Cholinergic system changes of falls and freezing of gait in Parkinson's disease

Abstract

Objective Postural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls. Methods Ninety‐four PD subjects underwent clinical assessment and VAChT ([ 18 F]FEOBV) PET. Results Thirty‐five subjects (37.2%) reported a history of falls, and 15 (16%) had observed FoG. Univariate volume‐of‐interest analyses demonstrated significantly reduced thalamic ( p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum ( p = 0.0012) and limbic archicortex ( p = 0.004) in freezers compared to nonfreezers. Whole‐brain voxel‐based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions. Interpretation Our findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol 2019;85:538–549

Abnormal center of mass control during balance: a new biomarker of falls in people with Parkinson’s disease

“…52,53 Second, based on other studies using similar patient cohorts, it is very likely that patients with high values of antagonist activity had considerable cholinergic deficits in regions including the thalamus. 34,54,55 The latency on the antagonist pathway we identified is consistent with involvement of supraspinal centers. 49 In particular, longer-latency stretch responses in TA (>95 ms) can be modulated with transcranial magnetic stimulation, which suggests involvement of supraspinal centers.…”

“…Taken together with imaging studies in older adults with and without PD, 34 the elevated values of ! " ′ in PD suggest that -in addition to the dopaminergic degeneration characteristic of PD -patients with high values of ! "…”

Changing views of the pathophysiology of Parkinsonism

“…148 The former is supported by the finding that the catecholaminergic locus coeruleus appears to be damaged in parkinsonian monkeys that show FOG (compared to those without FOG), 149 by neuromelanin MRI findings in parkinsonian patients with and without FOG, 150 and by the (empirically determined) effectiveness of medications that alters catecholamine release or levels in the brain, such as atomoxetine, 151,152 or L-threo-DOPS. [153][154][155][156] Cholinergic dysfunction is implicated by imaging studies that show cholinergic loss in cortical regions, 148,157 and in the striatum 157 of patients with FOG. Studies in rodents and monkeys have supported the notion that severe gait abnormalities may arise in situations where both the dopaminergic nigrostriatal system and cholinergic cells in the pedunculopontine nucleus (area) are destroyed.…”

[18F]Fluoroethoxybenzovesamicol in Parkinson's disease patients: Quantification of a novel cholinergic positron emission tomography tracer

“…Previously, [ 18 F]FEOBV has been evaluated in Lewy body dementia, Alzheimer's disease, and healthy controls . Furthermore, [ 18 F]FEOBV was implemented in PD research by evaluating the role of vesicular acetylcholine transporter binding in the clinical symptomology of falling and freezing . We aimed to further quantify [ 18 F]FEOBV as a cholinergic PET tracer in PD by comparing PD and controls and evaluating the test–retest variability in both groups.…”