Cholinergic changes play a fundamental role in the natural history of
dementia with Lewy bodies and
Lewy body disease in general. Despite important achievements in the field of
cholinergic research, significant challenges remain. We conducted a study with four main objectives: (i) to examine the integrity of
cholinergic terminals in newly diagnosed
dementia with Lewy bodies; (ii) to disentangle the
cholinergic contribution to
dementia by comparing
cholinergic changes in Lewy body patients with and without
dementia; (iii) to investigate the in vivo relationship between
cholinergic terminal loss and
atrophy of
cholinergic cell clusters in the basal forebrain at different stages of
Lewy body disease; and (iv) to test whether any asymmetrical degeneration in
cholinergic terminals would correlate with motor dysfunction and hypometabolism. To achieve these objectives, we conducted a comparative cross-sectional study of 25 newly diagnosed
dementia with Lewy bodies patients (age 74 ± 5 years, 84% male), 15 healthy control subjects (age 75 ± 6 years, 67% male) and 15
Parkinson's disease patients without
dementia (age 70 ± 7 years, 60% male). All participants underwent 18F-fluoroetoxybenzovesamicol PET and high-resolution structural MRI. In addition, we collected clinical 18F-fluorodeoxyglucose PET images. Brain images were normalized to standard space and regional tracer uptake and volumetric indices of basal forebrain degeneration were extracted. Patients with
dementia showed spatially distinct reductions in
cholinergic terminals across the cerebral cortex, limbic system, thalamus and brainstem. Also,
cholinergic terminal binding in cortical and limbic regions correlated quantitatively and spatially with
atrophy of the basal forebrain. In contrast, patients without
dementia showed decreased
cholinergic terminal binding in the cerebral cortex despite preserved basal forebrain volumes. In patients with
dementia,
cholinergic terminal reductions were most severe in limbic regions and least severe in occipital regions compared to those without
dementia. Interhemispheric asymmetry of
cholinergic terminals correlated with asymmetry of brain metabolism and lateralized motor function. In conclusion, this study provides robust evidence for severe
cholinergic terminal loss in newly diagnosed
dementia with Lewy bodies, which correlates with structural imaging measures of
cholinergic basal forebrain degeneration. In patients without
dementia, our findings suggest that loss of
cholinergic terminal function occurs 'before' neuronal cell degeneration. Moreover, the study supports that degeneration of the
cholinergic system is important for brain metabolism and may be linked with degeneration in other transmitter systems. Our findings have implications for understanding how
cholinergic system pathology contributes to the clinical features of
Lewy body disease, changes in brain metabolism and
disease progression patterns.