In most neurodegenerative diseases there are contradictory explanations of where the disease strikes and how it progresses. For a majority of scientists it begins somewhere in the brain, while for a minority it appears in guts, mucous membranes or muscles.
Aggregation of alpha-synuclein into inclusion bodies, termed Lewy pathology, is a defining feature of Parkinson's disease (PD) and Dementia with Lewy bodies (LBD), a less agressive form of the Parkinson's disease.
The Braak staging system is based on the idea that Lewy pathology starts in the olfactory bulb and enteric nervous system, and invades the brain via the vagus nerve. Alternative hypotheses propose that Lewy pathology does not start in the gut but inside the central nervous system (CNS), or possibly via an isolated olfactory entry route followed by intra-cerebral propagation.
A potential problem with both the Braak and DLB consortium staging systems is that relatively little emphasis is put on the magnitude of Lewy pathology in a given region. Assignment of a case to a specific category or stage is based mainly on the spatial distribution of pathology. Thus, two patients who display Lewy pathology in the same anatomical regions, but who have quite different levels of pathology in those regions, will nevertheless be labeled with the same Braak or DLB consortium stage.
A recent paper analyzed 124 Lewy pathology-positive post mortem cases in a population-based sample of subjects aged over 85 years (Raunio et al., 2019). The authors showed that approximately two-thirds of the cases conformed to a caudo-rostral pattern with relatively more pathology in the brainstem than in the telencephalon.
The remaining one-third showed an amygdala-centered pattern with a peak of pathology in the “center of the brain”, including the amygdala, entorhinal cortex, and SN, and then relatively less pathology in the lower brainstem, spinal intermediolateral column (IML), and also in neocortical regions.
Here, the authors use two existing post mortem datasets to explore the possibility that clinical body-first and brain-first subtypes are equivalent to the caudo-rostral and amygdala-centered patterns of Lewy pathology seen at post mortem.
In summary, caudo-rostral and amygdala-centered profiles of Lewy pathology seem to be the two most common patterns seen in post mortem studies. In cases with a low global burden of Lewy pathology, thought to be early prodromal disease, the patterns are particularly clear. Therefore, it seems likely that patients with Lewy body disorders most commonly evolve from one of these two initial conditions.
Using in vivo, multi-modal imaging, it was recently shown that patients with prodromal and de novo PD can be divided into two clusters compatible with brain-first and body-first etiology.
In this paper the authors argue that body-first patients, in whom the sympathetic system degenerates before the dopamine system, are equivalent to post mortem cases with a caudo-rostral distribution of Lewy pathology. In early caudo-rostral cases, the autonomic structures display more pathology than the substantia nigra and limbic structures.
In contrast, brain-first patients show dopaminergic degeneration before sympathetic denervation. The scientists remarked that these patients are equivalent to post mortem cases with an amygdala-centered distribution of Lewy pathology, where limbic structures and the nigra show more pathology than do the autonomic structures.
This hypothesis could be tested in future studies, especially once a PET tracer targeting alpha-synuclein becomes available.
This line of reasoning suggests that the gut-first hypothesis posed by Braak and colleagues is only valid for that part of LBD patients, which the authors refer to as the body-first subtype.
Importantly, if the Lewy pathology in the remaining part of patients truly originates inside the brain or olfactory bulb and generally shows a top-down direction of propagation, it will be much more difficult to identify brain-first LBD at the prodromal stage.
These patients will generally not develop the most recognizable prodromal symptoms such as RBD and autonomic dysfunction until after parkinsonism or dementia have manifested.
If correct, this further emphasizes the importance of developing robust biomarkers in body fluids to detect brain-first LBD at an early stage, where neuroprotective treatments will be most effective.