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Corey T. McMillan

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9 papers

1 author row

YNICL Journal 2025 Journal Article

Executive dysfunction relates to salience network desegregation in behavioural variant frontotemporal dementia

Melanie A. Matyi
Hamsanandini Radhakrishnan
Christopher A. Olm
Jeffrey S. Phillips
Philip A. Cook
Emma Rhodes
James C. Gee
David J. Irwin

BACKGROUND: The organization of the brain into distinct networks increases (i.e., differentiation) during development and decreases (i.e., de-differentiation) during healthy aging, changes that are associated with improvements and worsening of cognition, respectively. Given that behavioral variant frontotemporal degeneration (bvFTD) is a neurodegenerative disease associated with executive dysfunction and selective vulnerability of the salience network, we tested the hypotheses that bvFTD structural networks are de-differentiated compared to cognitively normal controls (CNC) and that network de-differentiation relates to worse executive function. METHODS: In a sample of 90 patients with bvFTD and 71 age-matched CNC with diffusion MRI data we generated probabilistic tractography maps and calculated system segregation, a metric that compares within-network to between-network connectivity, to reflect the extent to which brain networks were differentiated. Patients with bvFTD also completed tests of executive function (digit span backwards, phonemic fluency, category fluency) and a control task (lexical retrieval). We assessed group differences in system segregation, reflecting network differentiation, and, within bvFTD, associations between system segregation and neuropsychological test performance. RESULTS: = 0.021) but not lexical retrieval. CONCLUSIONS: Results demonstrate associations between executive dysfunction and salience network de-differentiation in patients with bvFTD. Our findings indicate that brain network de-differentiation, reflecting reduced neural capacity for specialized processing, may contribute to the emergence of executive dysfunction in bvFTD.

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YNICL Journal 2025 Journal Article

Posterior hippocampal sparing in Lewy body disorders with Alzheimer’s copathology: An in vivo MRI study

Jesse S. Cohen
Jeffrey Phillips
Sandhitsu R. Das
Christopher A. Olm
Hamsanandini Radhakrishnan
Emma Rhodes
Katheryn A.Q. Cousins
Sharon X. Xie

BACKGROUND: Lewy body disorders (LBD), encompassing Parkinson disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB), are characterized by alpha-synuclein pathology but often are accompanied by Alzheimer's disease (AD) neuropathological change (ADNC). The medial temporal lobe (MTL) is a primary locus of tau accumulation and associated neurodegeneration in AD. However, it is unclear the extent to which AD copathology in LBD (LBD/AD+) contributes to MTL-specific patterns of degeneration. We employ a MTL subregional segmentation strategy of T1-weighted (T1w) MRI in biomarker-supported or autopsy-confirmed LBD and LBD/AD+ to investigate the anatomic consequences of co-occurring LBD/AD+ pathology on neurodegeneration. METHODS: < 185.7 pg/mL n = 126 (75.4 %)). The T1 Automated Segmentation of Hippocampal Subfields (ASHS) pipeline was used to compute volume and thickness measurements of MTL subregions in LBD/AD- and LBD/AD+. Linear regression tested the association of AD copathology and subregion volume/thickness, covarying for age and sex, and intracranial volume for volume measurements. Secondary analyses correlated MTL subregional volume/thickness with cognition and neuropathology. RESULTS: LBD/AD+ had decreased volume/thickness compared to LBD/AD- in all MTL subregions except posterior hippocampus. The greatest effect sizes were seen in Brodmann Area 35 (BA35) (Cohen's d = 0.62, p = 0.002, β = 0.107 ± 0.034), and entorhinal cortex (ERC) (Cohen's d = 0.56, p = 0.006, β = 0.088 ± 0.031). Smaller differences were seen in the parahippocampal cortex (PHC) (Cohen's d = 0.5, p = 0.012, β = 0.082 ± 0.033), BA36 (Cohen's d = 0.47, p = 0.021, β = 0.090 ± 0.039) and anterior hippocampus (Cohen's d = 0.45, p = 0.029, β = 111.790 ± 50.595). Verbal memory scores positively correlated with volume/thickness in anterior and posterior hippocampus, BA35, ERC and PHC, while visuospatial memory positively correlated only in BA35. In the subset of participants with autopsy, lower ERC volume was associated with a higher tau load in ERC (adjusted odds ratio 0.013, 95 % CI [0.0002, 0.841], uncorrected p = 0.041). CONCLUSIONS: Relative to LBD/AD-, LBD/AD+ has greater T1w MRI evidence of atrophy in multiple MTL subregions. Atrophy in MTL subregions associates with memory performance and tau pathological load. The observed pattern of atrophy largely follows expectation from AD Braak stages, except for posterior hippocampus. Longitudinal studies are needed to validate the hypothesized spread of neurodegeneration.

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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 2021 Journal Article

Social and leisure activity are associated with attenuated cortical loss in behavioral variant frontotemporal degeneration

Nikolas G. Kinney
Jessica Bove
Jeffrey S. Phillips
Katheryn A.Q Cousins
Christopher A. Olm
Daniel G. Wakeman
Corey T. McMillan
Lauren Massimo

Behavioral variant frontotemporal degeneration (bvFTD) is clinically characterized by progressive decline in social and executive domains. Previous work suggests that early lifestyle factors such as education and occupational attainment may relate to structural integrity and moderate the rate of cognitive decline in bvFTD, but the role of other cognitively stimulating activities is understudied. We sought to investigate the effect of such activities on cortical thickness (CT) in bvFTD. bvFTD patients (n = 31) completed a baseline MRI scan, and informants for the patients completed the Lifetime of Experiences Questionnaire (LEQ), which measures specific activities considered to be undertaken primarily within one particular life phase, such as education (young-life), occupation (mid-life), and social/leisure activity (late-life). At baseline, linear models assessed the effect of LEQ scores from each life phase on regional CT. A subset (n = 19) of patients completed longitudinal MRI, and to evaluate the association of LEQ with longitudinal rates of CT decline, we derived individualized slopes of decline using linear mixed effects models and these were related to LEQ scores from each life phase. At baseline, a higher late-life LEQ score was associated with less atrophy in left superior and inferior anterior temporal regions as well as right middle temporal gyrus. Longitudinally, we observed that higher late-life LEQ scores were associated with an attenuated rate of CT loss in insular cortex. Late-life LEQ score was positively associated with both relatively preserved CT early in bvFTD and a slower rate of cortical loss in regions important for social functioning. These findings suggest that social and leisure activities may contribute to a form of resilience against pathologic effects of disease.

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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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