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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 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.

Background: Gait disturbance is an early, disabling feature of Parkinson's disease (PD) that is typically refractory to dopaminergic medication. The cortical cholinergic system, originating in the nucleus basalis of Meynert of the basal forebrain, has been implicated. However, it is not known if degeneration in this region relates to a worsening of disease-specific gait impairment. Objective: To evaluate associations between sub-regional cholinergic basal forebrain volumes and longitudinal progression of gait impairment in PD. Methods: 99 PD participants and 47 control participants completed gait assessments via an instrumented walkway during 2 minutes of continuous walking, at baseline and for up to 3 years, from which 16 spatiotemporal characteristics were derived. Sub-regional cholinergic basal forebrain volumes were measured at baseline via MRI and a regional map derived from post-mortem histology. Univariate analyses evaluated cross-sectional associations between sub-regional volumes and gait. Linear mixed-effects models assessed whether volumes predicted longitudinal gait changes. Results: There were no cross-sectional, age-independent relationships between sub-regional volumes and gait. However, nucleus basalis of Meynert volumes predicted longitudinal gait changes unique to PD. Specifically, smaller nucleus basalis of Meynert volume predicted increasing step time variability (P = 0.019) and shortening swing time (P = 0.015); smaller posterior nucleus portions predicted shortening step length (P = 0.007) and increasing step time variability (P = 0.041). Conclusions: This is the first study to demonstrate that degeneration of the cortical cholinergic system predicts longitudinal progression of gait impairments in PD. Measures of this degeneration may therefore provide a novel biomarker for identifying future mobility loss and falls. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disor