Murray Grossman

William Penn University, Filadelfia, Pennsylvania, United States

Are you Murray Grossman?

Claim your profile

Publications (335)1777.22 Total impact

  • Amy Price · Michael Bonner · Jonathan Peelle · Murray Grossman
    [Show abstract] [Hide abstract]
    ABSTRACT: Our knowledge of objects reflects the statistics of the visual environment. From our experiences in the world, we store information about categories of objects and the features that define them. One important statistical property of objects is the co-occurrence of their constituent features. For example, the round shape of an apple co-occurs frequently with the color red, but not the color blue. Here we examine the neural mechanisms that encode such feature co-occurrence statistics at the interface of perception and memory. In an fMRI experiment, subjects viewed images of colored objects while performing an unrelated scrambled-object detection task. The stimuli included exemplars from three different categories: apples, leaves, and roses. To create stimuli that sampled a range of co-occurrence statistics, each exemplar image had its color systematically manipulated to be red, pink, yellow, green, or blue (Fig.1A). We quantified co-occurrence frequencies of color-object combinations (e.g., "yellow apple") in a large lexical corpus. A separate norming study demonstrated that this metric was strongly correlated with subjective ratings of color-object typicality. Importantly, the co-occurrence of object and color information is independent of the frequencies of each feature alone. We tested the hypothesis that feature co-occurrence information is encoded in semantic memory regions and automatically retrieved during object perception. Using representational similarity analysis, we identified regions where response patterns were similar for category exemplars with similar co-occurrence statistics (Fig.2B). We expected that the angular gyrus would encode combinatorial information given its proposed role in semantic integration. Indeed, we found that this region and the anterior fusiform cortex encode high-level feature co-occurrence statistics, while early visual cortex, lateral-occipital complex, and inferior-temporal cortex did not. These results suggest that regions at the interface of vision and semantic memory encode combinatorial information that underlies real-world knowledge of objects and is independent of coding for individual features. Meeting abstract presented at VSS 2015.
    Journal of Vision 09/2015; 15(12):1119. DOI:10.1167/15.12.1119 · 2.39 Impact Factor
  • Murray Grossman
    The Lancet Neurology 08/2015; DOI:10.1016/S1474-4422(15)00182-9 · 21.90 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1–42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: When the message of a speaker goes beyond the literal or logical meaning of the sentences used, a pragmatic inference is required to understand the complete meaning of an utterance. Here we study one example of pragmatic inference, called scalar implicature. Such an inference is required when a weaker term "some" is used in a sentence like "Some of the students passed the exam" because the speaker presumably had a reason not to use a stronger term like "all". We investigated the comprehension of scalar implicatures in a group of 17 non-aphasic patients with behavioral variant frontotemporal degeneration (bvFTD) in order to test the contribution of non-linguistic decision-making ability and the role of prefrontal cortex in supporting the computation of pragmatic inferences. The results of two experiments point to a deficit in producing alternative interpretations beyond a logical reading. bvFTD patients thus prefer the narrowly literal or logical interpretation of a scalar term when they must generate a possible alternative interpretation by themselves, but patients prefer a pragmatic reading when offered a choice between the logical and the pragmatic interpretation of the same sentence. An imaging analysis links bvFTD patients' spontaneous tendency toward a narrowly logical interpretation with atrophy in ventromedial prefrontal cortex. Our findings are consistent with the pragmatic tolerance hypothesis, which proposes that difficulty generating alternative interpretations of an utterance, rather than a frank inability to compute an inference, affects the comprehension of a scalar term. Copyright © 2015. Published by Elsevier Ltd.
    Neuropsychologia 07/2015; 75. DOI:10.1016/j.neuropsychologia.2015.07.002 · 3.30 Impact Factor
  • Amy R. Price · Harrison McAdams · Murray Grossman · Roy H. Hamilton
    [Show abstract] [Hide abstract]
    ABSTRACT: Transcranial direct current stimulation (tDCS) is a brain stimulation technique used to examine causal relationships between brain regions and cognitive functions. The effects from tDCS are complex, and the extent to which stimulation reliably affects different cognitive domains is not fully understood and continues to be debated. To conduct a meta-analysis of studies examining the effects of single-session anodal tDCS on language. The meta-analysis examined the behavioral results from eleven experiments of single-session anodal tDCS and language processing in healthy adults. The means and standard deviations of the outcome measures were extracted from each experiment and entered into the meta-analyses. In the first analysis, we examined the effects of single-session tDCS across all language studies. Next, a series of sub-analyses examined the effects of tDCS on specific tasks and stimulation protocols. There was a significant effect from anodal single-session tDCS in healthy adults compared to sham (P = 0.001) across all language measures. Next, we found significant effects on specific stimulation protocols (e.g., offline measures, P = 0.002), as well as specific tasks and electrode montages (e.g., verbal fluency measures and left prefrontal cortex, P = 0.035). The results indicate that single-session tDCS produces significant and reliable effects on language measures in healthy adults. Copyright © 2015 Elsevier Inc. All rights reserved.
    Brain Stimulation 06/2015; DOI:10.1016/j.brs.2015.06.013 · 4.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).
    Nature Communications 06/2015; 6. DOI:10.1038/ncomms8247 · 11.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We often estimate an unknown value based on available relevant information, a process known as cognitive estimation. In this study, we assess the cognitive and neuroanatomic basis for quantitative estimation by examining deficits in patients with focal neurodegenerative disease in frontal and parietal cortex. Executive function and number knowledge are key components in cognitive estimation. Prefrontal cortex has been implicated in multilevel reasoning and planning processes, and parietal cortex has been associated with number knowledge required for such estimations. We administered the Biber cognitive estimation test (BCET) to assess cognitive estimation in 22 patients with prefrontal disease due to behavioral variant frontotemporal dementia (bvFTD), to 17 patients with parietal disease due to corticobasal syndrome (CBS) or posterior cortical atrophy (PCA) and 11 patients with mild cognitive impairment (MCI). Both bvFTD and CBS/PCA patients had significantly more difficulty with cognitive estimation than controls. MCI were not impaired on BCET relative to controls. Regression analyses related BCET performance to gray matter atrophy in right lateral prefrontal and orbital frontal cortices in bvFTD, and to atrophy in right inferior parietal cortex, right insula, and fusiform cortices in CBS/PCA. These results are consistent with the hypothesis that a frontal-parietal network plays a crucial role in cognitive estimation.
    Frontiers in Human Neuroscience 06/2015; 9(317). DOI:10.3389/fnhum.2015.00317 · 2.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We investigated whether chromosome 9 open reading frame 72 hexanucleotide repeat expansion (C9orf72 expansion) size in peripheral DNA was associated with clinical differences in frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) linked to C9orf72 repeat expansion mutations. A novel quantification workflow was developed to measure C9orf72 expansion size by Southern blot densitometry in a cross-sectional cohort of C9orf72 expansion carriers with FTD (n = 39), ALS (n = 33), both (n = 35), or who are unaffected (n = 21). Multivariate linear regressions were performed to assess whether C9orf72 expansion size from peripheral DNA was associated with clinical phenotype, age of disease onset, disease duration and age at death. Mode values of C9orf72 expansion size were significantly shorter in FTD compared to ALS (p = 0.0001) but were not associated with age at onset in either FTD or ALS. A multivariate regression model correcting for patient's age at DNA collection and disease phenotype revealed that C9orf72 expansion size is significantly associated with shorter disease duration (p = 0.0107) for individuals with FTD, but not with ALS. Despite considerable somatic instability of the C9orf72 expansion, semi-automated expansion size measurements demonstrated an inverse relationship between C9orf72 expansion size and disease duration in patients with FTD. Our finding suggests that C9orf72 repeat size may be a molecular disease modifier in FTD linked to hexanucleotide repeat expansion.
    Acta Neuropathologica 05/2015; 130(3). DOI:10.1007/s00401-015-1445-9 · 10.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To examine the influence of occupational attainment and education on survival in autopsy-confirmed cases of frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD). We performed a retrospective chart review of 83 demographically matched, autopsy-confirmed FTLD (n = 34) and AD (n = 49) cases. Each patient's primary occupation was classified and ranked. Level of education was recorded in years. Survival was defined as time from symptom onset until death. Linear regression was used to test for associations among occupational attainment, education, and patient survival. Median survival was 81 months for FTLD and 95 months for AD. Years of education and occupational attainment were similar for both groups. We found that higher occupational attainment was associated with longer survival in FTLD but not AD. Our findings suggest that higher occupational attainment is associated with longer survival in autopsy-confirmed FTLD. The identification of protective factors associated with FTLD survival has important implications for estimates of prognosis and longitudinal studies such as treatment trials. © 2015 American Academy of Neurology.
    Neurology 04/2015; 84(20). DOI:10.1212/WNL.0000000000001595 · 8.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The scope of reference of a word's meaning can be highly variable. We present a novel paradigm to investigate the flexible interpretation of word meaning. We focus on quantifiers such as "many" or "few," a class of words that depends on number knowledge but can be interpreted in a flexible manner. Healthy young adults performed a truth value judgment task on pictorial arrays of varying amounts of blue and yellow circles, deciding whether the sentence "Many/few of the circles are yellow" was an adequate description of the stimulus. The study consisted of two experiments, one focusing on "many," one on "few." Each experiment had three blocks. In a first "baseline" block, each individual's criterion for "many" and "few" was assessed. In a second "adaptation" block, subjects received feedback about their decisions that was different from their initial judgments in an effort to evaluate the flexibility of a subject's interpretation. A third "test" block assessed whether adaptation of quantifier meaning induced in block 2 then was generalized to alter a subject's baseline meaning for "many" and "few." In Experiment 1, a proportion of yellow circles as small as 40% was reinforced as "many"; in Experiment 2, a proportion of yellow circles as large as 60% was reinforced as "few." Subjects learned the new criterion for "many" in Experiment 1, which also affected their criterion for "few" although it had never been mentioned. Likewise, in Experiment 2, subjects changed their criterion for "few," with a comparable effect on the criterion for "many" which was not mentioned. Thus, the meaning of relational quantifiers like "many" and "few" is flexible and can be adapted. Most importantly, adapting the criterion for one quantifier (e.g., "many") also appeared to affect the reciprocal quantifier (in this case, "few"). Implications of this result for psychological interventions and for investigations of the neurobiology of the language-number interface are discussed.
    Frontiers in Psychology 04/2015; 6:441. DOI:10.3389/fpsyg.2015.00441 · 2.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To use in vivo neuroimaging and postmortem neuropathologic analysis in C9orf72 repeat expansion patients to investigate the hypothesis that C9orf72 promoter hypermethylation is neuroprotective and regionally selective. Twenty patients with a C9orf72 repeat expansion participating in a high-resolution MRI scan and a clinical examination and a subset of patients (n = 11) were followed longitudinally with these measures. Gray matter (GM) density was related to C9orf72 promoter hypermethylation using permutation-based testing. Regional neuronal loss was measured in an independent autopsy series (n = 35) of C9orf72 repeat expansion patients. GM analysis revealed that hippocampus, frontal cortex, and thalamus are associated with hypermethylation and thus appear to be relatively protected from mutant C9orf72. Neuropathologic analysis demonstrated an association between reduced neuronal loss and hypermethylation in hippocampus and frontal cortex. Longitudinal neuroimaging revealed that hypermethylation is associated with reduced longitudinal decline in GM regions protected by hypermethylation and longitudinal neuropsychological assessment demonstrated that longitudinal decline in verbal recall is protected by hypermethylation. These cross-sectional and longitudinal neuroimaging studies, along with neuropathologic validation studies, provide converging evidence for neuroprotective properties of C9orf72 promoter hypermethylation. These findings converge with prior postmortem studies suggesting that C9orf72 promoter hypermethylation may be a neuroprotective target for drug discovery. © 2015 American Academy of Neurology.
    Neurology 03/2015; 84(16). DOI:10.1212/WNL.0000000000001495 · 8.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Up to half of patients with amyotrophic lateral sclerosis (ALS) may have cognitive difficulty, but most cognitive measures are confounded by a motor component. Studies relating impaired cognition in ALS to disease in gray matter and white matter are rare. Our objective was to assess executive function in patients with ALS using a simple, untimed measure with minimal motor demands, and to relate performance to structural disease. We gave the Visual-Verbal Test to 56 patients with ALS and 29 matched healthy controls. This brief, untimed measure of cognitive flexibility first assesses participants' ability to identify a feature shared by 3 of 4 simple geometric designs. The participants' cognitive flexibility is challenged when they are next asked to identify a different feature shared by another combination of 3 of the same 4 geometric designs. In a subset of 17 patients who underwent magnetic resonance imaging, regression analyses related test performance to gray matter atrophy and reduced white matter fractional anisotropy. The patients with ALS showed significant impairment in cognitive flexibility (P<0.01), with 48.2% making an error on the test. Regression analyses related impaired cognitive flexibility to gray matter atrophy in inferior frontal and insular regions, and to reduced fractional anisotropy in white matter projections in the inferior fronto-occipital and uncinate fasciculi and corpus callosum. Our patients with ALS had impaired cognitive flexibility on an untimed measure with minimal motor demands, a finding related in part to a large-scale frontal network that is degraded in ALS.
    Cognitive and behavioral neurology: official journal of the Society for Behavioral and Cognitive Neurology 03/2015; 28(1):17-26. DOI:10.1097/WNN.0000000000000049 · 0.95 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. Here we report the results of a moderate-scale sequencing study aimed at identifying new genes contributing to predisposition for ALS. We performed whole exome sequencing of 2,874 ALS patients and compared them to 6,405 controls. Several known ALS genes were found to be associated, and the non-canonical IκB kinase family TANK-Binding Kinase 1 (TBK1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention. Copyright © 2015, American Association for the Advancement of Science.
    Science 02/2015; 347(6229). DOI:10.1126/science.aaa3650 · 33.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human thought and language rely on the brain's ability to combine conceptual information. This fundamental process supports the construction of complex concepts from basic constituents. For example, both "jacket" and "plaid" can be represented as individual concepts, but they can also be integrated to form the more complex representation "plaid jacket." Although this process is central to the expression and comprehension of language, little is known about its neural basis. Here we present evidence for a neuroanatomic model of conceptual combination from three experiments. We predicted that the highly integrative region of heteromodal association cortex in the angular gyrus would be critical for conceptual combination, given its anatomic connectivity and its strong association with semantic memory in functional neuroimaging studies. Consistent with this hypothesis, we found that the process of combining concepts to form meaningful representations specifically modulates neural activity in the angular gyrus of healthy adults, independent of the modality of the semantic content integrated. We also found that individual differences in the structure of the angular gyrus in healthy adults are related to variability in behavioral performance on the conceptual combination task. Finally, in a group of patients with neurodegenerative disease, we found that the degree of atrophy in the angular gyrus is specifically related to impaired performance on combinatorial processing. These converging anatomic findings are consistent with a critical role for the angular gyrus in conceptual combination. Copyright © 2015 the authors 0270-6474/15/353276-09$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2015; 35(7):3276-84. DOI:10.1523/JNEUROSCI.3446-14.2015 · 6.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: For social interactions to be successful, individuals must establish shared mental representations that allow them to reach a common understanding and "get on the same page". We refer to this process as social coordination. While examples of social coordination are ubiquitous in daily life, relatively little is known about the neuroanatomic basis of this complex behavior. This is particularly true in a language context, as previous studies have used overly complex paradigms to study this. Although traditional views of language processing and the recent interactive-alignment account of conversation focus on peri-Sylvian regions, our model of social coordination predicts prefrontal involvement. To test this hypothesis, we examine the neural basis of social coordination during conversational exchanges in non-aphasic patients with behavioral variant frontotemporal degeneration (bvFTD). bvFTD patients show impairments in executive function and social comportment due to disease in frontal and anterior temporal regions. To investigate social coordination in bvFTD, we developed a novel language-based task that assesses patients' ability to convey an object's description to a conversational partner. Experimental conditions manipulated the amount of information shared by the participant and the conversational partner, and the associated working memory demands. Our results indicate that, although patients did not have difficulty identifying the features of the objects, they did produce descriptions that included insufficient or inappropriate adjectives and thus struggled to communicate effectively. Impaired performance was related to gray matter atrophy particularly in medial prefrontal and orbitofrontal cortices. Our findings suggest an important role for non-language brain areas that belong to a large-scale neurocognitive network for social coordination. Copyright © 2015. Published by Elsevier Ltd.
    Neuropsychologia 01/2015; 69. DOI:10.1016/j.neuropsychologia.2015.01.028 · 3.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Frontotemporal lobar degeneration (FTLD) comprises two main classes of neurodegenerative diseases characterized by neuronal/glial proteinaceous inclusions (i.e., proteinopathies) including tauopathies (i.e., FTLD-Tau) and TDP-43 proteinopathies (i.e., FTLD-TDP) while other very rare forms of FTLD are known such as FTLD with FUS pathology (FTLD-FUS). This review focuses mainly on FTLD-Tau and FLTD-TDP, which may present as several clinical syndromes: a behavioral/dysexecutive syndrome (behavioral variant frontotemporal dementia); language disorders (primary progressive aphasia variants); and motor disorders (amyotrophic lateral sclerosis, corticobasal syndrome, progressive supranuclear palsy syndrome). There is considerable heterogeneity in clinical presentations of underlying neuropathology and current clinical criteria do not reliably predict underlying proteinopathies ante-mortem. In contrast, molecular etiologies of hereditary FTLD are consistently associated with specific proteinopathies. These include MAPT mutations with FTLD-Tau and GRN, C9orf72, VCP and TARDBP with FTLD-TDP. The last decade has seen a rapid expansion in our knowledge of the molecular pathologies associated with this clinically and neuropathologically heterogeneous group of FTLD diseases. Moreover, in view of current limitations to reliably diagnose specific FTLD neuropathologies prior to autopsy, we summarize the current state of the science in FTLD biomarker research including neuroimaging, biofluid and genetic analyses. We propose that combining several of these biomarker modalities will improve diagnostic specificity in FTLD through a personalized medicine approach. The goals of these efforts are to enhance power for clinical trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated pathologies and work toward the goal of defining clinical endophenotypes of FTD.
    Acta Neuropathologica 12/2014; 129(4). DOI:10.1007/s00401-014-1380-1 · 10.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Quantitative examinations of speech production in amyotrophic lateral sclerosis (ALS) are rare. To identify language features minimally confounded by a motor disorder, we investigated linguistic and motor sources of impaired sentence expression in ALS, and we related deficits to gray matter (GM) and white matter (WM) MRI abnormalities. We analyzed a semi-structured speech sample in 26 ALS patients and 19 healthy seniors for motor- and language-related deficits. Regression analyses related grammaticality to GM atrophy and reduced WM fractional anisotropy (FA). Results demonstrated that ALS patients were impaired relative to controls on quantity of speech, speech rate, speech articulation errors, and grammaticality. Speech rate and articulation errors were related to the patients' motor impairment, while grammatical difficulty was independent of motor difficulty. This was confirmed in subgroups without dysarthria and without executive deficits. Regressions related grammatical expression to GM atrophy in left inferior frontal and anterior temporal regions and to reduced FA in superior longitudinal and inferior frontal-occipital fasciculi. In conclusion, patients with ALS exhibit multifactorial deficits in sentence expression. They demonstrate a deficit in grammatical expression that is independent of their motor disorder. Impaired grammatical expression is related to disease in a network of brain regions associated with syntactic processing.
    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 12/2014; 16(1-2):1-9. DOI:10.3109/21678421.2014.974617 · 2.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To relate changes in fractional anisotropy associated with behavioral variant frontotemporal dementia to measures of apathy and disinhibition. Apathy and disinhibition are the 2 most common behavioral features of behavioral variant frontotemporal dementia, and these symptoms are associated with accelerated patient decline and caregiver stress. However, little is known about how white matter disease contributes to these symptoms. We collected neuropsychiatric data, volumetric magnetic resonance imaging, and diffusion-weighted imaging in 11 patients who met published criteria for behavioral variant frontotemporal dementia and had an autopsy-validated cerebrospinal fluid profile consistent with frontotemporal lobar degeneration. We also collected imaging data on 34 healthy seniors for analyses defining regions of disease in the patients. We calculated and analyzed fractional anisotropy with a white matter tract-specific method. This approach uses anatomically guided data reduction to increase sensitivity, and localizes results within canonically defined tracts. We used nonparametric, cluster-based statistical analysis to relate fractional anisotropy to neuropsychiatric measures of apathy and disinhibition. The patients with behavioral variant frontotemporal dementia had widespread reductions in fractional anisotropy in anterior portions of frontal and temporal white matter, compared to the controls. Fractional anisotropy correlated with apathy in the left uncinate fasciculus and with disinhibition in the right corona radiata. In patients with behavioral variant frontotemporal dementia, apathy and disinhibition are associated with distinct regions of white matter disease. The implicated fiber tracts likely support frontotemporal networks that are involved in goal-directed behavior.
    Cognitive and behavioral neurology: official journal of the Society for Behavioral and Cognitive Neurology 12/2014; 27(4):206-14. DOI:10.1097/WNN.0000000000000044 · 0.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Segmenting and quantifying gliomas from MRI is an important task for diagnosis, planning intervention, and for tracking tumor changes over time. However, this task is complicated by the lack of prior knowledge concerning tumor location, spatial extent, shape, possible displacement of normal tissue, and intensity signature. To accommodate such complications, we introduce a framework for supervised segmentation based on multiple modality intensity, geometry, and asymmetry feature sets. These features drive a supervised whole-brain and tumor segmentation approach based on random forest-derived probabilities. The asymmetry-related features (based on optimal symmetric multimodal templates) demonstrate excellent discriminative properties within this framework. We also gain performance by generating probability maps from random forest models and using these maps for a refining Markov random field regularized probabilistic segmentation. This strategy allows us to interface the supervised learning capabilities of the random forest model with regularized probabilistic segmentation using the recently developed ANTsR package-a comprehensive statistical and visualization interface between the popular Advanced Normalization Tools (ANTs) and the R statistical project. The reported algorithmic framework was the top-performing entry in the MICCAI 2013 Multimodal Brain Tumor Segmentation challenge. The challenge data were widely varying consisting of both high-grade and low-grade glioma tumor four-modality MRI from five different institutions. Average Dice overlap measures for the final algorithmic assessment were 0.87, 0.78, and 0.74 for "complete", "core", and "enhanced" tumor components, respectively.
    Neuroinformatics 11/2014; 13(2). DOI:10.1007/s12021-014-9245-2 · 2.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: C9orf72 promoter hypermethylation inhibits the accumulation of pathologies which have been postulated to be neurotoxic. We tested here whether C9orf72 hypermethylation is associated with prolonged disease in C9orf72 mutation carriers. C9orf72 methylation was quantified from brain or blood using methylation-sensitive restriction enzyme digest-qPCR in a cross-sectional cohort of 118 C9orf72 repeat expansion carriers and 19 non-carrier family members. Multivariate regression models were used to determine whether C9orf72 hypermethylation was associated with age at onset, disease duration, age at death, or hexanucleotide repeat expansion size. Permutation analysis was performed to determine whether C9orf72 methylation is heritable. We observed a high correlation between C9orf72 methylation across tissues including cerebellum, frontal cortex, spinal cord and peripheral blood. While C9orf72 methylation was not significantly different between ALS and FTD and did not predict age at onset, brain and blood C9orf72 hypermethylation was associated with later age at death in FTD (brain: β = 0.18, p = 0.006; blood: β = 0.15, p < 0.001), and blood C9orf72 hypermethylation was associated with longer disease duration in FTD (β = 0.03, p = 0.007). Furthermore, C9orf72 hypermethylation was associated with smaller hexanucleotide repeat length (β = -16.69, p = 0.033). Finally, analysis of pedigrees with multiple mutation carriers demonstrated a significant association between C9orf72 methylation and family relatedness (p < 0.0001). C9orf72 hypermethylation is associated with prolonged disease in C9orf72 repeat expansion carriers with FTD. The attenuated clinical phenotype associated with C9orf72 hypermethylation suggests that slower clinical progression in FTD is associated with reduced expression of mutant C9orf72. These results support the hypothesis that expression of the hexanucleotide repeat expansion is associated with a toxic gain of function.
    Acta Neuropathologica 11/2014; 129(1). DOI:10.1007/s00401-014-1365-0 · 10.76 Impact Factor

Publication Stats

13k Citations
1,777.22 Total Impact Points


  • 1995–2015
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 1992–2015
    • University of Pennsylvania
      • • Department of Neurology
      • • Department of Medicine
      • • Department of Radiology
      Filadelfia, Pennsylvania, United States
  • 2013
    • Treatment Research Institute, Philadelphia PA
      Filadelfia, Pennsylvania, United States
    • Emory University
      • School of Medicine
      Atlanta, Georgia, United States
  • 1993–2013
    • Hospital of the University of Pennsylvania
      • • Department of Neurology
      • • Department of Pathology and Laboratory Medicine
      Filadelfia, Pennsylvania, United States
  • 2011
    • Pennsylvania State University
      • Department of Neurology
      University Park, Maryland, United States
  • 2010
    • Drexel University College of Medicine
      • Department of Neurology
      Philadelphia, Pennsylvania, United States
    • University of Washington Seattle
      • Department of Medicine
      Seattle, Washington, United States
  • 2005–2008
    • Columbia University
      • • Department of Neurology
      • • Department of Psychology
      New York City, New York, United States
  • 2006
    • Stratford University
      Stratford, Connecticut, United States
  • 2004
    • University of Michigan
      Ann Arbor, Michigan, United States
    • University of California, San Francisco
      • Department of Neurology
      San Francisco, CA, United States
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 1987
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States