Murray Grossman
VerifiedUniversity of Pennsylvania · Rehabilitation Medicine
Active 1956–2025
About
Murray Grossman, M.D., Ed.D., is a faculty member in the Department of Neurology at the Perelman School of Medicine at the University of Pennsylvania. His research focuses on biomarker studies in neurodegenerative diseases, particularly assessing behavioral, imaging, and biofluid measures in patients with frontotemporal degeneration spectrum disorders, including primary progressive aphasia, behavioral variant FTD, amyotrophic lateral sclerosis, corticobasal degeneration, and progressive supranuclear palsy. He also studies parkinson spectrum disorders with the goal of identifying the most reflective behavioral, neuroimaging, and biofluid measures of underlying proteinopathy in these patient groups, and participates in clinical treatment trials. Grossman's clinical expertise includes young-onset neurodegenerative conditions such as frontotemporal degeneration spectrum disorders, parkinson spectrum disorders like Parkinson's disease and Lewy body disease, corticobasal degeneration, progressive supranuclear palsy, and amyotrophic lateral sclerosis. He is the director of the Penn Frontotemporal Degeneration Center.
Research topics
- Medicine
- Biology
- Neuroscience
- Psychology
- Pathology
- Internal medicine
- Radiology
- Genetics
- Computer Science
- Artificial Intelligence
- Psychiatry
- Oncology
- Developmental psychology
- Cell biology
- Chemistry
- Molecular biology
- Clinical psychology
- Bioinformatics
Selected publications
Nature Communications · 2025-04-25 · 13 citations
articleOpen accessFrontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyzes, we further identify genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified C3AR1, SMG8, VIPR1, RBPJL, L3MBTL1 and ANO9, as novel subtype-specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signaling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications. Here the authors identify TNIP1 as a risk factor for a fatal neurodegenerative disorder and discover specific genetic loci associated with the three main subtypes of this disorder. The findings highlight distinct disease mechanisms, emphasizing the roles of immunity and the notch signaling pathway.
Clinicopathological characterization of vacuolar tauopathy associated with <i>VCP</i> D395G
Alzheimer s & Dementia · 2025-07-01 · 3 citations
articleOpen accessINTRODUCTION: 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.
Alzheimer s & Dementia · 2024-12-01
articleOpen accessAbstract Background The anterior portion of the MTL is one of the first regions targeted by pathology in sporadic Alzheimer’s disease (AD) indicating the potential for imaging metrics from this region to serve as valuable imaging biomarkers. However, most existing automated approaches for MTL segmentation do not incorporate anterior MTL subregions, and the few that do fail to account for its complex anatomical variability. Leveraging a unique postmortem dataset consisting of histology and structural MRI scans we aimed to develop an anatomically valid segmentation protocol for anterior entorhinal cortex (ERC), Brodmann Area (BA) 35, and BA36 and apply it for automated MTL segmentation of in vivo 3 tesla (T) MRI. Method We included 20 cases between 61 to 97 years of age (50% females) with and without neurodegenerative diseases (11 vs. 9 cases) to ensure broad generalizability of the developed protocol. Postmortem digitized MTL Nissl‐stained coronal histology serial sections from these cases were registered to same‐subject 0.2×0.2×0.2‐mm 3 9.4T postmortem MRI and annotated by an expert neuroanatomist. To develop the segmentation protocol, we determined the location of the histological borders of interest in relation to anatomical landmarks observable on in vivo MRI. The protocol was first applied manually to 29 3T in vivo MRI scans and then used to train an automatic segmentation method T1‐ASHS (Automatic Segmentation of Hippocampal Subfields). Intra‐rater reliability of a manual rater and five‐fold cross‐validation accuracy of T1‐ASHS were assessed with the Dice Similarity Index (DSI). Result Segmentation rules for the borders of ERC, BA35 and BA36 based on systematic analysis of inter‐landmark distances on histological sections are shown in Figure 1. Intra‐rater reliability for the manual rater applying these rules to 15 in vivo 3T MRI scans was high (Table‐1; Figure‐2). Comparing manual segmentations with the automated ones generated by T1‐ASHS showed moderate reliability, reflecting the challenging anatomy of this region. However, segmentation accuracy for the whole MTL including the newly added region was comparable to the previously reported accuracy for MTL without this region (Table‐1). Conclusion Future work will examine trhe utility of morphometric measures of anterior MTL regions enabled by this protocol for early AD.
The Lancet Neurology · 2024-04-15 · 23 citations
articleOpen accessBACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and β coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (β -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (β 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (β 2·66 [0·63 to 4·70], p=0·011), H1i (β -3·66 [-6·83 to -0·48], p=0·025), and H1u (β -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (β -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.
medRxiv · 2024-06-25 · 5 citations
preprintOpen accessAbstract Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified VIPR1 , RBPJL , and L3MBTL1 as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.
Acta Neuropathologica · 2024-02-03 · 4 citations
letterOpen accessWe read with great interest the paper by Hart de Ruyter et al. [5] in the February issue of Acta Neuropathologica assessing the presence of p-tau (total tau (HT7), p-tau Ser202/Thr205, and p-tau Thr217) in the retina in relation to tau pathology in the brain in primary tauopathies and Alzheimer's disease compared with non-tau-associated pathologies.In tauopathies, several phospho-epitopes of tau were present in the inner plexiform layer (IPL), outer plexiform layer (OPL), and inner nuclear layer (INL).The presence of retinal tau was further correlated with tau depositions in hippocampus and cortical regions.The authors suggest retinal p-tau as a potential biomarker for primary tauopathies.In this letter, we would like to add crucial early imaging data that (1) investigate the structural consequences of tau deposition, (2) support the use of retinal tau markers as a diagnostic tool for tauopathies given their presence early in the course of the disease, and (3) demonstrate the feasibility of these findings outside of pathology studies.For our investigations, we employed optical coherence tomography (OCT) imaging data from the multi-site 4 Repeat Tauopathy Neuroimaging Initiative (4RTNI), which generated a deeply phenotyped cohort including imaging, body fluid samples, and cognitive testing in patients with progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and healthy controls [10].OCT is an imaging method using interference of low-coherence light to produce highresolution cross-sectional retinal images [8].
Alzheimer s & Dementia · 2024-12-01
articleOpen accessBACKGROUND: Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN-related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. METHOD: Utilizing T1 and task-free functional magnetic resonance imaging (tf-fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel-wise whole brain degree and GRN-relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity. RESULT: NfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN-FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers. CONCLUSION: In presymptomatic carriers, the co-occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf-fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.
Journal of Speech Language and Hearing Research · 2024-01-12 · 14 citations
articleOpen accessPURPOSE: Multiple methods have been suggested for quantifying syntactic complexity in speech. We compared eight automated syntactic complexity metrics to determine which best captured verified syntactic differences between old and young adults. METHOD: = 36, ages 53-89 years) healthy participants, manually transcribed and segmented into sentences. We manually verified that older participants produced fewer complex structures. We developed a metric of syntactic complexity using automatically extracted syntactic structures as features in a multidimensional metric. We compared our metric to seven other metrics: Yngve score, Frazier score, Frazier-Roark score, developmental level, syntactic frequency, mean dependency distance, and sentence length. We examined the success of each metric in identifying the age group using logistic regression models. We repeated the analysis with automatic transcription and segmentation using an automatic speech recognition (ASR) system. RESULTS: Our multidimensional metric was successful in predicting age group (area under the curve [AUC] = 0.87), and it performed better than the other metrics. High AUCs were also achieved by the Yngve score (0.84) and sentence length (0.84). However, in a fully automated pipeline with ASR, the performance of these two metrics dropped (to 0.73 and 0.46, respectively), while the performance of the multidimensional metric remained relatively high (0.81). CONCLUSIONS: Syntactic complexity in spontaneous speech can be quantified by directly assessing syntactic structures and considering them in a multivariable manner. It can be derived automatically, saving considerable time and effort compared to manually analyzing large-scale corpora, while maintaining high face validity and robustness. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24964179.
Imaging Neuroscience · 2024-03-01 · 1 citations
articleOpen accessSenior authorRegional cerebral blood flow (CBF) changes quantified using arterial spin labeling (ASL) are altered in neurodegenerative disorders such as frontotemporal lobar degeneration due to tau (FTLD-tau), but the relationship between ASL CBF and pathologic burden has not been assessed. Our objective was to determine whether regional ASL CBF acquired antemortem in patients with FTLD-tau is related to pathologic burden measured at autopsy in those same regions in the same patients to directly test the imaging-pathology relationship. In this case-control study, data were acquired between 3/4/2010 and 12/16/2018. Data processing and analysis were completed in 2023. Twenty-one participants with autopsy-confirmed FTLD-tau (N = 10 women, mean[SD] age 67.9[7.56] years) along with 25 control participants (N = 15 women, age 64.7[7.53]) were recruited through the cognitive neurology clinic at the University of Pennsylvania. All participants had ASL and T1-weighted images collected antemortem. ASL images were processed to estimate CBF and T1-weighted images were processed to estimate gray matter (GM) volumes in regions corresponding to regions sampled postmortem. Digital quantification of pathologic burden was performed to find the percent area occupied (%AO) of pathologic FTLD-tau at autopsy. Regional CBF and GM volumes were both related to pathologic burden in the same regions from the same participants. Strengths of model fits of imaging measures to pathologic burden were compared. CBF in FTLD-tau and controls were compared, with results considered significant at p < 0.05 after Bonferroni correction. We found that relative to controls, FTLD-tau displayed hypoperfusion in anterior cingulate, orbitofrontal, middle frontal, and superior temporal regions, as well as angular gyrus. For patients with FTLD-tau regional CBF was significantly associated with pathologic burden (beta = -1.07, t = -4.80, p < 0.005). Models including both GM volume and CBF provided significantly better fits to pathologic burden data than single modality models (p < 0.05, Bonferroni-corrected). Our results indicate that reduced CBF measured using ASL MRI is associated with increased pathologic burden in FTLD-tau and adds complementary predictive value of pathologic burden to structural MRI.
Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease
Annals of Clinical and Translational Neurology · 2024-01-23 · 10 citations
articleOpen accessOBJECTIVE: Alzheimer's disease neuropathologic change and alpha-synucleinopathy commonly co-exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta-amyloid compared to alpha-synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia. METHODS: We used digital histology to measure percent area-occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha-synucleinopathy, and a co-pathology group with both Alzheimer's and alpha-synuclein pathologic diagnoses. Multiple tau monoclonal antibodies were used to detect early (AT8, MC1) and mature (TauC3) epitopes of tangle progression. We used linear/logistic regression to compare groups and test the association between pathologies and clinical features. RESULTS: There were lower levels of tau pathology (β = 1.86-2.96, p < 0.001) across all tau antibodies in the co-pathology group compared to the pure Alzheimer's pathology group. Among individuals with alpha-synucleinopathy, higher alpha-synuclein was associated with greater early tau (AT8 β = 1.37, p < 0.001; MC1 β = 1.2, p < 0.001) but not mature tau (TauC3 p = 0.18), whereas mature tau was associated with beta-amyloid (β = 0.21, p = 0.01). Finally, lower tau, particularly TauC3 pathology, was associated with lower frequency of both core clinical features and categorical clinical diagnosis of dementia with Lewy bodies. INTERPRETATION: Mature tau may be more closely related to beta-amyloidosis than alpha-synucleinopathy, and pathophysiological processes of tangle maturation may influence the clinical features of dementia in mixed Lewy-Alzheimer's pathology.
Recent grants
NIH · $2.1M · 2018
NIH · $33.7M · 2018
NIH · $6.8M · 2016
NIH · $3.1M · 2008
NIH · $4.9M · 2012
Frequent coauthors
- 598 shared
John Q. Trojanowski
University of Pennsylvania
- 546 shared
David J. Irwin
University of Pennsylvania
- 379 shared
Corey T. McMillan
University of Pennsylvania
- 327 shared
Bruce L. Miller
University Memory and Aging Center
- 313 shared
Vivianna M. Van Deerlin
University of Pennsylvania
- 257 shared
Virginia M.‐Y. Lee
California University of Pennsylvania
- 219 shared
David A. Wolk
California University of Pennsylvania
- 215 shared
Lauren Elman
University of Pennsylvania
Education
- 1989
Resident, Neurology
Hospital of the University of Pennsylvania
- 1986
intern, Medicine
Royal Victoria Hospital
- 1981
postdoctoral fellowship, Brain Sciences
Massachusetts Institute of Technology
- 1977
EdD, Aphasia Research Center
Boston University
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