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BACKGROUND: Prior studies indicate more severe brainstem cholinergic deficits in Progressive Supranuclear Palsy (PSP) compared to Parkinson’s disease (PD), but the extent and topography of subcortical deficits remains poorly understood. OBJECTIVE: To investigate differential cholinergic systems changes in progressive supranuclear palsy (PSP, n=8) versus Parkinson’s disease (PD, n=107) and older controls (n=19) using vesicular acetylcholine transporter [(18)F]-fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET). METHODS: A whole-brain voxel-based PET analysis using Statistical Parametric Mapping (SPM) software (SPM12) for inter-group comparisons using parametric [(18)F]-FEOBV DVR images. RESULTS: Voxel-based analyses showed lower FEOBV binding in the tectum, metathalamus, epithalamus, pulvinar, bilateral frontal opercula, anterior insulae, superior temporal pole, anterior cingulum, some striatal subregions, lower brainstem, and cerebellum in PSP versus PD (p

To examine regional cerebral vesicular acetylcholine transporter (VAChT) ligand [

Background Effects of fatigue on health in older age are well studied, yet little is known about the clinical relevance of energy perception. Aims To explore cross-sectional associations of self-reported energy with physical and mental health metrics in the Health, Aging, and Body Composition Study. Methods Participants rated their energy from 0 to 10; the outcome was energy dichotomized at the median (≥ 7 = higher energy). Four domains were assessed: depressive symptoms (Center for Epidemiologic Studies Depression Scale); physical performance (function: usual and rapid gait speed; fitness: 400-m walk time); physical activity (casual walking, walking for exercise, and intense exercise); and cognitive function (Modified Mini-Mental State Examination and Digit Symbol Substitution Test). Covariates bivariately associated with energy entered a multivariable logistic regression model, adjusted for demographics, chronic conditions, and strength. Results Depressive symptoms, physical performance and activity, but not cognition, were bivariately associated with energy (p p Discussion In this cohort with a range of chronic conditions and fatigue, perceiving higher energy levels may reflect better emotional and physical health. Conclusion Energy should be considered in multidimensional clinical assessments of older age.

© 2020, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. Purpose of Review: This paper aims to review novel trends in cholinergic neuroimaging in Alzheimer and Lewy body parkinsonian disorders. Recent Findings: The spectrum of cholinergic imaging is expanding with the availability of spatially more precise radioligands that allow assessment of previously less recognized subcortical and cortical structures with more dense cholinergic innervation. In addition, advances in MRI techniques now allow quantitative structural or functional assessment of both the cholinergic forebrain and the pedunculopontine nucleus, which may serve as non-invasive prognostic predictors. Multimodal imaging approaches, such as PET-MRI or multiligand PET, offer new insights into the dynamic and interactive roles of the cholinergic system at both local and larger-scale neural network levels. Summary: Our understanding of the heterogeneous roles of the cholinergic system in age-related diseases is evolving. Multimodal imaging approaches that provide complimentary views of the cholinergic system will be necessary to shed light on the impact of cholinergic degeneration on regional and large-scale neural networks that underpin clinical symptom manifestation in neurodegeneration.

PURPOSE OF REVIEW: Brain cholinergic denervation is a major feature of Alzheimer’s disease (AD) and Dementia with Lewy bodies (DLB). We reviewed the topography of assessed by cholinergic molecular imaging study in these two major types of dementia. A small meta-analysis directly comparing vesicular acetylcholine transporter (VAChT) PET scans of AD vs. DLB patients is presented. RECENT FINDINGS: VAChT PET studies showed evidence of extensive cortical cholinergic denervation in both forms of dementia, while multiple subcortical structures were also in DLB. Novel analysis revealed evidence of metathalamic denervation in AD, and epithalamus, premotor/sensorimotor cortical, and striatal losses in DLB. SUMMARY: Topographically distinct cortical and subcortical cholinergic lesions can distinguish AD and DLB, and new structures have been highlighted here. Differential vulnerability of specific cholinergic projections are likely associated with specific clinical features of these disorders. Improved understanding of the mechanisms and roles of cholinergic neurotransmission in regions with cholinergic deficits may lead to symptomatic therapies.

PURPOSE OF REVIEW: Although the cholinergic hypothesis of dementia provided a successful paradigm for the development of new drugs for dementia, this hypothesis has waned in popularity. Cholinergic brain imaging may provide novel insights into the viability of this hypothesis. RECENT FINDINGS: Cholinergic receptor and forebrain volumetric studies suggest an important role of the cholinergic system in maintaining brain network integrity that may deteriorate with cognitive decline in Alzheimer disease (AD) and Lewy body disorders (LBD). Bidirectional changes in regional receptor expression may suggest the presence of compensatory responses to neurodegenerative injury. Cholinergic system changes are more complex in LBD because of additional subcortical degenerations compared to AD. Cholinergic-dopaminergic interactions affect attentional, verbal learning and executive functions, and impairments in these two transmitter systems may jointly increase the risk of dementia in Parkinson disease. SUMMARY: The cholinergic hypothesis is evolving from a primary focus on memory toward expanded cognitive functions modulated by regionally more complex and interactive brain networks. Cholinergic network adaptation may serve as a novel research target in neurodegeneration.

Subjects at risk of dementia benefit from participation in mentally stimulating activities, but no prior studies have investigated similar associations in Parkinson disease (PD). The aim of this study was to investigate the relationship between times spent engaging in mentally stimulating activities and cognitive functions in PD while accounting for the degree of primary neurodegenerations. PD patients (N = 41, 33 males; age 68.5 ± 7.2; Hoehn and Yahr stage 2.6 ± 0.6) completed the Community Health Activities Model Program for Seniors questionnaire, mini-mental state examination (MMSE), and [11C]dihydrotetrabenazine dopaminergic and [11C]piperidinyl propionate acetylcholinesterase PET imaging. The subset of mentally stimulating activity items of the Community Health Activities Model Program for Seniors questionnaire was used to develop a rating scale as primary outcome variable in this study. Findings showed that mean rating scale score of time spent in mentally stimulating activities over a 4-week timespan was 20.0 ± 8.3 h and mean MMSE score was 28.4 ± 1.9. Regression analysis showed that duration of participation in mentally stimulating activities was a significant predictor of MMSE scores (standardized β = 0.39, t = 2.8, p = 0.009; total model: F (6,34) = 3.5, p = 0.005) independent from significant effects for cortical cholinergic activity (β = 0.35, t = 2.4, p = 0.024). Caudate nucleus dopaminergic activity, age, education, or duration of disease were not significant regressors. Post hoc analysis did not show significant effects of motor disease severity or level of physical activities. We conclude that engagement in mentally stimulating activities is associated with better cognitive abilities in PD, independent of education, severity of motor disease, nigrostriatal dopaminergic and cortical cholinergic degenerations.

Parkinsonian-like motor impairments are common in the elderly. The etiology of these symptoms in the absence of clinically diagnosable Parkinson's disease (PD) is unknown. The aim of this study was to evaluate associations between striatal dopaminergic neuron losses that occur with aging and gait in healthy adults. Forty healthy subjects aged 21-85 years old underwent [(11)C]-beta-CFT dopamine transporter (DAT) positron emission tomography (PET). Subjects were also asked to walk in a gait laboratory at their own pace. Gait variables of interest included average general spatiotemporal characteristics of walking patterns and their standard deviation reflecting gait variability. Segmented nonlinear models were used to investigate the relationship between striatal DAT activity and gait while controlling for age. Gait speed, cadence, and single and double support durations were significantly slower than age-based predictions in adults with lower striatal DAT activity (P0.05). After controlling for age, striatal DAT activity was not significantly associated with average step length and step width and with gait variability. We conclude that dopaminergic physiology influences certain aspects of gait independent of age-related changes. The findings of this study may augur novel therapeutic approaches to treating gait disorders in the elderly.

Positron emission tomography (PET) or single photon emission computer tomography (SPECT) imaging provides the means to study neurochemical processes in vivo. These methods have been applied to examine monoaminergic and cholinergic changes in neurodegenerative disorders. These investigations have provided important insights into disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The most intensely studied monoaminergic transmitter is dopamine. The extent of presynaptic nigrostriatal dopaminergic denervation can be quantified in PD and may serve as a diagnostic biomarker. Dopaminergic receptor imaging may help to distinguish idiopathic PD from atypical parkinsonian disorders. Cholinergic denervation has been identified not only in AD but also in PD and more severely in parkinsonian dementia. PET or SPECT can also provide biomarkers to follow progression of disease or evaluate the effects of therapeutic interventions. Cholinergic receptor imaging is expected to play a major role in new drug development for dementing disorders.

We recently reported findings that loss of cortical acetylcholinesterase (AChE) activity is greater in parkinsonian dementia than in Alzheimer’s disease (AD). In this study we determined cognitive correlates of in vivo cortical AChE activity in patients with parkinsonian dementia (PDem, n = 11), Parkinson’s disease without dementia (PD, n = 13), and in normal controls (NC, n = 14) using N–[11C]methyl–piperidin–4–yl propionate ([11C]PMP) AChE positron emission tomography (PET). Cortical AChE activity was significantly reduced in the PDem (–20.9%) and PD (–12.7 %) subjects (P < 0.001) when compared with the control subjects. Analysis of the cognitive data within the patient groups demonstrated that scores on the WAIS-III Digit Span, a test of working memory and attention, had most robust correlation with cortical AChE activity (R = 0.61, p < 0.005). There were also significant correlations between cortical AChE activity and other tests of attentional and executive functions, such as the Trail Making and Stroop Color Word tests. There was no significant correlation between cortical AChE activity and duration of motor disease (R = –0.01, ns) or severity of parkinsonian motor symptoms (R = 0.14, ns). We conclude that cortical cholinergic denervation in PD and parkinsonian dementia is associated with decreased performance on tests of attentional and executive functioning.

There is increasing interest in the clinical effects of cholinergic basal forebrain and tegmental pedunculopontine complex (PPN) projection degeneration in Parkinson’s disease (PD). Recent evidence supports an expanded role beyond cognitive impairment, including effects on olfaction, mood, REM sleep behavior disorder, and motor functions. Cholinergic denervation is variable in PD without dementia and may contribute to clinical symptom heterogeneity. Early in vivo imaging evidence that impaired cholinergic integrity of the PPN associates with frequent falling in PD is now confirmed by human post-mortem evidence. Brainstem cholinergic lesioning studies in primates confirm the role of the PPN in mobility impairment. Degeneration of basal forebrain cholinergic projections correlates with decreased walking speed. Cumulatively, these findings provide evidence for a new paradigm to explain dopamine-resistant features of mobility impairments in PD. Recognition of the increased clinical role of cholinergic system degeneration may motivate new research to expand indications for cholinergic therapy in PD.