To evaluate the concept of “brain-first” and “body-first” types of Lewy body diseases (LBDs) based on long-term longitudinal data.

The Braak staging system of Parkinson’s disease conceptualizes propagation of alpha-synucleinopathy from the autonomic nervous system to the brain. Recently, Borghammer and colleagues introduced a concept of “brain-first” and “body-first” bi-directional disease progression in LBDs, the latter type corresponding roughly to Braak’s hypothesis. Longitudinal follow-up data in the same patients are necessary to evaluate these concepts.

Clinical and laboratory findings were analyzed from 6 patients with LBDs (3 brain-first, 3 body-first) who had serial evaluations over many years. Brain-first LBD was defined by initially unilateral, levodopa-responsive bradykinesia and resting tremor without evidence of autonomic failure. Body-first LBD was defined by chronic neurogenic orthostatic hypotension (nOH) and sympathetic noradrenergic deficiency with skin biopsy evidence of increased deposition of alpha-synuclein in sympathetic noradrenergic nerves during the disease course. Serial cardiac noradrenergic neuroimaging by 18F-dopamine and putamen dopaminergic neuroimaging by 18F-DOPA positron emission tomography were done.

Follow-up data from the time of symptom onset until death or until 2021 were reviewed from 3 brain-first (21, 23, and 25 years) and 3 body-first (12, 22, and 28 years) patients. The brain-first patients had persistently decreased putamen/occipital cortex ratios (PUT/OCC) of 18F-DOPA-derived radioactivity and eventual loss of cardiac 18F-dopamine-derived radioactivity. The latency for identification of cardiac noradrenergic deficiency varied substantially (2, 7, and 11 years). Among the body-first patients, in 1 decreased PUT/OCC ratios were first noted at 4 years from the onset of symptomatic nOH; in the other 2 PUT/OCC ratios were not decreased during follow-up.

The data fit with the brain-first/body-first dichotomy; however, in brain-first LBD the time to development of cardiac noradrenergic deficiency and in body-first LBD the time to development of putamen dopaminergic deficiency are variable.