Julia Kofler, MD

Neuropathology of neurodegenerative disease 

A major component of my research program is directing the adult and pediatric neurodegenerative brain banks, which involves collection, diagnostic evaluation and distribution of brain tissue samples from donors with a wide range of neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Frontotemporal Lobar Degeneration, ALS, Chronic Traumatic Encephalopathy and pediatric Leukodystrophies. Trainees in my lab will have opportunities to attend gross brain cutting and microscopic slide conferences to become familiar with the neuropathologic features of these disorders. Given the central nature of the brain bank, my laboratory is engaged in a wide range of collaborative research projects with local, national and international investigators. Our own research focuses on the following three topics. 

Genome-wide association studies have identified several novel risk genes for late-onset Alzheimer’s disease (AD). Since the biological functions of many of these genes are only poorly characterized, it is uncertain how they mediate increased AD risk. To determine if these genes affect tau or amyloid deposition in the brain, we study the impact of risk alleles on AD pathology burden and comorbidities and have identified several associations of known risk factors with neurodegenerative pathologies. Additionally, we have identified several novel candidate genes associated with our pathology endophenotypes and are beginning to investigate the biological pathways underlying these associations. In a newly funded project, we are expanding these studies to identify genetic modifiers of white matter myelin and oligodendrocyte pathologies, which are frequently seen in AD brains, and will complement these studies by analyzing bulk and spatially defined gene expression levels in the white matter. For neuropathology data analysis, we are currently developing novel digital image analysis and machine learning pipelines.

A more severe phenotype of AD is identified by the occurrence of psychosis. We are aiming to identify the pathobiology underlying this phenotype and have recently published findings that the psychosis phenotype is associated with higher phospho-Tau burden, higher prevalence of TDP-43 pathology and a shift in the synaptic proteome. In follow-up RNAseq studies using cell type proportion analysis, differential expression and Weighted Gene Correlation Network Analysis (WGCNA), we have identified reduced vulnerability of excitatory neurons and post-transcriptional synaptic compensation as possible mechanisms conferring resilience to psychosis. Ongoing studies are aimed to further dissect pathogenetic pathways by performing more comprehensive proteomics analyses, epigenetic analyses and single cell RNAseq studies.

Repetitive traumatic brain injury (concussions), such as sustained by contact sport participants, can lead to a neurodegenerative disease process called Chronic Traumatic Encephalopathy. While initial neuropathologic diagnostic criteria have been established for CTE, many unanswered questions remain about the frequency of CTE in symptomatic and asymptomatic athletes and about the spectrum of neuropathologic findings. To address these questions, we are developing a brain banking cohort of former contact sport participants, who will be followed longitudinally until death to collect information about their medical, trauma and cognitive histories. Postmortem examinations will allow us to better define the relationship between trauma exposure, cognitive trajectory and pathologic changes in the brain and to identify factors of resilience and vulnerability. In parallel, we are a participating site in the CONNECT-TBI consortium, a network of neuropathologists with expertise in neurodegenerative diseases, who will meet regularly for consensus reviews of brain autopsy cases with a TBI history and to refine diagnostic criteria.