Braak's Unfinished Hypothesis: A Clinicopathological Case Report of alpha-Synuclein Peripheral Neuropathy Preceding Parkinsonism by 20 Years

Background: alpha-synuclein aggregates in the form of Lewy bodies and Lewy neurites are the pathological hallmark of Parkinson disease (PD) and dementia with Lewy bodies (DLB). Autopsy studies suggest that alpha-synuclein aggregates appear in localized areas of the central nervous system before spreading in a sequential pattern from the brainstem to the cerebral cortex, known as the Braak hypothesis. Increased prevalence of peripheral neuropathy in PD is recognized, with multiple hypothesized mechanisms including alpha-synuclein deposition. Method: We describe a patient who developed a peripheral sensory neuropathy at age 60, which progressed insidiously over the following decade. Results: During the patient's eighth decade, the patient developed a fluctuant cognitive disturbance with hallucinations before becoming overtly parkinsonian at age 78 years leading to a diagnosis of DLB. At this point, histology slides from a sural nerve biopsy taken at age 72 were re-evaluated and immunohistochemistry demonstrated alpha-synuclein deposition. Conclusion: This case provides important in vivo clinical correlation for the Braak hypothesis, extending its scope beyond idiopathic PD. A growing body of evidence supports the alpha-synuclein spreading hypothesis that posits the pathologic process begins in the peripheral nerves and spreads trans-synaptically to the CNS in an ascending pattern.