Accurate diagnosis of neurodegenerative diseases is hindered by the inaccessibility of the brain. Currently, it relies on evaluation of clinical features, however, overlapping symptoms across disorders might confound diagnosis thus delaying proper interventions. Moreover, as clinical manifestation is preceded by an asymptomatic prodromal stage during which neuronal degeneration is ongoing, these disorders are often diagnosed at an advanced stage. The goal of my group is to develop a biomarker panel based on quantification of DNA methylation of selected genes that can discriminate PD patients from healthy subjects in a simple blood test. This highly innovative approach represents the core of our translational research.

Leveraging our multiple studies in blood methylation, including cohorts from the National Institutes of Neurological Disorders and Stroke; Harvard Biomarkers Study and Parkinson’s Progression Markers Initiative we are defining candidate biomarkers of disease progression and response to medications. 

We completed the first longitudinal study of blood methylation biomarkers in PD (Henderson-Smith et al. Epigenetics 2019); a collaborative endeavor with researchers at Arizona State University and The Harvard Biomarker Study, which included ~ 800 samples, and identified dynamic changes in blood methylation that accompany disease progression and uncovered a previously unsuspected effect of dopaminergic therapies on blood methylation. 

We are currently performing methylomic analysis on a large portion of the Parkinson’s Progression Markers Initiative (PPMI), a study funded by the MJFF, and including more than ~2,400 longitudinal blood samples from cases and controls.  

DNA methylation markers to classify Lewy Body disorders

Lewy body diseases (LBD) are a heterogeneous group of disorders characterized by the accumulation of α-synuclein in Lewy body structures. LBD, including PD-Dementia (PDD) and Dementia with Lewy Bodies (DLB) present with wide clinico-pathological variation and differentiation between these disorders is based on the type and timing of clinical manifestations. However, the lack of specific biomarkers hampers determination of clinical subtypes in Lewy body dementia. Expanding our work on PD biomarkers, we also completed the profiling of blood methylation in DLB and PDD cases in collaboration with the Harvard Biomarker Study and Parkinson’s Disease Biomarkers Program (PDBP). Our results showed unique methylation profiles that differentiate both disorders; uncovering methylation sites associated with cardinal features of disease, including cognitive decline and REM-sleep behavioral disorder. Notably, we identified a set of differentially methylated sites that show promising characteristics as a disease classifier, based on their discriminating power. Read the compete study at Nasamram et al. Alzheimers Dement (Amst). 2021 Feb 20;13(1):e12156.