Investigating the relationship between cholinergic system integrity and Parkinson’s disease symptoms using MRI and EEG

Cholinergic cells of the basal forebrain (cBF) and pedunculopontine nucleus (PPN) are implicated in Parkinson’s disease (PD), but current understanding of their role in PD symptomology is limited. Neuropathological and recent in vivo imaging research implies that cBF and PPN degeneration is associated with PD cognitive and mobility impairments. There remains a need to identify and validate widely accessible markers of cholinergic system degeneration to better understand its contribution to these symptoms. The aim of this thesis was to investigate how structural changes in the cBF and PPN relate to cortical activity and cognitive and mobility performance in people with PD, people with mild cognitive impairment (MCI), and healthy age-matched controls. T1 and diffusion-weighted images were used in combination with stereotactic maps of the cBF and PPN to extract volumetric and diffusivity metrics from these regions as in vivo surrogate markers of structural integrity. These structural measures were assessed for their relationship with resting-state EEG, and cognitive and functional mobility performance. People with PD showed reduced cBF volumes compared to healthy controls, and elevated PPN diffusivity compared to people with MCI. Subregional cBF volumes correlated with EEG changes in the theta-alpha range in people with PD and people with MCI. Volume loss in the cBF was also shown to mediate the relationship between executive function and Timed Up and Go dual-task performance in people with PD. PPN diffusivity metrics demonstrated correlations with cognitive performance and EEG changes in the alpha range in people with PD, and in the beta-gamma range in people with MCI. Cortical activity measured with EEG may hold physiological relevance for structural changes occurring in the cBF and PPN. Volumetric loss in the cBF may impair the attentional-executive control of mobility functions. Elevated PPN diffusivity may impair attentional performance during tasks that require sensorimotor integration

Quantitative EEG and cholinergic basal forebrain atrophy in Parkinson's disease and mild cognitive impairment

Cholinergic degeneration is a key feature of dementia in neurodegenerative conditions including Alzheimer's disease (AD) and Parkinson's disease (PD). Quantitative electro-encephalography (EEG) metrics are altered in both conditions from early stages, and recent research in people with Lewy body and AD dementia suggests these changes may be associated with atrophy in cholinergic basal forebrain nuclei (cBF). To determine if these relationships exist in predementia stages of neurodegenerative conditions, we studied resting-state EEG and in vivo cBF volumes in 31 people with PD (without dementia), 21 people with mild cognitive impairment (MCI), and 21 age-matched controls. People with PD showed increased power in slower frequencies and reduced alpha reactivity compared to controls. Volumes of cholinergic cell clusters corresponding to the medial septum and vertical and horizontal limb of the diagonal band, and the posterior nucleus basalis of Meynert, correlated positively with; alpha reactivity in people with PD (p< 0.01); and pre-alpha power in people with MCI (p< 0.05). These results suggest that alpha reactivity and pre-alpha power are related to changes in cBF volumes in MCI and PD without dementia

Free-water imaging of the cholinergic basal forebrain and pedunculopontine nucleus in Parkinson's disease

Free-water imaging can predict and monitor dopamine system degeneration in people with Parkinson's disease. It can also enhance the sensitivity of traditional diffusion tensor imaging (DTI) metrics for indexing neurodegeneration. However, these tools are yet to be applied to investigate cholinergic system degeneration in Parkinson's (which involves both the pedunculopontine nucleus (PPN) and cholinergic basal forebrain (cBF)). Free-water imaging, free-water-corrected DTI, and volumetry were used to extract structural metrics from the cBF and PPN in 99 people with Parkinson's and 46 age-matched controls. Cognitive ability was tracked over 4.5-years. Pearson's partial correlations revealed that free-water-corrected DTI metrics in the PPN were associated with performance on cognitive tasks that required participants to make rapid choices (behavioural flexibility). Volumetric, free-water content and DTI metrics in the cBF were elevated in a sub-group of people with Parkinson's with evidence of cognitive impairment, and linear mixed modelling revealed that these metrics were differently associated with current and future changes to cognition. Free water and free-water-corrected DTI can index cholinergic degeneration that could enable stratification of patients in clinical trials of cholinergic interventions for cognitive decline. In addition, degeneration of the PPN impairs behavioural flexibility in Parkinson's, which may explain this region's role in increased risk of falls

Free-water imaging of the cholinergic basal forebrain and pedunculopontine nucleus in Parkinson\u27s disease

Free-water imaging can predict and monitor dopamine system degeneration in people with Parkinson\u27s disease. It can also enhance the sensitivity of traditional diffusion tensor imaging (DTI) metrics for indexing neurodegeneration. However, these tools are yet to be applied to investigate cholinergic system degeneration in Parkinson\u27s disease, which involves both the pedunculopontine nucleus and cholinergic basal forebrain. Free-water imaging, free-water-corrected DTI and volumetry were used to extract structural metrics from the cholinergic basal forebrain and pedunculopontine nucleus in 99 people with Parkinson\u27s disease and 46 age-matched controls. Cognitive ability was tracked over 4.5 years. Pearson\u27s partial correlations revealed that free-water-corrected DTI metrics in the pedunculopontine nucleus were associated with performance on cognitive tasks that required participants to make rapid choices (behavioural flexibility). Volumetric, free-water content and DTI metrics in the cholinergic basal forebrain were elevated in a sub-group of people with Parkinson\u27s disease with evidence of cognitive impairment, and linear mixed modelling revealed that these metrics were differently associated with current and future changes to cognition. Free water and free-water-corrected DTI can index cholinergic degeneration that could enable stratification of patients in clinical trials of cholinergic interventions for cognitive decline. In addition, degeneration of the pedunculopontine nucleus impairs behavioural flexibility in Parkinson\u27s disease, which may explain this region\u27s role in increased risk of falls