[Pathophysiological process underlying Parkinson's disease: motor & non-motor symptoms]

Area of Science:

• Neuroscience
• Neuropathology
• Movement Disorders

Context:

• The Braak hypothesis proposes alpha-synucleinopathy begins in the medulla oblongata and progresses rostrally, affecting the substantia nigra later in Parkinson's disease (PD).
• Prodromal non-motor symptoms like constipation, depression, REM-sleep behavior disorder (RBD), and hyposmia are linked to early PD pathology in areas like the olfactory bulb.
• Recent findings indicate a significant proportion of PD cases do not fit the Braak staging, often showing amygdala-predominant alpha-synucleinopathy.

Purpose:

• To investigate the role of the amygdala in early alpha-synucleinopathy and its contribution to hyposmia in Parkinson's disease.
• To explore potential alternative pathological pathways in PD progression beyond the established Braak hypothesis.
• To correlate metabolic changes in the amygdala with olfactory deficits in PD patients.

Summary:

• While the Braak hypothesis suggests a specific progression of alpha-synucleinopathy in PD, a substantial number of cases exhibit amygdala-predominant pathology.
• Lewy pathology in the olfactory bulb is linked to amygdala involvement, and the amygdala's role in odor perception suggests it contributes to early hyposmia in PD.
• Metabolic alterations in the amygdala correlate with impaired odor identification, supporting the amygdala's involvement in olfactory dysfunction and suggesting a distinct pathological process originating in the olfactory bulb and extending to the amygdala.

Impact:

• Challenges the strict adherence to the Braak hypothesis by highlighting alternative early pathological sites in PD.
• Identifies the amygdala as a potential key player in early PD, particularly concerning non-motor symptoms like hyposmia.
• Provides new insights into the neuropathological mechanisms underlying PD, potentially leading to earlier diagnostic markers and targeted therapies.