Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis

Abstract

Parkinson's disease (PD) is a highly heterogeneous disorder, which probably consists of multiple subtypes. Aggregation of misfolded alpha-synuclein and propagation of these proteinacious aggregates through interconnected neural networks is believed to be a crucial pathogenetic factor. It has been hypothesized that the initial pathological alpha-synuclein aggregates originate in the enteric or peripheral nervous system (PNS) and invade the central nervous system (CNS) via retrograde vagal transport. However, evidence from neuropathological studies suggests that not all PD patients can be reconciled with this hypothesis. Importantly, a small fraction of patients do not show pathology in the dorsal motor nucleus of the vagus. Here, it is hypothesized that PD can be divided into a PNS-first and a CNS-first subtype. The former is tightly associated with REM sleep behavior disorder (RBD) during the prodromal phase and is characterized by marked autonomic damage before involvement of the dopaminergic system. In contrast, the CNS-first phenotype is most often RBD-negative during the prodromal phase and characterized by nigrostriatal dopaminergic dysfunction prior to involvement of the autonomic PNS. The existence of these subtypes is supported by in vivo imaging studies of RBD-positive and RBD-negative patient groups and by histological evidence-reviewed herein. The present proposal provides a fresh hypothesis-generating framework for future studies into the etiopathogenesis of PD and seems capable of explaining a number of discrepant findings in the neuropathological literature.

Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Mitochondrial DNA Profiling of Parkinson’s Disease

“…Neuronal and systemic alterations of mtDNA have also been documented in AD [29,30], suggesting a possible common pathogenic mechanism. This aspect is supported by a recent study on neuromolecular imaging that brings the etiology of Parkinson's to the gastrointestinal tract via beta amyloid [31]. It has been previously reported that peripheral blood samples from AD patients exhibited an increased presence of variants in 89.7% of nucleotide positions (np) along the whole mtDNA sequence when compared to control subjects [30].…”

“…Diagnostic accuracy varies considerably depending on disease duration (lower on first visit), age, clinician expertise, and increasing understanding of this pathology. In this context, advances in live imaging, such as neuromolecular imaging, could improve the understanding as well as diagnosis of PD [31,86]. Often, failure in recognizing other pathologies causing neurodegenerative disorder or secondary parkinsonism as well as the absence of a true progressive parkinsonian disorder are common causes of diagnostic error [85].…”

Deep Brain Stimulation Effects on Olfactory Dysfunction of Parkinson’s Disease - A Meta-Analysis

“…Here we adopt an idea of paper that patients with PD contain highly heterogeneous symptoms and display capricious involvement of different neuro-regions during the early phases of disease and this heterogeneity can be partly explained by de ning PD into a PNS-rst and a CNS-rst subtype [27]. According to this review, PD patients with olfactory function early impaired onset may possible belong to the PNS-rst subtype.…”

Gut microbiome signatures of risk and prodromal markers of Parkinson’s disease

“…Lactobacillus was decreased in individuals with possible RBD, whereas an increase in PD patients has previously been shown repeatedly. It is possible that subtypes of prodromal PD exist with varying involvement of the gut (e.g., RBD representing a subtype with early autonomic denervation) 47 . Also, the microbiome may (differentially) change over time, i.e.…”