There are no disease mechanism(s)-associated laboratory-based biomarkers in clinical use for Dementia with Lewy Bodies (DLB), Parkinson's Disease with Dementia (PDD), or Parkinson's Disease (PD). This void is detrimental to the diagnosis of our patients and their proper stratification in clinical trials. It also precludes the development of cause-directed treatment. 'State, rate, fate, and trait' biomarkers are urgently needed to improve early diagnosis (state), track disease progression (rate), predict critical endpoints (fate), and identify risk in pre-symptomatic persons (trait).

Heterozygous mutations in GBA1, the gene encoding the enzyme beta-glucocerebrosidase (GCase), increase risk of cognitive impairment in alpha-synucleinopathies but not AD. GCase hydrolyzes glycosylceramide to glucose, ceramide, and sphingosine. Converging evidence implicates aberrant sphingolipid metabolism in both cognitive phenoconversion and disease progression. Thus, our goal is to identify and validate blood- and/or cerebrospinal fluid-based sphingolipid 'state, rate, fate' biomarkers for DLB, PDD, and PD. We apply an interdisciplinary approach capitalizing on our teams' (a) expertise in translational lipidomics, (b) unprecedented access to PD, PDD, Alzheimer's Disease (AD), DLB, DLB+AD, PD+AD patient (and age-matched control) cohorts, (c) ongoing lipidomic and alpha-synuclein assessment of post-mortem brain tissue, and (d) development of the first bi-genic mouse model of PD/DLB to compare circulating and central lipid profiles as validate critical indicators of neurodegenerative disease."