 11C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two of them also displayed abnormal 11C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.

Original languageEnglish (US)
Pages (from-to)2777-2785
Number of pages9
JournalBrain
Volume128
Issue number12
DOIs
StatePublished - Dec 2005

Fingerprint

Positron-Emission Tomography
Parkinson Disease
Dopamine Plasma Membrane Transport Proteins
Levodopa
Mutation
Dopamine
Vesicular Monoamine Transport Proteins
Methylphenidate
Carboxy-Lyases
Membrane Transport Proteins
Dopamine D2 Receptors
Dopaminergic Neurons
Putamen
Parkinsonian Disorders
Substantia Nigra
Leucine
Phosphotransferases
Up-Regulation
Down-Regulation
Pathology

Keywords

  • Genetics
  • Parkinson's disease
  • Pathophysiology
  • Positron emission tomography

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Adams, J. R., Van Netten, H., Schulzer, M., Mak, E., Mckenzie, J., Strongosky, A., ... Stoessl, A. J. (2005). PET in LRRK2 mutations: Comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation. Brain, 128(12), 2777-2785. https://doi.org/10.1093/brain/awh607

PET in LRRK2 mutations : Comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation. / Adams, John R.; Van Netten, Hinke; Schulzer, Michael; Mak, Edwin; Mckenzie, Jessamyn; Strongosky, Audrey; Sossi, Vesna; Ruth, Thomas J.; Lee, Chong S.; Farrer, Matthew; Gasser, Thomas; Uitti, Ryan J.; Calne, Donald B.; Wszolek, Zbigniew K; Stoessl, A. Jon.

In: Brain, Vol. 128, No. 12, 12.2005, p. 2777-2785.

Research output: Contribution to journalArticle

Adams, JR, Van Netten, H, Schulzer, M, Mak, E, Mckenzie, J, Strongosky, A, Sossi, V, Ruth, TJ, Lee, CS, Farrer, M, Gasser, T, Uitti, RJ, Calne, DB, Wszolek, ZK & Stoessl, AJ 2005, 'PET in LRRK2 mutations: Comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation', Brain, vol. 128, no. 12, pp. 2777-2785. https://doi.org/10.1093/brain/awh607
Adams JR, Van Netten H, Schulzer M, Mak E, Mckenzie J, Strongosky A et al. PET in LRRK2 mutations: Comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation. Brain. 2005 Dec;128(12):2777-2785. https://doi.org/10.1093/brain/awh607
Adams, John R. ; Van Netten, Hinke ; Schulzer, Michael ; Mak, Edwin ; Mckenzie, Jessamyn ; Strongosky, Audrey ; Sossi, Vesna ; Ruth, Thomas J. ; Lee, Chong S. ; Farrer, Matthew ; Gasser, Thomas ; Uitti, Ryan J. ; Calne, Donald B. ; Wszolek, Zbigniew K ; Stoessl, A. Jon. / PET in LRRK2 mutations : Comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation. In: Brain. 2005 ; Vol. 128, No. 12. pp. 2777-2785.
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AU - Mckenzie, Jessamyn

AU - Strongosky, Audrey

AU - Sossi, Vesna

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AB - Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: 18F-6-fluoro-L-dopa ( 18F-dopa) to assess dopamine (DA) synthesis and storage, 11C-(±)α-dihydrotetrabenazine ( 11C-DTBZ) for the vesicular monoamine transporter, and 11C-d-threo-methylphenidate ( 11C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two of them also displayed abnormal 11C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.

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