The Braak hypothesis, characterized by the anatomist Heiko Braak and his colleagues in 2003, posits that Parkinson’s disease begins in the peripheral nervous system and travels systematically through the central nervous system. Based on autopsy studies that looked at the distribution of alpha-synuclein in the brains of patients with Parkinson’s disease, Braak demonstrated that Lewy body pathology then spreads through the central nervous system in such a way that it can be described in stages, beginning in the lower brain stem and olfactory system and ending in the neocortex, at which point Parkinson’s is at its most severe.

Subsequent studies have identified discrepancies in the Braak hypothesis; it does not describe the course of Parkinson’s in every case. However, in a paper recently published in Movement Disorders, Donlon et al present the case of a patient whose disease course correlates with the Braak hypothesis.

A male patient first presented with numbness and tingling in his feet at age 60. By age 70 he experienced orthostatic hypotension, urinary incontinence, constipation, and delayed gastric emptying, indicating the involvement of the autonomic nervous system. Amyloidosis and syphilis were ruled out, but the cause of his symptoms was still unclear. At age 72, he underwent a sural nerve biopsy, which showed some nerve fiber loss. At this point, his physicians suspected an abnormal immune response as the cause of his symptoms, but the patient did not improve with immunoglobin or immunosuppressant therapy.

By age 74, the patient developed hallucinations and cognitive impairment. He began to vocalize and thrash out while sleeping, suggestive of REM sleep behavior disorder. At age 78, the patient presented with a hoarse voice and bradykinesia without tremor. A DaT scan was performed, and the patient was diagnosed with dementia with Lewy bodies. At this point, the man’s physicians decided to reexamine the results from the sural nerve biopsy and discovered alpha-synuclein deposition throughout the sural nerve.

The authors note that although sensory neuropathy is more common in patients with Parkinson’s than in the general population, it is rarely the first sign of dementia with Lewy bodies. Yet this case demonstrates alpha-synucleinopathy in the peripheral nervous system six years before a clinical diagnosis of dementia with Lewy bodies.

Donlon et al note that their case study supports the potential use of sural nerve biopsies in identifying prodromal synucleinopathies. This is a minor surgical procedure but requires a few days of down time when the patient cannot bear any weight on the biopsied leg. However, less invasive skin biopsies have been demonstrated to be highly sensitive and specific for the detection of alpha-synuclein in the peripheral nervous system, even very early in the course of Parkinson’s disease, dementia with Lewy bodies, and other synucleinopathies.

The Braak hypothesis, although imperfect, still serves as an important construct for understanding the progression of synucleinopathies. And we now have the diagnostic tools to detect alpha-synuclein in some cases even before the full clinical spectrum of disease has presented itself.