Microbiome-gut-brain dysfunction in prodromal and symptomatic Lewy body diseases

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PROJECT SUMMARY/ABSTRACT Cognitive decline in Lewy body dementias [Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB); a category of Alzheimer’s disease and related dementias (ADRD)], causes significant functional impairment and does not respond well to existing treatments. Perhaps the greatest challenge for developing effective treatments is the lack of a mechanistic understanding of the key events driving pathophysiology. Increasing evidence suggests that a perturbed gut microbiome (dysbiosis) driven by a bloom in sulfate reducing bacteria and increased intestinal permeability may be key mechanisms driving disease pathogenesis in Lewy body diseases. There is a need to evaluate whether these factors are present early in the disease course and associated with known disease processes, such as midbrain degeneration and clinical outcomes. Idiopathic REM Sleep behavior disorder (iRBD), is one of the earliest and most specific prodromal indicators of Lewy body diseases as up to 96.6% of iRBD patients will progress to an alpha-synucleinopathy at 14 years follow up. This population therefore provides an opportunity to conduct a novel evaluation of the presence of a bloom in SRB/dysbiosis and increased intestinal permeability early in the disease and whether these mechanisms are associated with known disease processes (increases in α-synuclein, midbrain degeneration and clinical outcomes). The proposed project will conduct a prospective, cross-sectional study to test the hypothesis that abnormal lactulose breath tests with elevated H2S concentration (as a marker of dysbiosis and a bloom of SRB in the gut) are present at prodromal stages of the disease and associated with increases in markers of increased intestinal permeability and microbial translocation of lipopolysaccharide (total bacterial 16S rRNA gene and lipopolysaccharide binding protein; LBP), known disease processes (plasma concentration of α-synuclein, MRI biomarkers of integrity of SNc and LC) and clinical outcomes. We will recruit prodromal (iRBD), symptomatic Lewy body disease patients (PD and DLB) and HC to evaluate our hypotheses. Consistent with several objectives outlined in PAR-22-211, the completion of the proposed project will advance our mechanistic understanding of the effects of a boom in SRB/dysbiosis, potentially identifying targets for disease modifying treatments. Should our results determine an important role of gut SRB bloom/dysbiosis in the pathophysiology of Lewy body diseases, these measurements could be incorporated into routine clinical practice to screen for emerging pathogenic processes. Notably, many potential treatments targeting the microbiome are readily available and subsequent clinical trials can evaluate whether interventions targeting a bloom in SRB/dysbiosis could be used to intervene before overt motor and cognitive symptoms develop.