Targeting the pedunculopontine nucleus in Parkinson’s disease: Time to go back to the drawing board

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147041/1/mds27540.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147041/2/mds27540_am.pd

Color discrimination errors associate with axial motor impairments in Parkinson’s Disease

BackgroundVisual function deficits are more common in imbalance‐predominant compared to tremor‐predominant PD, suggesting a pathophysiological role of impaired visual functions in axial motor impairments.ObjectiveTo investigate the relationship between changes in color discrimination and motor impairments in PD while accounting for cognitive or other confounder factors.MethodsPD subjects (n = 49, age 66.7 ± 8.3 years; Hoehn & Yahr stage 2.6 ± 0.6) completed color discrimination assessment using the Farnsworth‐Munsell 100 Hue Color Vision Test, neuropsychological, motor assessments, and [11C]dihydrotetrabenazine vesicular monoamine transporter type 2 PET imaging. MDS‐UPDRS sub‐scores for cardinal motor features were computed. Timed Up & Go mobility and walking tests were assessed in 48 subjects.ResultsBivariate correlation coefficients between color discrimination and motor variables were significant only for the Timed Up & Go test (RS = 0.44, P = 0.0018) and the MDS‐UPDRS axial motor scores (RS = 0.38, P = 0.0068). Multiple regression confounder analysis using the Timed Up & Go as outcome parameter showed a significant total model (F(5,43) = 7.3, P < 0.0001) with significant regressor effects for color discrimination (standardized β = 0.32, t = 2.6, P = 0.012), global cognitive Z‐score (β = −0.33, t = −2.5, P = 0.018), duration of disease (β = 0.26, t = 1.8, P = 0.038), but not for age or striatal dopaminergic binding. The color discrimination test was also a significant independent regressor in the MDS‐UPDRS axial motor model (standardized β = 0.29, t = 2.4, P = 0.022; total model t(5,43) = 6.4, P = 0.0002).ConclusionsColor discrimination errors associate with axial motor features in PD independent of cognitive deficits, nigrostriatal dopaminergic denervation, and other confounder variables. These findings may reflect shared pathophysiology between color discrimination visual impairments and axial motor burden in PD.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141397/1/mdc312527.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141397/2/mdc312527_am.pd

Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders

There are two major sources of cholinergic projections in the brain. The nucleus basalis of Meynert provides the principal cholinergic input of the cortical mantle and the pedunculopontine nucleus-laterodorsal tegmental complex (PPN-LDTC; hereafter referred to as PPN) provides the major cholinergic input to the thalamus. Cortical cholinergic denervation has previously been shown to be part of Alzheimer and parkinsonian dementia but there is less information about subcortical thalamic cholinergic denervation. We investigated thalamic cholinergic afferent integrity by measuring PPN-Thalamic (PPN-Thal) acetylcholinesterase (AChE) activity via PET imaging in Alzheimer (AD), Parkinson disease without dementia (PD), Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB)

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

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149240/1/ana25430_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149240/2/ana25430.pd

Extra‐nigral pathological conditions are common in Parkinson's disease with freezing of gait: An in vivo positron emission tomography study

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 SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108363/1/mds25929.pd

Identification of cholinergic centro-cingulate topography as main contributor to cognitive functioning in Parkinson’s disease: Results from a data-driven approach

Background: Degeneration of the cholinergic system plays an important role in cognitive impairment in Parkinson’s disease (PD). Positron emission tomography (PET) imaging using the presynaptic vesicular acetylcholine transporter (VAChT) tracer [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV) allows for regional assessment of cholinergic innervation. The purpose of this study was to perform a data-driven analysis to identify co-varying cholinergic regions and to evaluate the relationship of these with cognitive functioning in PD. Materials and methods: A total of 87 non-demented PD patients (77% male, mean age 67.9 ± 7.6 years, disease duration 5.8 ± 4.6 years) and 27 healthy control (HC) subjects underwent [18F]FEOBV brain PET imaging and neuropsychological assessment. A volume-of-interest based factor analysis was performed for both groups to identify cholinergic principal components (PCs). Results: Seven main PCs were identified for the PD group: (1) bilateral posterior cortex, (2) bilateral subcortical, (3) bilateral centro-cingulate, (4) bilateral frontal, (5) right-sided fronto-temporal, (6) cerebellum, and (7) predominantly left sided temporal regions. A complementary principal component analysis (PCA) analysis in the control group showed substantially different cholinergic covarying patterns. A multivariate linear regression analyses demonstrated PC3, PC5, and PC7, together with motor impairment score, as significant predictors for cognitive functioning in PD. PC3 showed most robust correlations with cognitive functioning (p < 0.001). Conclusion: A data-driven approach identified covarying regions in the bilateral peri-central and cingulum cortex as a key determinant of cognitive impairment in PD. Cholinergic vulnerability of the centro-cingulate network appears to be disease-specific for PD rather than being age-related. The cholinergic system may be an important contributor to regional and large scale neural networks involved in cognitive functioning

Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders

OBJECTIVE: There are two major sources of cholinergic projections in the brain. The nucleus basalis of Meynert provides the principal cholinergic input of the cortical mantle and the pedunculopontine nucleus-laterodorsal tegmental complex (PPN-LDTC; hereafter referred to as PPN) provides the major cholinergic input to the thalamus. Cortical cholinergic denervation has previously been shown to be part of Alzheimer and parkinsonian dementia but there is less information about subcortical thalamic cholinergic denervation. We investigated thalamic cholinergic afferent integrity by measuring PPN-Thalamic (PPN-Thal) acetylcholinesterase (AChE) activity via PET imaging in Alzheimer (AD), Parkinson disease without dementia (PD), Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB). METHODS: AD (n=13; mean age 75.4±5.5), PD (n=11; age 71.4±6.4), PDD (n=6; age 70.8±4.7), DLB (n=6; age 68.0±8.6) and normal controls (NC; n=14; age 69.0±7.5) subjects underwent AChE [(11)C]-methyl-4-piperidinyl propionate (PMP) PET imaging. PPN-Thal PET data were analyzed using the Nagatsuka method. RESULTS: There were no significant differences in mean age between the groups (F=1.86, p=0.134). Kruskal-Wallis testing demonstrated a significant group effect for PPN-Thal AChE hydrolysis rates (F=9.62, P<0.0001). Compared to NC, reduced thalamic k3 hydrolysis rate was noted in subjects with PDD (−19.8%; AChE k3 hydrolysis rates 0.1072±0.0143 min(−1)), DLB (−17.4%; 0.1103±0.0112 min(−1)) and PD (−12.8%; 0.1165±0.0114 min(−1)). Each of these 3 subgroups were statistically different from AD subjects (−0.7%; 0.1326±0.0095 min(−1)) who showed relatively spared thalamic k3 hydrolysis rates which were comparable to NC (0.1336±0.0142 min(−1)). CONCLUSIONS: Thalamic cholinergic denervation is present in PD, PDD, and DLB but not in AD. Neurodegenerative involvement of thalamic cholinergic afferent projections may contribute to disease-specific motor and cognitive abnormalities