Filling gaps in alpha-synuclein related dementias: Identifying critical biomarkers or cognitive conversion in the sphingolipidome
Ottawa Hospital Research Institute, University of Ottawa
The differential diagnosis of Dementia with Lewy Bodies, Parkinson’s Disease with Dementia or of Parkinson’s Disease (without any Dementia) rests on clinical observations alone. ‘State, rate, fate, and trait’ biomarkers are urgently needed to improve early diagnosis (state), track disease progression (rate), predict prognosis (fate), and identify risk in pre-symptomatic persons (trait). Mutations in the GBA1 gene increase risk of developing Dementia with Lewy Bodies and Parkinson’s Disease. GBA1 encodes the enzyme β-glucocerebrosidase. β-glucocerebrosidase hydrolyzes a family of fats (lipids) known as glycosylceramides to glucose, ceramide, and sphingosine. These lipids are part of a larger family of lipids called sphingolipids. Earlier onset and faster cognitive decline in Parkinson’s Disease are linked to aberrant sphingolipid metabolism. There are over 500 different sphingolipids. Here, we ask can changes in these sphingolipids be used to “map” disease progression? Our goal is to identify and validate sphingolipid ‘state, rate, fate’ biomarkers for Dementia with Lewy Bodies, Parkinson’s Disease with Dementia and Parkinson’s Disease. We predict that the sphingolipidome of circulating plasma and/or cerebrospinal fluid of individuals will reflect disease-related phenotypes. These lipid profiles will ultimately emerge as informative biomarkers, either alone or taken together with other analytes such as changes in alpha-synuclein metabolites, of disease state, rate, fate, and trait.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
New biomarkers are urgently required to improve patient care. Currently, there are no disease mechanism(s)-associated laboratory-based biomarkers in clinical use for Dementia with Lewy Bodies, Parkinson’s Disease with Dementia, or Parkinson’s Disease. 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. Compensatory changes in global sphingolipid metabolism have emerged as critical disease readouts. Commonly conceived as single entities, each sphingolipid family is, in fact, composed of 50+ functionally distinct lipid species, with unique acyl chain lengths, degrees of unsaturation, and glycosylation. Profiling the changes in species composition in plasma and cerebrospinal fluid over the course of disease represents an exquisitely sensitive, and largely unexplored, readout of metabolic status. These studies will also help to inform the value of lipidomic approaches not only in Dementia with Lewy Bodies, Parkinson’s Disease with Dementia or Parkinson’s Disease but also other neurodegenerative diseases.
Using a lipidomic approach to profile all of the sphingolipids in plasma, cerebrospinal fluid over time, and at the end of disease in brain in Dementia with Lewy Bodies, Parkinson’s Disease with Dementia, and Parkinson’s Disease and comparing these changes with cognitive and motor indices of disease progression, we expect to identify and validate new biomarkers for these devastating disorders. We seek to identify sphingolipids that can be used to improve early diagnosis segregating from Dementia with Lewy Bodies from Parkinson’s Disease with Dementia from Parkinson’s Disease (state), track disease progression in response to potential clinical intervention (rate), predict conversion from Parkinson’s Disease to Parkinson’s Disease with Dementia (fate), and, ideally, identify risk in pre-symptomatic persons to enable early intervention (trait).