Objective: To investigate the relationship between basal forebrain (BF) neurodegeneration and cholinergic system in body vs brain-first Parkinson’s disease (PD) subtypes.

Background: Free water imaging can reflect the extent of the neurodegenerative process, including inflammatory components. A recently proposed body-first (REM sleep onset antedating motor impairments > 1 yr) compared to motor-onset (brain-first) PD subtypes suggests evidence of more severe neurodegeneration in the body-first subtype.  Prior studies have shown greater free water volumes of the cholinergic forebrain in cognitively impaired PD persons but specific information about REM sleep phenotyping has been lacking.

Method: 71 PD (28 body-first and 43 brain-first) underwent dMRI and cholinergic transporter [¹⁸F]FEOBV PET. Groups were compared on their BF free-water volume fraction using ANCOVA (to control for number of iterations used to estimate free-water for each participant). LASSO regressions (10-fold cross-validation to select optimal penalty) were subsequently used to predict BF free-water in body-first and brain-first groups.

Results: ANCOVA demonstrated higher basal forebrain free-water volume fraction in the body-first compared to the brain-first PD subgroups (β=0.76, P=0.001). LASSO regression predicting basal forebrain free-water in brain-first subtype retained bidirectional cortical and subcortical cholinergic bindings as regressors and accounted for 63.1% of the variance in BF free-water of brain-first PD individuals. No regressors were retained in the LASSO regression predicting basal forebrain free-water from regional cholinergic binding in body-first PD subgroup. Post-hoc ANCOVA interaction model confirmed that basal forebrain free-water is only predictive of cholinergic system changes in the brain-first subtype (β=1.15, P<0.001).

Conclusion: Greater free water volumes of the cholinergic forebrain are present in body compared to brain-first PD, suggesting more severe neurodegenerative and related inflammatory processes in body-first PD which lead to changes in cholinergic system. Lower BF free-water values among brain-first participants allowed us to capture the relationship between basal forebrain degeneration and cholinergic system changes which has already reached a plateau among body-first participants in our sample due to extent of neurodegeneration observed among them.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/free-water-imaging-of-the-cholinergic-forebrain-in-body-vs-brain-first-parkinsons-disease-subtypes/