Genotype-phenotype relationships to uncover mechanisms that contribute to neurodegenerative disease heterogeneity
The goal of this work is to study sources of genetic variation that contribute to heterogeneity in neurodegenerative disease and aging. Pathogenic autosomal dominant genetic mutations are present in approximately 20% of FTLD and ALS patients. Other sources of genetic variation include single nucleotide polymorphisms (SNPs) and epigenetic factors that may provide genetic modifiers and targets for treatment of inherited and sporadic forms of disease. Through targeted SNP analyses, our lab has identified several SNPs that contribute to neuroanatomic, clinical, neuropathological and prognostic heterogeneity in FTLD and ALS. We have also suggested through converging neuropathological, neuroimaging, and clinical analyses that epigenetic hypermethylation of C9orf72 is protective for FTLD and ALS.
biological aging mechanisms associated with tau pathology and neurodegeneration
Another goal of our research is to use genetic approaches involving biological aging to understand the risk factors for the accumulation of neurofibrillary tau tangle (NFTs) pathology found in AD and PART. To date nearly all aging has defined age-related neuropathological risk in chronological measurements (i.e., years since birth). However, the rates of actual “biological” aspects of aging appear to differ between individuals, with some individuals displaying features of aging that are accelerated (biological age older than their chronological age) or delayed (biological age younger than their chronological age). The goal of this work, currently funded by a R01 (AG066152), is to investigate several genetic sources of biological aging mechanisms underlying risk and severity for NFT and Aβ molecular pathology and associated neurodegeneration. Our lab recently provided the first clinical and first genetic characterization of PART that distinguishes it from AD. A significant proportion of the aging population has varying levels of molecular pathology and this research will help establish mechanisms by which heterogeneity in biological brain aging impacts the development and progression of neuropathology and neurodegeneration.
neuroimaging biomarkers for the diagnosis and longitudinal evaluation of neurodegenerative diseases
Neuropathological studies have identified four major molecular sources of neurodegenerative disease, including TDP-43, misfolded tau protein, amyloid, and alpha-synuclein pathology. As we enter an era of clinical trials for disease-modifying agents it is critical to develop screening tools to facilitate the in vivo diagnosis of the molecular pathology causing disease in an individual patient. Several studies in our laboratory highlight the role of multimodal neuroimaging of grey matter with MRI and white matter with DTI for discriminating between pathological sources of disease. We also demonstrate the consequences of co-pathologies (e.g., alpha-synuclein and amyloid) on regional distributions of disease. Our studies also use cross-validation to evaluate reliability in novel cohorts and we often validate our neuroimaging observations of autopsy-proven samples with neuropathological analyses of tissue in the same regions. We are currently also pursuing several imaging studies related to detecting the earliest anatomic alterations in pre-symptomatic forms of familial FTD and ALS and evaluating novel PET tracers and high-field 7T MRI techniques for state-of-the-art in vivo characterization of neurodegenerative conditions.
COLLABORATIONS
The Penn BiND Lab is actively involved in many local, national, and international collaborative projects. Some of which include:
Penn Frontotemporal Degeneration Center (FTDC)
The Clinical Research in ALS and related disorders for Therapeutic Develoment (CReATe) Consortium
Penn Alzheimer Disease Research Center (Penn ADRC)
Penn Institute on Aging U19 Center on Alpha-Synuclein Strains in Alzheimer's Disease and Related Disorders.