Biomarkers and Therapeutics

A primary hurdle to effective management of neurodegenerative diseases is the timing of interventions. Early changes in regions like the locus coeruleus do manifest as behavioral changes, but screening for Alzheimer’s disease solely based on these changes is infeasible. The behavioral changes, typically affective symptoms, sleep changes, or agitation, are subtle and nonspecific to Alzheimer’s disease. At the same time, existing biomarkers typically lack sensitivity for these stages. My research on biomarkers aims to deliver new tools to help detect early changes and risk-stratify individuals for subsequent cognitive decline.

Aiming to ultimately stop neurodegeneration among individuals in early stages, I am also working to develop novel therapeutics based on my pathophysiological research. Presently, I am developing treatment pipelines for familial diseases using gene-editing tools. After establishing competency with these pipelines, I aim to bring the pathophysiological work I pursue to the bedside.

Genome Editing Approaches for CADASIL Therapy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare neurological disease caused by mutations in Notch3. Such mutations cause the breakdown of neurovascular integrity due to the role of Notch3 in vascular smooth muscle cells and pericytes. Presently, CADASIL remains mostly untreatable with interventions mostly focused on addressing symptoms and minimizing risk factors for stroke. No disease-modifying treatment exists. Among neurodegenerative diseases, CADASIL is uniquely well-suited for gene engineering approaches. In collaboration with the VascBrain group at UCSF, led by Prof. Fanny Elahi, I am developing a gene-editing therapy for CADASIL. The pipeline developed for CADASIL will hopefully serve as a framework for other neurodegenerative diseases, like Alzheimer’s.

Risk stratification of older adults With loneliness

While there is a consensus that social isolation and loneliness are risk factors for negative health outcomes like dementia, they have not been granted sufficient attention by the healthcare system. Nearly 40 million individuals live alone in the United States, many of whom are older. Given the unique need to socially isolate during the COVID-19 pandemic, older individuals now are at particularly high risk of experiencing adverse cognitive effects of extreme, prolonged loneliness. Unfortunately, healthcare providers are without the ability to risk-stratify people to understand who may suffer adverse cognitive outcomes. A mechanistic understanding of how loneliness influences vulnerability to neurodegeneration can improve risk-stratification, inform on precise therapeutic targets, and drive educational and policy efforts to combat loneliness. I am working to build and deploy a targeted mass-spectrometry-based approach to measure neurotransmitters and associated metabolites in biofluid samples to understand how loneliness might increase risk for degeneration of subcortical neuromodulatory centers. I hope that this work will serve as a diagnostic template for the early stages of neurodegenerative diseases, opening a window for earlier disease-modifying intervention.

Featured publications

Ehrenberg AJ, Khatun A, Coomans E, Betts M, Capraro F, Thijssen E, Senkevich K, Bharucha T, Schott JM, Pereira J, Mattsson N, Grinberg LT, Jagust W, Lashley T, Carter SF, Ashton N, Hanrieder J, Zetterberg H, Schöll M, Paterson RW. Relevance of Biomarkers Across Different Neurodegenerative Diseases. Alzheimer’s Research and Therapy. 12(56). 2020. PMID: 32404143. PubMed

Betts MJ, Kirilina E, Otaduy MCG, Ivanov D, Acosta-Cabronero J, Callaghan MF, Lambert C, Cardenas-Blanco A, Pine K, Passamonti L, Loane C, Keuken MC, Trujillo P, Lüsebrink F, Mattern H, Liu KY, Priovoulos N, Fliessbach K, Dahl MJ, Maaß A, Madelung CF, Meder D, Ehrenberg AJ, Speck O, Weiskopf N, Dolan R, Inglis B, Tosun D, Morawski M, Zucca FA, Siebner HR, Mather M, Uludag K, Heinsen H, Poser BA, Howard R, Zecca L, Rowe JB, Grinberg LT, Jacobs HIL, Düzel E, Hämmerer D. Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases. Brain. 142(9): 2558–2571. 2019. PMID: 31327002. PubMed

Ehrenberg AJ, Suemoto CK, Resende EDPF, Petersen C, Leite REP, Rodriguez RD, Ferretti-Rebustini REL, You M, Oh J, Nitrini R, Pasqualucci CA, Jacob-Filho W, Kramer J, Gatchel J, Grinberg LT. Neuropathologic correlates of psychiatric symptoms in Alzheimer’s disease. Journal of Alzheimer’s Disease. 66(1): 115-126. 2018. PMID: 30223398. PubMed