New insights suggest that Parkinson’s disease may actually encompass two different subtypes:
- a "body-first" form and
- a "brain-first" form.
This revolves around the location where the disease first originates: in the brain or in the body.
The specific type of Parkinson one has could influence the clinical trajectory and progression of the disease.
Body-First Parkinson’s Disease
In the body-first type, alpha-synuclein pathology (the clumping together of alpha-synuclein proteins) is thought to originate in the autonomic nervous system, especially in the gastrointestinal tract. Key characteristics of this form include:
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Early autonomic dysfunction, such as constipation, irritable bowel disorder (IBD), and orthostatic hypotension (low blood pressure when standing up). These symptoms can occur years before the classical motor symptoms (e.g. tremor, slow movements, stiffness) emerge.
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Bilateral (affecting both sides of the body) and more symmetric motor symptoms (e.g. tremor, stiffness) at diagnosis.
- Frequent presence of features such as anosmia (being less able to smell properly) and sleep disturbances (e.g. REM sleep behavior disorder, RBD).
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Vagal nerve pathology and peripheral alpha-synuclein aggregates are often present. This means clumping of alpha-synuclein protein in nerves, including the vagal nerve which connects the gut with the brain.
- May have a slower motor progression, but a higher burden of non-motor symptoms.
This form is hypothesized to represent a "bottom-up" spread of disease, with peripheral structures, such as the nerves surrounding the gut, affected first and the pathology ascending toward the brainstem and eventually the substantia nigra, the region in the brain where most dopamine is produced.
Brain-First Parkinson’s Disease
In contrast, the brain-first form suggests that the pathology originates within the brain, particularly in the amygdala, limbic system, or substantia nigra, and then may descend to the periphery. Characteristics include:
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Absence or later onset of REM sleep behaviour disorder and autonomic symptoms (e.g. constipation, irritable bowel syndrome, orthostatic hypertension).
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Asymmetric motor symptoms at onset (for example a tremor in the left arm but not right arm), often with a more rapid motor decline.
- Fewer prodromal features (e.g. constipation, loss of smell, REM sleep dysregulation) prior to motor signs (e.g. tremor, stiffness, slow movements).
- Greater dopaminergic denervation visible on early neuroimaging (e.g., DAT-SPECT).
- Tends to follow a "top-down" pattern of neurodegeneration (from centers in the brain to other brain regions and to the body).
Clinical and Research Implications
Whether a patient has a body-first or brain-first form of Parkinson’s may have implications for early diagnosis and treatment. For instance:
- Patients with body-first PD might benefit more from early detection through autonomic biomarkers (e.g., colon biopsies, skin alpha-synuclein tests) and REM sleep behaviour disorder (RBD) screening.
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Brain-first PD may be more amenable to central nervous system-targeted neuroprotective strategies due to early nigral involvement.
- Therapeutic strategies like alpha-synuclein immunotherapy or vagal nerve modulation might have different efficacy depending on the subtype.
Moreover, this classification may help stratify patients in clinical trials, reducing heterogeneity (differences between patients), and improving the chances of demonstrating treatment efficacy.
Conclusion
The "body-first" and "brain-first" types are transforming Parkinson's disease research. This distinction underscores the importance of the gut-brain axis, and encourages comprehensive assessment of non-motor symptoms (e.g. constipation, loss of smell, REM sleep dysregulation), and pushes for the development of innovative diagnostic and therapeutic strategies.
While further research is needed, this evolving understanding promises to unlock new avenues for preventing, diagnosing, and ultimately, conquering Parkinson's disease from its earliest roots.
