title: Extra-nigral pathological conditions are common in Parkinson's disease with freezing of gait: an in vivo positron emission tomography study.
abstract: Cholinergic denervation has been associated with falls and slower gait speed and β-amyloid deposition with greater severity of axial motor impairments in Parkinson disease (PD). However, little is known about the association between the presence of extra-nigral pathological conditions and freezing of gait (FoG). Patients with PD (n = 143; age, 65.5 ± 7.4 years, Hoehn and Yahr stage, 2.4 ± 0.6; Montreal Cognitive Assessment score, 25.9 ± 2.6) underwent [(11) C]methyl-4-piperidinyl propionate acetylcholinesterase and [(11) C]dihydrotetrabenazine dopaminergic PET imaging, and clinical, including FoG, assessment in the dopaminergic "off" state. A subset of subjects (n = 61) underwent [(11) C]Pittsburgh compound-B β-amyloid positron emission tomography (PET) imaging. Normative data were used to dichotomize abnormal β-amyloid uptake or cholinergic deficits. Freezing of gait was present in 20 patients (14.0%). Freezers had longer duration of disease (P = 0.009), more severe motor disease (P < 0.0001), and lower striatal dopaminergic activity (P = 0.013) compared with non-freezers. Freezing of gait was more common in patients with diminished neocortical cholinergic innervation (23.9%, χ(2)  = 5.56, P = 0.018), but not in the thalamic cholinergic denervation group (17.4%, χ(2)  = 0.26, P = 0.61). Subgroup analysis showed higher frequency of FoG with increased neocortical β-amyloid deposition (30.4%, Fisher Exact test: P = 0.032). Frequency of FoG was lowest with absence of both pathological conditions (4.8%), intermediate in subjects with single extra-nigral pathological condition (14.3%), and highest with combined neocortical cholinopathy and amyloidopathy (41.7%; Cochran-Armitage trend test, Z = 2.63, P = 0.015). Within the group of freezers, 90% had at least one of the two extra-nigral pathological conditions studied. Extra-nigral pathological conditions, in particular the combined presence of cortical cholinopathy and amyloidopathy, are common in PD with FoG and may contribute to its pathophysiology. © 2014 International Parkinson and Movement Disorder Society.
authors.affiliation: Department of Radiology, Division of Nuclear Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Neurology, University of Michigan, Ann Arbor, MI, USA; Neurology Service and GRECC, VAAAHS, Ann Arbor, MI, USA.
authors.forename: Nicolaas I
authors.initials: NI
authors.lastname: Bohnen
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Frey
authors.forename: Stephanie
authors.initials: S
authors.lastname: Studenski
authors.forename: Vikas
authors.initials: V
authors.lastname: Kotagal
authors.forename: Robert A
authors.initials: RA
authors.lastname: Koeppe
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Constantine
authors.forename: Peter J H
authors.initials: PJ
authors.lastname: Scott
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.forename: Martijn L T M
authors.initials: ML
authors.lastname: Müller
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000814:Aniline Compounds; D052160:Benzothiazoles; D002247:Carbon Isotopes; D003430:Cross-Sectional Studies; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000502:physiology*; D020233:Gait Disorders, Neurologic / Q000000981:diagnostic imaging* / Q000209:etiology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000150:complications*; D049268:Positron-Emission Tomography; D013378:Substantia Nigra / Q000473:pathology*; D013747:Tetrabenazine / Q000031:analogs & derivatives; D013844:Thiazoles; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D052160:Benzothiazoles; D002247:Carbon Isotopes; C493452:SLC18A2 protein, human; D013844:Thiazoles; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D000110:Acetylcholinesterase; D013747:Tetrabenazine
keywords: PET; Parkinson's disease; acetylcholine; dopamine; gait freezing; β-amyloid