Although Parkinson disease (PD) is viewed traditionally as a motor syndrome secondary to nigrostriatal dopaminergic denervation, recent studies emphasize non-motor features. Non-motor comorbidities, ...such as cognitive impairment, are likely the result of an intricate interplay of multi-system degenerations and neurotransmitter deficiencies extending beyond the loss of dopaminergic nigral neurons. The pathological hallmark of parkinsonian dementia is the presence of extra-nigral Lewy bodies that can be accompanied by other pathologies, such as senile plaques. Lewy first identified the eponymous Lewy body in neurons of the nucleus basalis of Meynert (nbM), the source of cholinergic innervation of the cerebral cortex. Although cholinergic denervation is recognized as a pathological hallmark of Alzheimer disease (AD),
in vivo neuroimaging studies reveal loss of cerebral cholinergic markers in parkinsonian dementia similar to or more severe than in prototypical AD. Imaging studies agree with post-mortem evidence suggesting that basal forebrain cholinergic system degeneration appears early in PD and worsens coincident with the appearance of dementia. Early cholinergic denervation in PD without dementia appears to be heterogeneous and may make specific contributions to the PD clinical phenotype. Apart from well-known cognitive and behavioral deficits, central, in particular limbic, cholinergic denervation may be associated with progressive deficits of odor identification in PD. Recent evidence indicates also that subcortical cholinergic denervation, probably due to degeneration of brainstem pedunculopontine nucleus neurons, may relate to the presence of dopamine non-responsive gait and balance impairments, including falls, in PD.
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 (18FFEOBV) 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
Methodological advances have facilitated extensive revision of traditional views of thalamic and cholinergic contributions to cognition and behavior. Increasing attention to the integrative ...capabilities of the thalamus highlights its role beyond a simple sensory relay, recognizing its complex connectivity and role in orchestrating different phases of attention. Correspondingly, modern conceptualizations position the cholinergic system as key in integrating sensory information with attention and goals. These theoretical developments have occurred largely in parallel but have a large conceptual overlap. We review this overlap, including evidence from animal, patient, neuroimaging, and computational studies, and suggest that thalamo-cholinergic cognition plays a key role in coordinating stable and flexible attention.
•New views on thalamic and cholinergic function reject traditional oversimplification.•Critical roles in coordinating top-down and bottom-up processing.•New methods have been important in this new understanding.•Important contributions to orchestrating stable vs flexible processing.
Cognitive decline in Parkinson's disease is related to cholinergic system degeneration, which can be assessed in vivo using structural MRI markers of basal forebrain volume and PET measures of ...cortical cholinergic activity. In the present study we aimed to examine the interrelation between basal forebrain degeneration and PET-measured depletion of cortical acetylcholinesterase activity as well as their relative contribution to cognitive impairment in Parkinson's disease. This cross-sectional study included 143 Parkinson's disease participants without dementia and 52 healthy control participants who underwent structural MRI, PET scanning with 11C-methyl-4-piperidinyl propionate (PMP) as a measure of cortical acetylcholinesterase activity, and a detailed cognitive assessment. Based on the fifth percentile of the overall cortical PMP PET signal from the control group, people with Parkinson's disease were subdivided into a normo-cholinergic (n = 94) and a hypo-cholinergic group (n = 49). Volumes of functionally defined posterior and anterior basal forebrain subregions were extracted using an established automated MRI volumetry approach based on a stereotactic atlas of cholinergic basal forebrain nuclei. We used Bayesian t-tests to compare basal forebrain volumes between controls, and normo- and hypo-cholinergic Parkinson's participants after covarying out age, sex and years of education. Associations between the two cholinergic imaging measures were assessed across all people with Parkinson's disease using Bayesian correlations and their respective relations with performance in different cognitive domains were assessed with Bayesian ANCOVAs. As a specificity analysis, hippocampal volume was added to the analysis. We found evidence for a reduction of posterior basal forebrain volume in the hypo-cholinergic compared to both normo-cholinergic Parkinson's disease Bayes factor against the null model (BF10) = 8.2 and control participants (BF10 = 6.0), while for the anterior basal forebrain the evidence was inconclusive (BF10 < 3). In continuous association analyses, posterior basal forebrain volume was significantly associated with cortical PMP PET signal in a temporo-posterior distribution. The combined models for the prediction of cognitive scores showed that both cholinergic markers (posterior basal forebrain volume and cortical PMP PET signal) were independently related to multi-domain cognitive deficits, and were more important predictors for all cognitive scores, including memory scores, than hippocampal volume. We conclude that degeneration of the posterior basal forebrain in Parkinson's disease is accompanied by functional cortical changes in acetylcholinesterase activity and that both PET and MRI cholinergic imaging markers are independently associated with multi-domain cognitive deficits in Parkinson's disease without dementia. Comparatively, hippocampal atrophy only seems to have minimal involvement in the development of early cognitive impairment in Parkinson's disease.
Parkinson's disease (PD) is a common neurodegenerative disorder resulting in motor, cognitive, psychiatric, sleep, sensory, and autonomic disturbances. The wide spectrum of morbidity is a major ...source for disability and impaired quality of life in patients with PD. A key pathological abnormality in PD is the loss of dopaminergic neurons in the substantia nigra resulting in loss of dopaminergic nerve terminals in the striatum. Normal aging is also associated with substantial loss of striatal dopaminergic nerve terminal function at a rate of 5%-8% per decade of adult life. Therefore, normal aging between the ages of 25-75 years may result in about half the severity of losses as those seen in PD. The facts that aging is a major risk for PD and that normal aging is associated with substantial loss of striatal dopaminergic nerve terminal functions raise questions about shared biological vulnerabilities.
Objectives
Structural imaging of the cholinergic basal forebrain may provide a biomarker for cholinergic system integrity that can be used in motor and non‐motor outcome studies in Parkinson's ...disease. However, no prior studies have validated these structural metrics with cholinergic nerve terminal in vivo imaging in Parkinson's disease. Here, we correlate cholinergic basal forebrain morphometry with the topography of vesicular acetylcholine transporter in a large Parkinson's sample.
Methods
18F‐Fluoroethoxybenzovesamicol vesicular acetylcholine transporter positron emission tomography was carried out in 101 non‐demented people with Parkinson's (76.24% male, mean age 67.6 ± 7.72 years, disease duration 5.7 ± 4.4 years). Subregional cholinergic basal forebrain volumes were measured using magnetic resonance imaging morphometry. Relationships were assessed via volume‐of‐interest based correlation analysis.
Results
Subregional volumes of the cholinergic basal forebrain predicted cholinergic nerve terminal loss, with most robust correlations occurring between the posterior cholinergic basal forebrain and temporofrontal, insula, cingulum, and hippocampal regions, and with modest correlations in parieto‐occipital regions. Hippocampal correlations were not limited to the cholinergic basal forebrain subregion Ch1‐2. Correlations were also observed in the striatum, thalamus, and brainstem.
Interpretation
Cholinergic basal forebrain morphometry is a robust predictor of regional cerebral vesicular acetylcholine transporter bindings, especially in the anterior brain. The relative lack of correlation between parieto‐occipital binding and basal forebrain volumes may reflect the presence of more diffuse synaptopathy in the posterior cortex due to etiologies that extend well beyond the cholinergic system. ANN NEUROL 2023;93:991–998
Most individuals with Parkinson's disease experience cognitive decline. Mounting evidence suggests this is partially caused by cholinergic denervation due to α-synuclein pathology in the cholinergic ...basal forebrain. Alpha-synuclein deposition causes inflammation, which can be measured with free water fraction, a diffusion MRI-derived metric of extracellular water. Prior studies have shown an association between basal forebrain integrity and cognition, cholinergic levels and cognition, and basal forebrain volume and acetylcholine, but no study has directly investigated whether basal forebrain physiology mediates the relationship between acetylcholine and cognition in Parkinson's disease. We investigated the relationship between these variables in a cross-sectional analysis of 101 individuals with Parkinson's disease. Cholinergic levels were measured using fluorine-18 fluoroethoxybenzovesamicol (18F-FEOBV) PET imaging. Cholinergic innervation regions of interest included the medial, lateral capsular and lateral perisylvian regions and the hippocampus. Brain volume and free water fraction were quantified using T1 and diffusion MRI, respectively. Cognitive measures included composites of attention/working memory, executive function, immediate memory and delayed memory. Data were entered into parallel mediation analyses with the cholinergic projection areas as predictors, cholinergic basal forebrain volume and free water fraction as mediators and each cognitive domain as outcomes. All mediation analyses controlled for age, years of education, levodopa equivalency dose and systolic blood pressure. The basal forebrain integrity metrics fully mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and attention/working memory, and partially mediated the relationship between medial acetylcholine and attention/working memory. Basal forebrain integrity metrics fully mediated the relationship between medial, lateral capsular and lateral perisylvian acetylcholine and free water fraction. For all mediations in attention/working memory and executive function, the free water mediation was significant, while the volume mediation was not. The basal forebrain integrity metrics fully mediated the relationship between hippocampal acetylcholine and delayed memory and partially mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and delayed memory. The volume mediation was significant for the hippocampal and lateral perisylvian models, while free water fraction was not. Free water fraction in the cholinergic basal forebrain mediated the relationship between acetylcholine and attention/working memory and executive function, while cholinergic basal forebrain volume mediated the relationship between acetylcholine in temporal regions in memory. These findings suggest that these two metrics reflect different stages of neurodegenerative processes and add additional evidence for a relationship between pathology in the basal forebrain, acetylcholine denervation and cognitive decline in Parkinson's disease.
Sleep disturbances are common and a major source of disability in Parkinson's disease (PD). Primary and secondary insomnia, rapid eye movement sleep behavior disorder (RDB), central sleep apnea, ...restless legs, and nocturnal akinesia are common sleep disturbances in PD. Prodromal presence of RBD is associated with a more severe motor and non-motor PD subtype implying a significant disease-modifying effect of this parasomnia. Other disease-modifying mechanisms of sleep disturbances in PD include impaired glymphatic clearance, endoplasmic reticulum stress, nocturnal brain deoxygenation and inflammatory processes among others. Impairments of neural circuit switching and imbalance between inhibitory and excitatory neuronal populations are likely responsible for episodic sleep disturbances, in particular RBD. As neural circuits may predict patterns of α-synuclein propagation in the nervous system, impairments of such circuits are of high relevance for PD pathophysiology. Future research is needed to determine whether appropriate treatment for disturbed sleep might slow progression of PD.
Previous studies of animal models of Parkinson disease (PD) suggest an imbalance between striatal acetylcholine and dopamine, although other studies have questioned this. To our knowledge, there are ...no previous in vivo neuroimaging studies examining striatal acetylcholine-dopamine imbalance in PD patients. Using cholinergic and dopaminergic PET (
F-fluoroethoxybenzovesamicol
F-FEOBV and
C-dihydrotetrabenazine
C-DTBZ, respectively) and correlational tractography, our aim was to investigate the acetylcholine-dopamine interaction at 2 levels of dopaminergic loss in PD subjects: integrity loss of the nigrostriatal dopaminergic white matter tract and loss at the presynaptic-terminal level.
The study involved 45 subjects with mild to moderate PD (36 men, 9 women; mean age, 66.3 ± 6.3 y, disease duration, 5.8 ± 3.6 y; Hoehn and Yahr stage, 2.2 ± 0.6) and 15 control subjects (9 men, 6 women; mean age, 69.1 ± 8.6 y). PET imaging was performed using standard protocols. We first estimated the integrity of the dopaminergic nigrostriatal white matter tracts in PD subjects by incorporating molecular information from striatal
C-DTBZ PET into the fiber tracking process using correlational tractography (based on quantitative anisotropy QA, a measure of tract integrity). Subsequently, we used voxel-based correlation to test the association of the mean QA of the nigrostriatal tract of each cerebral hemisphere with the striatal
F-FEOBV distribution volume ratio (DVR) in PD subjects. The same analysis was performed for
C-DTBZ DVR in 12 striatal subregions (presynaptic-terminal level).
Unlike
C-DTBZ DVR in striatal subregions, the mean QA of the nigrostriatal tract of the most affected hemisphere showed a negative correlation with a striatal cluster of
F-FEOBV DVR in PD subjects (corrected
= 0.039). We also found that the mean
F-FEOBV DVR within this cluster was higher in the PD group than in the control group (
= 0.01). Cross-validation analyses confirmed these findings. We also found an increase in bradykinesia ratings associated with increased acetylcholine-dopamine imbalance in the most affected hemisphere (
= 0.41,
= 0.006).
Our results provide evidence for the existence of striatal acetylcholine-dopamine imbalance in early PD and may provide an avenue for testing in vivo effects of therapeutic strategies aimed at restoring striatal acetylcholine-dopamine balance in PD.
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