In the central Lewy body diseases (LBDs) Parkinson's disease and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests, substantial central neurodegeneration has already occurred. Biomarkers of preclinical disease are needed to test strategies that might delay the onset of symptomatic central LBDs and extend healthspan. The prospective, longitudinal PDRisk study asked whether cardiac sympathetic neuroimaging, cerebrospinal fluid catecholamine metabolites, cardiovascular physiological biomarkers, and alpha-synuclein seeding activity predict central LBDs in at-risk individuals. This review highlights and builds on several findings from this unique study. Some concepts induced from the present and previous data are: 1) Central LBDs can begin outside the brain ("body-first"), with early involvement of cardiac sympathetic nerves as evidenced by ¹⁸F-dopamine positron emission tomography (PET) and normal initial putamen dopaminergic innervation by ¹⁸F-DOPA PET. 2) DLB can follow a similar body-first progression pattern. 3) Body-first LBDs entail tri-phasic temporal sequences, corresponding conceptually to homeostasis, dyshomeostasis, and symptomatic disease, noted in the heart years before the striatum. 4) LBDs feature a vesicular storage defect in extant catecholaminergic terminals, exemplifying the "sick-but-not-dead" phenomenon. 5) There are multiple other functional abnormalities in residual catecholaminergic terminals in LBDs. 6) Based on computational modeling, disease-modifying treatments begun in the dyshomeostatic phase might delay the onset of symptomatic LBDs, compressing morbidity.
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