About

Vivianna M. Van Deerlin, MD, PhD, is a Professor of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania. She serves as the Director of the Molecular Pathology Laboratory and the Interim Director of the Division of Precision and Computational Diagnostics at Penn Medicine. Her research interests are focused on the genetics of neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). Her laboratory collaborates with Penn neurologists and the Center for Neurodegenerative Diseases to conduct genetic and genome-wide studies, aiming to better understand these diseases and identify therapeutic targets. She works with genetic counselors and emphasizes the education of patients and the translation of genetic research findings into clinical laboratories to benefit patients and families. Her work in FTLD involves studying its clinical manifestations, neuropathological subtypes, and genetic causes, including mutations in genes such as MAPT and GRN. Her research has contributed to identifying mutations associated with FTLD and ALS, including TARDBP (TDP-43) mutations, and discovering genetic risk factors like TMEM106B through genome-wide association studies. She performs genetic analyses to identify mutations, study their pathogenicity, and explore phenotypic variability and brain pathology correlations. Her clinical expertise is in Molecular Pathology, directing a CLIA-certified molecular pathology laboratory that provides testing across oncology, infectious diseases, genetics, and pharmacogenetics, with a focus on developing oncology-based tests and molecular infectious disease testing. She also sponsors a fellowship training program in Molecular Genetic Pathology to prepare future molecular laboratory directors and surgical pathologists.

Research topics

• Medicine
• Genetics
• Biology
• Internal medicine
• Pathology
• Neuroscience
• Bioinformatics
• Gerontology
• Chemistry
• Family medicine
• Psychology
• Oncology
• Cancer research
• Molecular biology
• Psychiatry
• Cell biology
• Immunology
• Surgery

Selected publications

• T-cell receptor gamma (TRG) diversity predicts peripheral blood involvement in primary cutaneous T-cell lymphoma

  Blood Neoplasia · 2026-02-05

  articleOpen access
  PublisherDOI

• Idiotypic-susceptible Alzheimer’s disease: a clinically relevant, neurofibrillary tangle subtype

  Acta Neuropathologica · 2026-05-02

  articleOpen access

  Neurofibrillary tangles in Alzheimer's disease (AD) stereotypically spread from the medial temporal lobe to association areas and then to idiotypic areas (i.e., primary motor, somatosensory, auditory, and visual). Previous studies have reported variable and clinically relevant tangle densities across the hippocampus and association cortices, but the idiotypic tangle burden is understudied. In this study, we measured tangle density using immunohistochemistry in three idiotypic cortices (primary motor, somatosensory, and visual), three association cortices (middle frontal, superior temporal, and inferior parietal), and two hippocampal sectors (CA1 and subiculum) in 144 cases with a high level of AD neuropathologic change. Clinical diagnoses included late-onset AD (LOAD, n = 50), early-onset AD (EOAD, n = 21), behavioral variant frontotemporal dementia (bvFTD, n = 19), corticobasal syndrome (CBS, n = 18), logopenic primary progressive aphasia (lvPPA, n = 21), and posterior cortical atrophy (PCA, n = 15). We algorithmically assigned cases outside the interquartile ranges of mean tangle ratios of association:hippocampal, idiotypic:association, and idiotypic:hippocampal to mutually exclusive subtypes: idiotypic-susceptible, associative-predominant, limbic-predominant, or typical Braak (for all remaining cases). Regional tangle burdens differentiated subtypes, while female sex, younger ages, and longer disease durations also influenced tangle severity. Compared to typical Braak cases, idiotypic-susceptible and associative-predominant cases exhibited shorter disease duration and younger age at death while limbic-predominant cases were older. The MAPT H1H1 haplotype also differed by subtype, being most prevalent in limbic-predominant and least common in idiotypic-susceptible and associative-predominant subtypes. Clinically, the idiotypic-susceptible subtype associated with CBS (56%), the associative-predominant subtype with bvFTD (53%), and the limbic-predominant subtype with LOAD (14%). The typical Braak subtype characterized 74-76% of amnestic AD cases and 32-53% of non-amnestic AD cases. Moreover, k-means clustering corroborated four clusters including the idiotypic-susceptible and associative-predominant patterns. Our results confirm previously described tau subtypes and describe an idiotypic-predominant subtype with clinical relevance and distinct demographic and genetic characteristics in AD.

  PublisherDOI

• TDP-43 loss induces cryptic polyadenylation in ALS/FTD

  Nature Neuroscience · 2025-10-21 · 16 citations

  articleOpen access

  Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 are cellular hallmarks of amyotrophic lateral sclerosis (ALS). TDP-43 nuclear loss causes de-repression of cryptic exons, yet cryptic alternative polyadenylation (APA) events have been largely overlooked. In this study, we developed a bioinformatic pipeline to reliably identify alternative last exons, 3' untranslated region (3'UTR) extensions and intronic polyadenylation APA event types, and we identified cryptic APA sites induced by TDP-43 loss in induced pluripotent stem cell (iPSC)-derived neurons. TDP-43 binding sites are enriched at sites of these cryptic events, and TDP-43 can both repress and enhance APA. All categories of cryptic APA were also identified in ALS and frontotemporal dementia (FTD) postmortem brain tissue. RNA sequencing (RNA-seq), thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) and ribosome profiling (Ribo-seq) revealed that distinct cryptic APA categories have different downstream effects on transcript levels and that cryptic 3'UTR extensions can increase RNA stability, leading to increased translation. In summary, we demonstrate that TDP-43 nuclear depletion induces cryptic APA, expanding the palette of known consequences of TDP-43.

  PublisherOA PDFDOI

• Clinicopathological characterization of vacuolar tauopathy associated with <i>VCP</i> D395G

  Alzheimer s & Dementia · 2025-07-01 · 3 citations

  articleOpen access

  INTRODUCTION: The clinical, radiological, and pathological features have not been well documented for the recently discovered autosomal-dominant vacuolar tauopathy (VT) harboring the Valosin-containing protein (VCP) p.Asp395Gly variant. METHODS: We investigated the clinical, neuropsychological, physiological, laboratory, and radiological data and neuropathological findings in five symptomatic VT cases who met the diagnostic criteria for frontotemporal dementia (FTD). Radiological data were also collected from two pre-symptomatic carriers. RESULTS: All participants had heterozygous c.1184A > G, p.Asp395Gly in VCP. All symptomatic cases exhibited cognitive, behavioral, and/or language dysfunction indicative of FTD in their 30s to 50s. Neuroimaging studies revealed marked bilateral frontal neurodegeneration and occipital lobar diffusion abnormalities. Post mortem examination of three cases and brain biopsy of one case revealed abundant three- and four-repeat tau deposition and neocortical microvacuolization. Radiological changes were not evident in two pre-symptomatic carriers in their 20s. DISCUSSION: This study reveals distinct clinical-radiological-pathological correlations in VT, expanding the spectrum of early-onset frontotemporal lobar degeneration (FTLD). HIGHLIGHTS: We characterized the clinical, radiological, and pathological features of vacuolar tauopathy (VT). Five VT cases exhibited a behavioral syndrome, often with aphasic features, with marked frontal lobar atrophy and hypometabolism. Magnetic resonance imaging (MRI) of VT cases revealed occipital lobar diffusion abnormalities. Diffuse neurofibrillary tangles (NFTs) and microvacuolization were observed in the neocortex, with an inverse distribution.

  PublisherDOI

• Aleukemic soft-tissue relapse post allogeneic hematopoietic cell transplantation in T-prolymphocytic leukemia

  Leukemia & lymphoma/Leukemia and lymphoma · 2025-02-08

  article
  PublisherDOI

• Ambient Air Pollution and the Severity of Alzheimer Disease Neuropathology

  JAMA Neurology · 2025-09-08 · 12 citations

  articleOpen access

  Importance: Exposure to fine particulate matter air pollution (PM2.5) may increase risk for dementia. It is unknown whether this association is mediated by dementia-related neuropathologic change found at autopsy. Objective: To examine associations between PM2.5 exposure, dementia severity, and dementia-associated neuropathologic change. Design, Setting, and Participants: This cohort study used data associated with autopsy cases collected from 1999 to 2022 at the Center for Neurodegenerative Disease Research Brain Bank at the University of Pennsylvania. Data were analyzed from January to June 2025. Participants included 602 cases with common forms of dementia and/or movement disorders and older controls after excluding 429 cases with missing data on neuropathologic measures, demographic factors, APOE genotype, or residential address. Exposures: One-year mean PM2.5 concentration prior to death or prior to last Clinical Dementia Rating Sum of Boxes (CDR-SB) assessment was estimated using a spatiotemporal prediction model at residential addresses. Main Outcomes and Measures: Dementia severity was measured by CDR-SB scores. Ten dementia-associated neuropathologic measures representing Alzheimer disease, Lewy body disease, limbic-predominant age-related transactive response DNA-binding protein (TDP)-43 encephalopathy, and cerebrovascular disease were graded or staged. Linear, logistic, and structural equation models were used to examine the associations between PM2.5, CDR-SB, and neuropathologic measures, adjusting for demographic factors and APOE ε4 allele status. Results: In a total of 602 autopsy cases (median [IQR] age at death, 78 [71-85] years; 328 male [54.5%] and 274 female [45.5%]), higher PM2.5 exposure prior to death was associated with increased odds of more severe Alzheimer disease neuropathologic change (ADNC) (odds ratio, 1.19; 95% CI, 1.11-1.28). In a subset of 287 cases with CDR-SB records (median [IQR] age at death, 79 [72-86] years; 154 [53.7%] male and 133 female [46.3%]), higher PM2.5 exposure prior to CDR-SB assessment was associated with greater cognitive and functional impairment (β = 0.48; 95% CI, 0.22-0.74). Lastly, 63% of the association between higher PM2.5 exposure and greater cognitive and functional impairment was statistically mediated by ADNC (β = 0.30; 95% CI, 0.04-0.53). Conclusions and Relevance: In this study, PM2.5 exposure was associated with increased dementia severity and increased ADNC. Population-based studies are needed to better understand this relationship.

  PublisherOA PDFDOI

• Disparate and shared transcriptomic signatures associated with cortical atrophy in genetic behavioral variant frontotemporal degeneration

  Molecular Neurodegeneration · 2025-02-07 · 2 citations

  articleOpen access

  BACKGROUND: Cortical atrophy is a common manifestation in behavioral variant frontotemporal degeneration (bvFTD), exhibiting spatial heterogeneity across various genetic subgroups, which may be driven by distinct biological mechanisms. METHODS: We employed an integrative imaging transcriptomics approach to identify both disparate and shared transcriptomic signatures associated with cortical thickness in bvFTD with C9orf72 repeat expansions or pathogenic variants in GRN or MAPT. Functional enrichment analyses were conducted on each gene list significantly associated with cortical thickness. Additionally, we mapped neurotransmitter receptor/transporter density maps to the cortical thickness maps, to uncover different correlation patterns for each genetic form. Furthermore, we examined whether the identified genes were enriched for pathology-related genes by using previously identified genes linked to TDP-43 positive neurons and genes associated with tau pathology. RESULTS: For each genetic form of bvFTD, we identified cortical thickness signatures and gene sets associated with them. The cortical thickness associated genes for GRN-bvFTD were significantly involved in neurotransmitter system and circadian entrainment. The different patterns of spatial correlations between synaptic density and cortical thinning, further confirmed the critical role of neurotransmission and synaptic signaling in shaping brain structure, especially in the GRN-bvFTD group. Furthermore, we observed significant overlap between genes linked to TDP-43 pathology and the gene sets associated with cortical thickness in C9orf72-bvFTD and GRN-bvFTD but not the MAPT-bvFTD group providing specificity for our associations. C9orf72-bvFTD and GRN-bvFTD also shared genes displaying consistent directionality, with those exhibiting either positive or negative correlations with cortical thickness in C9orf72-bvFTD showing the same direction (positive or negative) in GRN-bvFTD. MAPT-bvFTD displayed more pronounced differences in transcriptomic signatures compared to the other two genetic forms. The genes that exhibited significantly positive or negative correlations with cortical thickness in MAPT-bvFTD showed opposing directionality in C9orf72-bvFTD and GRN-bvFTD. CONCLUSIONS: Overall, this integrative transcriptomic approach identified several new shared and disparate genes associated with regional vulnerability with increased biological interpretation including overlap with synaptic density maps and pathologically-specific gene expression. These findings illuminated the intricate molecular underpinnings contributing to the heterogeneous nature of disease distribution in bvFTD with distinct genetic backgrounds.

  PublisherDOI

• Cumulative incidence of motor and cognitive features in the amyotrophic lateral sclerosis—frontotemporal degeneration spectrum

  Brain Communications · 2025-01-01

  articleOpen access

  Abstract In frontotemporal degeneration and amyotrophic lateral sclerosis, subsequent motor or cognitive-behavioural features, respectively, are associated with shorter survival. However, factors influencing subsequent feature development remain largely unexplored. In this study, we examined whether the presence of a C9orf72 expansion or the initial clinical syndrome was associated with increased risk of subsequent feature development in individuals with amyotrophic lateral sclerosis and frontotemporal degeneration. We performed a retrospective evaluation of the entire disease course of individuals with an initial clinical syndrome of amyotrophic lateral sclerosis or frontotemporal degeneration who had neuropathological confirmation of TDP-43 proteinopathy at autopsy or a C9orf72 hexanucleotide repeat expansion. We examined the odds and hazard of subsequent feature development and assessed whether each was modified by the presence of a C9orf72 expansion or initial clinical syndrome. At autopsy, we evaluated the association between TDP-43 pathology burden in characteristic brain regions and features across this disease spectrum. For individuals with amyotrophic lateral sclerosis (n = 168) and frontotemporal degeneration (n = 73), binary logistic regression revealed increased odds (odds ratio = 3.49 [95% confidence interval 1.64–7.80], P = 0.002) and Cox proportional hazard analyses revealed an increased hazard (hazard ratio = 3.78 [95% confidence interval 1.86–7.65], P &amp;lt; 0.001) for developing subsequent features in those with a C9orf72 expansion compared to those without. Beyond C9orf72 expansion status, binary logistic regression revealed decreased odds (odds ratio = 0.25 [95% confidence interval 0.12–0.53], P &amp;lt; 0.001) and Cox proportional hazard analyses revealed a decreased hazard (hazard ratio = 0.48 [95% confidence interval 0.25–0.95], P = 0.03) for developing subsequent features in those with an initial amyotrophic lateral sclerosis clinical syndrome compared to those with an initial frontotemporal degeneration clinical syndrome. We observed a 94-month difference in the time after symptom onset of the initial clinical syndrome that a given person without a C9orf72 expansion reached the highest probability of developing subsequent features (0.12 [95% CI 0.03–0.19], 113.00 months) and a person with a C9orf72 expansion surpassed that probability (0.13 [95% CI 0.06–0.19], 19.00 months). The distribution of TDP-43 pathology across characteristic brain regions reflected both the initial clinical syndrome and subsequent features, with relatively preserved spinal cord only in frontotemporal degeneration cases without subsequent motor features (P &amp;lt; 0.0001) and relatively preserved neocortical regions only in amyotrophic lateral sclerosis cases without subsequent cognitive-behavioural features (P &amp;lt; 0.0001). These data highlight the need for clinician vigilance to detect the onset of subsequent motor and cognitive-behavioural features in patients carrying a C9orf72 expansion, regardless of initial clinical syndrome. C9orf72 clinical care can be enhanced through coordination between cognitive and neuromuscular clinics.

  PublisherOA PDFDOI

• Higher neighborhood deprivation is associated with accelerated disease progression in behavioral-variant frontotemporal degeneration

  medRxiv · 2025-05-13

  preprintOpen access

  INTRODUCTION: Neighborhood deprivation is associated with shorter survival, cognitive impairment and neurodegeneration in aging and Alzheimer's disease. However, the association of neighborhood deprivation with disease progression in behavioral-variant frontotemporal degeneration (bvFTD) is unknown. METHODS: We examined associations between tertiles of neighborhood deprivation, using the Area Deprivation Index (ADI), and survival in 311 individuals clinically diagnosed with bvFTD from the Penn FTD Center. In a subset (n=161) with complete baseline data across measures of global cognition, executive function, and language, we examined the association of ADI with longitudinal change. RESULTS: Compared to adults living in the least deprived neighborhoods, those living in the most deprived neighborhoods showed shorter survival after symptom onset and faster decline in global cognition, executive and language functions, independent of genetic risk. DISCUSSION: Living in more deprived neighborhoods was associated with an accelerated disease course in bvFTD, highlighting an important socioeconomic disparity in disease prognosis.

  PublisherOA PDFDOI

• Copy Number Variation and Haplotype Analysis of <scp>17q21.31</scp> Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells

  Movement Disorders · 2025-03-08 · 1 citations

  articleOpen access

  BACKGROUND: The 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP). OBJECTIVE: To investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP. METHODS: Utilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP. RESULTS: We found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub-haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up-regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down-regulating KANSL1. Single-nucleus RNA-seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up-regulates LRRC37A/LRRC37A2 in neuronal cells. CONCLUSIONS: The copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

  PublisherOA PDFDOI

Recent grants

• Frontotemporal Dementias: Genotypes and Phenotypes

  NIH · $61.9M · 2000–2022

• NIH Grant K08NS041408

  NIH · $656k · 2006

• Penn Alzheimer's Disease Research Center (ADRC)

  NIH · $30.9M · 2021–2026

Frequent coauthors

• John Q. Trojanowski

  University of Pennsylvania

  523 shared

• Murray Grossman

  313 shared

• Virginia M.‐Y. Lee

  California University of Pennsylvania

  285 shared

• Margaret L. Gulley

  195 shared

• Bruce L. Miller

  University Memory and Aging Center

  180 shared

• Debra G. B. Leonard

  University of Vermont

  173 shared

• Jan A. Nowak

  171 shared

• Raymond R. Tubbs

  170 shared