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Murray Grossman

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YNICL Journal 2023 Journal Article

Event-based modeling of T1-weighted MRI is related to pathology in frontotemporal lobar degeneration due to tau and TDP

  • Christopher A. Olm
  • Sarah E. Burke
  • Claire Peterson
  • Edward B. Lee
  • John Q. Trojanowski
  • Lauren Massimo
  • David J. Irwin
  • Murray Grossman

BACKGROUND: In previous studies of patients with frontotemporal lobar degeneration due to tau (FTLD-tau) and FTLD due to TDP (FTLD-TDP), cortical volumes derived from T1-weighted MRI have been used to identify a sequence of volume loss according to arbitrary volumetric criteria. Event-based modeling (EBM) is a probabilistic, generative machine learning model that determines the characteristic sequence of changes, or "events", occurring during disease progression. EBM also estimates an individual patient's disease "stage" by identifying which events have already occurred. In the present study, we use an EBM analysis to derive stages of regional anatomic atrophy in FTLD-tau and FTLD-TDP, and validated these stages against pathologic burden. METHODS: Sporadic autopsy-confirmed patients with FTLD-tau (N = 42) and FTLD-TDP (N = 21), and 167 healthy controls with available T1-weighted images were identified. A subset of patients had quantitative digital histopathology of cortex performed at autopsy (FTLD-tau = 30, FTLD-TDP = 17). MRI images were processed, producing regional measures of cortical volumes. K-means clustering was used to find cortical regions with similar amounts of GM volume changes (n = 5 clusters). EBM was used to determine the characteristic sequence of cortical atrophy of identified clusters in autopsy-confirmed FTLD-tau and FTLD-TDP, and estimate each patient's disease stage by cortical volume biomarkers. Linear regressions related pathologic burden to EBM-estimated disease stages. RESULTS: EBM for cortical volume biomarkers generated statistically robust characteristic sequences of cortical atrophy in each group of patients. Cortical volume-based EBM-estimated disease stage was associated with pathologic burden in FTLD-tau (R2 = 0.16, p = 0.017) and FTLD-TDP (R2 = 0.51, p = 0.0008). CONCLUSIONS: We provide evidence that EBM can identify sequences of pathologically-confirmed cortical atrophy in sporadic FTLD-tau and FTLD-TDP.

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YNICL Journal 2022 Journal Article

Ex vivo MRI and histopathology detect novel iron-rich cortical inflammation in frontotemporal lobar degeneration with tau versus TDP-43 pathology

  • M. Dylan Tisdall
  • Daniel T. Ohm
  • Rebecca Lobrovich
  • Sandhitsu R. Das
  • Gabor Mizsei
  • Karthik Prabhakaran
  • Ranjit Ittyerah
  • Sydney Lim

Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging therapeutic trials tailored to disease-specific mechanisms. Moreover, MRI-derived measures have had limited success to date discriminating between FTLD-Tau or FTLD-TDP. T2*-weighted (T2*w) ex vivo MRI has previously been shown to be sensitive to non-heme iron in healthy intracortical lamination and myelin, and to pathological iron deposits in amyloid-beta plaques and activated microglia in Alzheimer’s disease neuropathologic change (ADNC). However, an integrated, ex vivo MRI and histopathology approach is understudied in FTLD. We apply joint, whole-hemisphere ex vivo MRI at 7 T and histopathology to the study autopsy-confirmed FTLD-Tau (n = 4) and FTLD-TDP (n = 3), relative to ADNC disease-control brains with antemortem clinical symptoms of frontotemporal dementia (n = 2), and an age-matched healthy control. We detect distinct laminar patterns of novel iron-laden glial pathology in both FTLD-Tau and FTLD-TDP brains. We find iron-positive ameboid and hypertrophic microglia and astrocytes largely in deeper GM and adjacent WM in FTLD-Tau. In contrast, FTLD-TDP presents prominent superficial cortical layer iron reactivity in astrocytic processes enveloping small blood vessels with limited involvement of adjacent WM, as well as more diffuse distribution of punctate iron-rich dystrophic microglial processes across all GM lamina. This integrated MRI/histopathology approach reveals ex vivo MRI features that are consistent with these pathological observations distinguishing FTLD-Tau and FTLD-TDP subtypes, including prominent irregular hypointense signal in deeper cortex in FTLD-Tau whereas FTLD-TDP showed upper cortical layer hypointense bands and diffuse cortical speckling. Moreover, differences in adjacent WM degeneration and iron-rich gliosis on histology between FTLD-Tau and FTLD-TDP were also readily apparent on MRI as hyperintense signal and irregular areas of hypointensity, respectively that were more prominent in FTLD-Tau compared to FTLD-TDP. These unique histopathological and radiographic features were distinct from healthy control and ADNC brains, suggesting that iron-sensitive T2*w MRI, adapted to in vivo application at sufficient resolution, may eventually offer an opportunity to improve antemortem diagnosis of FTLD proteinopathies using tissue-validated methods.

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YNICL Journal 2018 Journal Article

Longitudinal structural gray matter and white matter MRI changes in presymptomatic progranulin mutation carriers

  • Christopher A. Olm
  • Corey T. McMillan
  • David J. Irwin
  • Vivianna M. Van Deerlin
  • Philip A. Cook
  • James C. Gee
  • Murray Grossman

Introduction: mutation carriers (pGRN+) compared to young controls (yCTL). Methods: = 11, mean age = 53.6) were identified. They completed a MRI session with T1-weighted imaging to assess GM density (GMD) and diffusion-weighted imaging (DWI) to assess fractional anisotropy (FA). Participants completed a follow-up session with T1 and DWI imaging (pGRN+ mean interval 2.20 years; yCTL mean interval 3.27 years). Annualized changes of GMD and FA were also compared. Results: Relative to yCTL, pGRN+ individuals displayed reduced GMD at baseline in bilateral orbitofrontal, insular, and anterior temporal cortices. pGRN+ also showed greater annualized GMD changes than yCTL at follow-up in right orbitofrontal and left occipital cortices. We also observed reduced FA at baseline in bilateral superior longitudinal fasciculus, left corticospinal tract, and frontal corpus callosum in pGRN+ relative to yCTL, and pGRN+ displayed greater annualized longitudinal FA change in right superior longitudinal fasciculus and frontal corpus callosum. Conclusions: Longitudinal MRI provides evidence of progressive GM and WM changes in pGRN+ participants relative to yCTL. Structural MRI illustrates the natural history of presymptomatic GRN carriers, and may provide an endpoint during disease-modifying treatment trials for pGRN+ individuals at risk for FTD.

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YNIMG Journal 2016 Journal Article

How the brain learns how few are “many”: An fMRI study of the flexibility of quantifier semantics

  • Stefan Heim
  • Corey T. McMillan
  • Robin Clark
  • Laura Baehr
  • Kylie Ternes
  • Christopher Olm
  • Nam Eun Min
  • Murray Grossman

Previous work has shown that the meaning of a quantifier such as “many” or “few” depends in part on quantity. However, the meaning of a quantifier may vary depending on the context, e. g. in the case of common entities such as “many ants” (perhaps several thousands) compared to endangered species such as “many pandas” (perhaps a dozen). In a recent study (Heim et al. , 2015 Front. Psychol.) we demonstrated that the relative meaning of “many” and “few” may be changed experimentally. In a truth value judgment task, displays with 40% of circles in a named color initially had a low probability of being labeled “many”. After a training phase, the likelihood of acceptance 40% as “many” increased. Moreover, the semantic learning effect also generalized to the related quantifier “few” which had not been mentioned in the training phase. Thus, fewer 40% arrays were considered “few. ” In the present study, we tested the hypothesis that this semantic adaptation effect was supported by cytoarchitectonic Brodmann area (BA) 45 in Broca's region which may contribute to semantic evaluation in the context of language and quantification. In an event-related fMRI study, 17 healthy volunteers performed the same paradigm as in the previous behavioral study. We found a relative signal increase when comparing the critical, trained proportion to untrained proportions. This specific effect was found in left BA 45 for the trained quantifier “many”, and in left BA 44 for both quantifiers, reflecting the semantic adjustment for the untrained but related quantifier “few. ” These findings demonstrate the neural basis for processing the flexible meaning of a quantifier, and illustrate the neuroanatomical structures that contribute to variable meanings that can be associated with a word when used in different contexts.

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YNIMG Journal 2014 Journal Article

Relating brain anatomy and cognitive ability using a multivariate multimodal framework

  • Philip A. Cook
  • Corey T. McMillan
  • Brian B. Avants
  • Jonathan E. Peelle
  • James C. Gee
  • Murray Grossman

Linking structural neuroimaging data from multiple modalities to cognitive performance is an important challenge for cognitive neuroscience. In this study we examined the relationship between verbal fluency performance and neuroanatomy in 54 patients with frontotemporal degeneration (FTD) and 15 age-matched controls, all of whom had T1- and diffusion-weighted imaging. Our goal was to incorporate measures of both gray matter (voxel-based cortical thickness) and white matter (fractional anisotropy) into a single statistical model that relates to behavioral performance. We first used eigenanatomy to define data-driven regions of interest (DD-ROIs) for both gray matter and white matter. Eigenanatomy is a multivariate dimensionality reduction approach that identifies spatially smooth, unsigned principal components that explain the maximal amount of variance across subjects. We then used a statistical model selection procedure to see which of these DD-ROIs best modeled performance on verbal fluency tasks hypothesized to rely on distinct components of a large-scale neural network that support language: category fluency requires a semantic-guided search and is hypothesized to rely primarily on temporal cortices that support lexical-semantic representations; letter-guided fluency requires a strategic mental search and is hypothesized to require executive resources to support a more demanding search process, which depends on prefrontal cortex in addition to temporal network components that support lexical representations. We observed that both types of verbal fluency performance are best described by a network that includes a combination of gray matter and white matter. For category fluency, the identified regions included bilateral temporal cortex and a white matter region including left inferior longitudinal fasciculus and frontal–occipital fasciculus. For letter fluency, a left temporal lobe region was also selected, and also regions of frontal cortex. These results are consistent with our hypothesized neuroanatomical models of language processing and its breakdown in FTD. We conclude that clustering the data with eigenanatomy before performing linear regression is a promising tool for multimodal data analysis.

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YNIMG Journal 2014 Journal Article

Sparse canonical correlation analysis relates network-level atrophy to multivariate cognitive measures in a neurodegenerative population

  • Brian B. Avants
  • David J. Libon
  • Katya Rascovsky
  • Ashley Boller
  • Corey T. McMillan
  • Lauren Massimo
  • H. Branch Coslett
  • Anjan Chatterjee

This study establishes that sparse canonical correlation analysis (SCCAN) identifies generalizable, structural MRI-derived cortical networks that relate to five distinct categories of cognition. We obtain multivariate psychometrics from the domain-specific sub-scales of the Philadelphia Brief Assessment of Cognition (PBAC). By using a training and separate testing stage, we find that PBAC-defined cognitive domains of language, visuospatial functioning, episodic memory, executive control, and social functioning correlate with unique and distributed areas of gray matter (GM). In contrast, a parallel univariate framework fails to identify, from the training data, regions that are also significant in the left-out test dataset. The cohort includes164 patients with Alzheimer's disease, behavioral-variant frontotemporal dementia, semantic variant primary progressive aphasia, non-fluent/agrammatic primary progressive aphasia, or corticobasal syndrome. The analysis is implemented with open-source software for which we provide examples in the text. In conclusion, we show that multivariate techniques identify biologically-plausible brain regions supporting specific cognitive domains. The findings are identified in training data and confirmed in test data.

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YNIMG Journal 2013 Journal Article

Category-specific semantic memory: Converging evidence from bold fMRI and Alzheimer's disease

  • Murray Grossman
  • Jonathan E. Peelle
  • Edward E. Smith
  • Corey T. McMillan
  • Philip Cook
  • John Powers
  • Michael Dreyfuss
  • Michael F. Bonner

Patients with Alzheimer's disease have category-specific semantic memory difficulty for natural relative to manufactured objects. We assessed the basis for this deficit by asking healthy adults and patients to judge whether pairs of words share a feature (e. g. “banana: lemon—COLOR”). In an fMRI study, healthy adults showed gray matter (GM) activation of temporal–occipital cortex (TOC) where visual–perceptual features may be represented, and prefrontal cortex (PFC) which may contribute to feature selection. Tractography revealed dorsal and ventral stream white matter (WM) projections between PFC and TOC. Patients had greater difficulty with natural than manufactured objects. This was associated with greater overlap between diseased GM areas correlated with natural kinds in patients and fMRI activation in healthy adults for natural kinds. The dorsal WM projection between PFC and TOC in patients correlated only with judgments of natural kinds. Patients thus remained dependent on the same neural network as controls during judgments of natural kinds, despite disease in these areas. For manufactured objects, patients' judgments showed limited correlations with PFC and TOC GM areas activated by controls, and did not correlate with the PFC–TOC dorsal WM tract. Regions outside of the PFC–TOC network thus may help support patients' judgments of manufactured objects. We conclude that a large-scale neural network for semantic memory implicates both feature knowledge representations in modality-specific association cortex and heteromodal regions important for accessing this knowledge, and that patients' relative deficit for natural kinds is due in part to their dependence on this network despite disease in these areas.

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YNIMG Journal 2013 Journal Article

Heteromodal conceptual processing in the angular gyrus

  • Michael F. Bonner
  • Jonathan E. Peelle
  • Philip A. Cook
  • Murray Grossman

Concepts bind together the features commonly associated with objects and events to form networks in long-term semantic memory. These conceptual networks are the basis of human knowledge and underlie perception, imagination, and the ability to communicate about experiences and the contents of the environment. Although it is often assumed that this distributed semantic information is integrated in higher-level heteromodal association cortices, open questions remain about the role and anatomic basis of heteromodal representations in semantic memory. Here we used combined neuroimaging evidence from functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to characterize the cortical networks underlying concept representation. Using a lexical decision task, we examined the processing of concepts in four semantic categories that varied on their sensory–motor feature associations (sight, sound, manipulation, and abstract). We found that the angular gyrus was activated across all categories regardless of their modality-specific feature associations, consistent with a heteromodal account for the angular gyrus. Exploratory analyses suggested that categories with weighted sensory–motor features additionally recruited modality-specific association cortices. Furthermore, DTI tractography identified white matter tracts connecting these regions of modality-specific functional activation with the angular gyrus. These findings are consistent with a distributed semantic network that includes a heteromodal, integrative component in the angular gyrus in combination with sensory–motor feature representations in modality-specific association cortices.

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YNIMG Journal 2010 Journal Article

Dementia induces correlated reductions in white matter integrity and cortical thickness: A multivariate neuroimaging study with sparse canonical correlation analysis

  • Brian B. Avants
  • Philip A. Cook
  • Lyle Ungar
  • James C. Gee
  • Murray Grossman

We use a new, unsupervised multivariate imaging and analysis strategy to identify related patterns of reduced white matter integrity, measured with the fractional anisotropy (FA) derived from diffusion tensor imaging (DTI), and decreases in cortical thickness, measured by high resolution T1-weighted imaging, in Alzheimer's disease (AD) and frontotemporal dementia (FTD). This process is based on a novel computational model derived from sparse canonical correlation analysis (SCCA) that allows us to automatically identify mutually predictive, distributed neuroanatomical regions from different imaging modalities. We apply the SCCA model to a dataset that includes 23 control subjects that are demographically matched to 49 subjects with autopsy or CSF-biomarker-diagnosed AD (n =24) and FTD (n =25) with both DTI and T1-weighted structural imaging. SCCA shows that the FTD-related frontal and temporal degeneration pattern is correlated across modalities with permutation corrected p <0. 0005. In AD, we find significant association between cortical thinning and reduction in white matter integrity within a distributed parietal and temporal network (p <0. 0005). Furthermore, we show that—within SCCA identified regions—significant differences exist between FTD and AD cortical-connective degeneration patterns. We validate these distinct, multimodal imaging patterns by showing unique relationships with cognitive measures in AD and FTD. We conclude that SCCA is a potentially valuable approach in image analysis that can be applied productively to distinguishing between neurodegenerative conditions.

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YNIMG Journal 2009 Journal Article

Registration based cortical thickness measurement

  • Sandhitsu R. Das
  • Brian B. Avants
  • Murray Grossman
  • James C. Gee

Cortical thickness is an important biomarker for image-based studies of the brain. A diffeomorphic registration based cortical thickness (DiReCT) measure is introduced where a continuous one-to-one correspondence between the gray matter–white matter interface and the estimated gray matter–cerebrospinal fluid interface is given by a diffeomorphic mapping in the image space. Thickness is then defined in terms of a distance measure between the interfaces of this sheet like structure. This technique also provides a natural way to compute continuous estimates of thickness within buried sulci by preventing opposing gray matter banks from intersecting. In addition, the proposed method incorporates neuroanatomical constraints on thickness values as part of the mapping process. Evaluation of this method is presented on synthetic images. As an application to brain images, a longitudinal study of thickness change in frontotemporal dementia (FTD) spectrum disorder is reported.

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YNIMG Journal 2008 Journal Article

Narrative speech production: An fMRI study using continuous arterial spin labeling

  • Vanessa Troiani
  • Maria A. Fernández-Seara
  • Ze Wang
  • John A. Detre
  • Sherry Ash
  • Murray Grossman

Functional magnetic resonance imaging (fMRI) with continuous arterial spin labeling (CASL) was employed to monitor brain activation during narrative production of a semi-structured speech sample in healthy young adults. Subjects were asked to describe a wordless children’s picture story. Significant activations were found in bilateral prefrontal and left temporal–parietal regions during narrative production relative to description of a single picture and relative to viewing the wordless picture story while producing a nonsense word. We conclude that inferior frontal cortex serves as a top–down organizational resource for narrative production and demonstrate the feasibility of collecting extended speech samples using CASL perfusion fMRI.

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YNIMG Journal 2007 Journal Article

Resolving sentence ambiguity with planning and working memory resources: Evidence from fMRI

  • Susana Novais-Santos
  • James Gee
  • Maliha Shah
  • Vanessa Troiani
  • Melissa Work
  • Murray Grossman

We used functional magnetic resonance imaging (fMRI) to test competing claims about the role of executive resources during the disambiguation of a sentence featuring a temporary structural ambiguity. Written sentences with a direct object (DO) structure or a sentential complement (SC) structure were shown to 19 healthy, right-handed, young adults in a phrase-by-phrase manner. These sentences contained a main verb that is statistically more likely to be associated with a DO structure or an SC structure. Half of each type of sentence also contained an extra phrase strategically located to stress working memory prior to disambiguating the sentence. We found that sentences featuring a less consistent verb-structure mapping recruit greater dorsolateral prefrontal cortex (dlPFC) activation than sentences with a more consistent verb-structure mapping, implicating strategic on-line planning during resolution of a temporary structural ambiguity. By comparison, we observed left inferior parietal cortex (IPC) activation in sentences with an increased working memory demand compared to sentences with a low working memory load. These findings are consistent with a large-scale neural network for sentence processing that recruits distinct planning and working memory processing resources as needed to support the comprehension of sentences.

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YNIMG Journal 2006 Journal Article

Category-specific effects in semantic memory: Category–task interactions suggested by fMRI

  • Murray Grossman
  • Phyllis Koenig
  • John Kounios
  • Corey McMillan
  • Melissa Work
  • Peachie Moore

Much work has investigated the neural representation of specific categories of knowledge, but relatively scant attention has been paid in the cognitive neuroscience literature to the semantic processes that contribute to semantic memory. In this study, we monitored regional cortical activity with fMRI while healthy young adults evaluated visually displayed NATURAL KIND, ARTIFACT, and ABSTRACT nouns with two standard tasks: Typicality judgments and Pleasantness judgments. We observed a significant interaction effect between the category of knowledge and the type of judgment used to evaluate members of these semantic categories. Typicality judgments recruited greater temporal–occipital activation relative to Pleasantness judgments of the same category, and this was seen for comparisons of all three semantic categories. However, when contrasted with Typicality judgments, Pleasantness judgments activated a different anatomic distribution for each semantic category. These findings are consistent with a dynamic approach to semantic memory that includes at least two components: semantic knowledge and semantic processes that interpret this knowledge in several ways depending on the particular semantic challenge.

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YNIMG Journal 2005 Journal Article

The neural basis for novel semantic categorization

  • Phyllis Koenig
  • Edward E. Smith
  • Guila Glosser
  • Chris DeVita
  • Peachie Moore
  • Corey McMillan
  • Jim Gee
  • Murray Grossman

We monitored regional cerebral activity with BOLD fMRI during acquisition of a novel semantic category and subsequent categorization of test stimuli by a rule-based strategy or a similarity-based strategy. We observed different patterns of activation in direct comparisons of rule- and similarity-based categorization. During rule-based category acquisition, subjects recruited anterior cingulate, thalamic, and parietal regions to support selective attention to perceptual features, and left inferior frontal cortex to helps maintain rules in working memory. Subsequent rule-based categorization revealed anterior cingulate and parietal activation while judging stimuli whose conformity with the rules was readily apparent, and left inferior frontal recruitment during judgments of stimuli whose conformity was less apparent. By comparison, similarity-based category acquisition showed recruitment of anterior prefrontal and posterior cingulate regions, presumably to support successful retrieval of previously encountered exemplars from long-term memory, and bilateral temporal-parietal activation for perceptual feature integration. Subsequent similarity-based categorization revealed temporal–parietal, posterior cingulate, and anterior prefrontal activation. These findings suggest that large-scale networks support relatively distinct categorization processes during the acquisition and judgment of semantic category knowledge.

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