Corey T Mcmillan

Corey T Mcmillan
University of Pennsylvania | UP · Department of Neurology

PhD

About

251
Publications
17,738
Reads
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6,439
Citations
Additional affiliations
July 2013 - present
University of Pennsylvania
Position
  • Research Assistant
August 2012 - present
University of Pennsylvania
Position
  • Research Associate
July 2009 - July 2012
University of Pennsylvania
Position
  • NRSA Postdoctoral Fellow
Education
August 2004 - January 2008
The University of Edinburgh
Field of study
  • Psychology
August 2003 - August 2004
The University of Edinburgh
Field of study
  • Psycholinguistics
September 1996 - June 2000
Temple University
Field of study
  • Psychology & Cognitive Neuroscience

Publications

Publications (251)
Article
Full-text available
Background Synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD). Consequently, a surrogate marker of synapse loss could be used to monitor early pathologic changes in patients with underlying FTLD. The aim of this study was to evaluate the relationship of antemortem cerebrospinal fluid (CSF) levels of 8 sy...
Article
Background: An understudied variant of Alzheimer’s disease (AD), the behavioral/dysexecutive variant of AD (bvAD), is associated with progressive personality, behavior, and/or executive dysfunction and frontal atrophy. Objective: This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to beh...
Article
Full-text available
Alzheimer’s disease neuropathologic change (ADNC) is clinically heterogenous and can present with a classic multidomain amnestic syndrome or focal non-amnestic syndromes. Here, we investigated the distribution and burden of phosphorylated and C-terminally cleaved tau pathologies across hippocampal subfields and cortical regions among phenotypic var...
Article
Objective: Plasma phosphorylated tau (p-tau181 ) is reliably elevated in Alzheimer's disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here we find novel evidence that plasma p-tau181 is elevated in amyotrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. W...
Article
Retromer is a heteropentameric complex that plays a specialized role in endosomal protein sorting and trafficking. Here, we report a reduction in the retromer proteins—vacuolar protein sorting 35 (VPS35), VPS26A, and VPS29—in patients with amyotrophic lateral sclerosis (ALS) and in the ALS model provided by transgenic (Tg) mice expressing the mutan...
Article
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Introduction: Lewy body diseases are pathologically characterized by α-synuclein pathology. Alzheimer's disease (AD) co-pathology can influence phenotypes. In vivo AD biomarkers can suggest the presence of this co-pathology in unusual cases, but pathological validation remains essential. Methods: This patient originally presented with corticobas...
Preprint
Objective Plasma phosphorylated tau (p-tau 181 ) is reliably elevated in Alzheimer’s disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here we find novel evidence that plasma p-tau 181 is elevated in amytrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. We...
Article
Full-text available
TDP-43 (TAR DNA-binding protein 43) aggregation and redistribution are recognised as a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. As TDP-43 inclusions have recently been described in the muscle of inclusion body myositis patients, this highlights the need to understand the role of TDP-43 beyond the central nervous system...
Article
Network analyses inform complex systems such as human brain connectivity, but this approach is seldom applied to gold-standard histopathology. Here, we use two complimentary computational approaches to model microscopic progression of the main subtypes of tauopathy versus TDP-43 proteinopathy in the human brain. Digital histopathology measures were...
Article
Full-text available
Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by ast...
Article
Objective: Amyotrophic lateral sclerosis (ALS) is a multi-system disorder characterized primarily by motor neuron degeneration, but may be accompanied by cognitive dysfunction. Statistically appropriate criteria for establishing cognitive impairment (CI) in ALS are lacking. We evaluate quantile regression (QR), that accounts for age and education,...
Article
Full-text available
Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1–3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in non...
Article
Full-text available
Frontotemporal lobar degeneration (FTLD) with either tau (FTLD-tau) or TDP-43 (FTLD-TDP) inclusions are distinct proteinopathies that frequently cause similar frontotemporal dementia (FTD) clinical syndromes. FTD syndromes often display macroscopic signatures of neurodegeneration at the level of regions and networks, but it is unclear if subregiona...
Article
Full-text available
Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is n...
Article
Full-text available
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 t...
Article
Recent models propose that spread of Alzheimer's disease (AD) pathology may be mediated by white matter connectivity. AD clinical variants exhibit partially distinct patterns of gray matter atrophy. However, it is less clear whether phenotypic differences extend to patients' white matter connectomes. We hypothesized that white matter connectivity w...
Article
Frontotemporal dementia (FTD) clinical diagnosis is challenged by the variable correspondence between the clinical syndrome and underlying neuropathological changes, the phenotypic overlap with Alzheimer's disease (AD) and the lack of pathophysiologic diagnostic biomarkers. As synapse degeneration is an early event in pathological frontotemporal lo...
Article
Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer’s disease (AD) have noted reduced increases or frank decreases in tau signal. It is unclear whether these reductions reflect measurement/processing error or biological changes in advanced neurodegeneration. We assessed regional and interindividual variation in...
Article
Blood neurofilament light chain (NfL) is a robust predictor of phenoconversion in familial frontotemporal lobar degeneration (fFTLD). The comparative value of CSF NfL and other CSF markers of degeneration in fFTLD remains unexplored. FLTD‐causing mutation carriers were recruited through ALLFTD (n = 113, 56.6% female, mean age 48.1 ± 13 years; 29 C9...
Article
Frontotemporal dementia spectrum disorders (FTD) display complex neuropathological substrates and poor clinicopathological correlations, which hinders therapy development. Plasma P‐tau217 is an emerging tool to screen for Alzheimer’s disease (AD) pathology and may have diagnostic value in FTD. Plasma P‐tau217 was measured cross‐sectionally by elect...
Article
Background: Up to 30% of frontotemporal dementia (FTD) cases are due to known pathogenic mutations (f-FTD). Little is known about the factors that predict who will choose to learn their results. Upcoming clinical trials in f-FTD may require disclosure prior to enrollment, even before symptom onset, and thus characterizing this sample is important....
Article
Cortico‐basal degeneration (CBD) and progressive supranuclear palsy (PSP) are 4R‐tauopathies characterized by progressive tau pathology spread that typically starts in the subcortex. Pre‐clinical studies suggest that tau spreads across connected neurons in an activity‐dependent manner, indicating that the brains’ connectome may mediate tau spreadin...
Article
Background: Non-amnestic presentations of Alzheimer's disease (naAD) correspond to focal cortical areas of high tau pathology that map to clinical symptoms. Moreover, previous work finds relative sparing of the hippocampal formation compared to typical amnestic AD (aAD); however, there is limited data on the regional patterns of tau pathology acro...
Article
Full-text available
Neurodegenerative diseases are challenging for systems biology due to the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics and proteins in iPSC-derived motor neurons from ALS patients carrying hexanucleotide expansi...
Article
Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis (ALS). While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease (AD), Parkinson’s disease (PD), H...
Preprint
Full-text available
Ex vivo MRI of the brain provides remarkable advantages over in vivo MRI for visualizing and characterizing detailed neuroanatomy. However, automated cortical segmentation methods in ex vivo MRI are not well developed, primarily due to limited availability of labeled datasets, and heterogeneity in scanner hardware and acquisition protocols. In this...
Article
Full-text available
Introduction: Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer's disease (AD) have noted reduced increases or frank decreases in tau signal. We investigated how such reductions related to analytical confounds and disease progression markers in atypical AD. Methods: We assessed regional and interindividual...
Preprint
Full-text available
Background. Frontotemporal dementia (FTD) clinical diagnosis is challenged by the variable correspondence between the clinical syndrome and underlying neuropathological changes, the phenotypic overlap with Alzheimer's disease (AD) and the lack of pathophysiologic diagnostic biomarkers. As synapse degeneration is an early event in pathological front...
Preprint
Full-text available
Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), including cortico-basal degeneration and progressive supranuclear palsy (PSP). Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4RTs, characterized not only by neuronal but also by astrogl...
Article
Full-text available
Abstract Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does n...
Article
The T allele in rs1768208 located in or near the myelin oligodendrocyte basic protein gene (MOBP) is a risk factor for frontotemporal degeneration pathology. We evaluated the hypothesis that the presence of a T allele in rs1768208 will be associated with rate of cognitive decline in behavioral variant frontotemporal degeneration (bvFTD) related to...
Article
Full-text available
Objective: To measure the correlation between single breath counting (SBC) and forced vital capacity (liters, FVCL) in amyotrophic lateral sclerosis (ALS) patients and to define the utility of SBC for determining when patients meet the threshold for initiation of noninvasive positive pressure ventilation (FVC < 50% predicted [FVCpred]). Methods: Bo...
Preprint
Full-text available
Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progre...
Article
Full-text available
Background Little is known about the heterogeneous etiology of suspected non-Alzheimer’s pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal...
Preprint
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 t...
Article
Full-text available
Excessive microglial activation might be a central pathological process in GRN-related frontotemporal dementia (FTD-GRN). We measured soluble triggering receptor expressed on myeloid cells 2 (sTREM2), which is shed from disease-associated microglia following cleavage of TREM2, in cerebrospinal fluid of 34 presymptomatic and 35 symptomatic GRN mutat...
Article
Full-text available
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 cog...
Article
Full-text available
Frontotemporal lobar degeneration proteinopathies with tau inclusions (FTLD-Tau) or TDP-43 inclusions (FTLD-TDP) are associated with clinically similar phenotypes. However, these disparate proteinopathies likely differ in cellular severity and regional distribution of inclusions in white matter (WM) and adjacent grey matter (GM), which have been un...
Preprint
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 cog...
Preprint
Full-text available
Importance Amyotrophic lateral sclerosis (ALS) is a multi-system disorder characterized primarily by motor neuron degeneration, but may be accompanied by cognitive dysfunction. Statistically appropriate criteria for establishing cognitive impairment (CI) in ALS are lacking. Objective Define thresholds for CI in ALS using quantile regression (QR) t...
Article
Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the...
Article
Full-text available
Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we o...
Article
The ATN framework combines cerebrospinal fluid (CSF) amyloidβ 1‐42 (Aβ1‐42), phosphorylated tau (p‐tau), and total tau (t‐tau) to diagnose individuals along the continuum of Alzheimer’s disease (AD). While ATN profiles indicative of AD are highly accurate, profiles indicating normal, non‐AD pathology, or concurrent AD and non‐AD pathology are incon...
Article
Aging is the most established risk factor for sporadic Alzheimer’s Disease (AD). However, relative risk of AD varies greatly across individuals. One potential explanation for this heterogeneity is that chronological age may not reflect differences in biological aging. One measure of biological age is the “epigenetic clock” which utilizes a weighted...
Article
The NIA/AA research framework proposes a biological definition of Alzheimer’s disease (AD) based on the presence of both amyloid and tau. However, AD frequently co‐occurs with other non‐AD pathologies, and it is unclear how these pathologies affect the progression of AD‐associated amyloid‐β and tau. We investigated regional heterogeneity in AD path...
Article
Amyotrophic Lateral Sclerosis (ALS) is a multi‐system neurodegenerative disorder with motor and cognitive deficits. Speech is affected both by motor processes associated with the articulation of utterances and by cognitive processes related to conveying a linguistic message. Previous studies in ALS have reported reduced speaking rate, longer pause...
Article
Full-text available
Neurodegeneration of the locus coeruleus (LC) in age-related neurodegenerative diseases such as Alzheimer’s disease (AD) is well documented. However, detailed studies of LC neurodegeneration in the full spectrum of frontotemporal lobar degeneration (FTLD) proteinopathies comparing tauopathies (FTLD-tau) to TDP-43 proteinopathies (FTLD-TDP) are lack...
Article
Introduction: The ATN framework provides an in vivo diagnosis of Alzheimer's disease (AD) using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N). ATN is rarely evaluated in pathologically confirmed patients and its poor sensitivity to suspected non-Alzheimer's pathophysiologies (SNAP),...
Article
Neurodegeneration in Alzheimer's disease (AD) is closely associated with accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in VCP was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau...
Article
Full-text available
Objectives: To investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD). Methods: We studied 72 LBD patients (Parkinson disease (PD) = 2, PD-MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological exami...
Article
Aims: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but co-morbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here, we use digital histological methods to test the association between hippocampal SYN pathology an...
Article
Background Accurate diagnosis and prognosis of frontotemporal lobar degeneration (FTLD) during life is an urgent concern in the context of emerging disease-modifying treatment trials. Few cerebrospinal fluid (CSF) markers have been validated longitudinally in patients with known pathology, and we hypothesized that CSF neurofilament light chain (NfL...
Article
Despite the ubiquity of metaphor in cognition and communication, it is absent from standard clinical assessments of language, and the neural systems that support metaphor processing are debated. Previous research shows that patients with focal brain lesions can display selective impairments in processing metaphor, suggesting that figurative languag...
Article
Full-text available
Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat...
Article
We compared the regional retention of ¹⁸F-flortaucipir in twenty patients with Lewy Body disorders (LBD), twelve matched Alzheimer’s disease patients with positive amyloid PET scans (AD+Aβ), and fifteen healthy-controls with negative amyloid PET scans (HC-Aβ) and the association in LBD between retention and CSF tau, cognitive performance, and neuro...
Article
Objective We implemented automated methods to analyze speech and evaluate the hypothesis that cognitive and motor factors impair prosody in partially distinct ways in patients with amyotrophic lateral sclerosis (ALS). METHODS We recruited 213 participants, including 67 with ALS (44 with motor ALS, 23 with ALS-frontotemporal degeneration (ALS-FTD))...
Preprint
Despite the ubiquity of metaphor in cognition and communication, it is absent from standard clinical assessments of language, and the neural systems that support metaphor processing are debated. Previous research shows that patients with focal brain lesions can display selective impairments in processing metaphor, suggesting that figurative languag...
Preprint
Full-text available
Background: Brain structure abnormalities throughout the course of Parkinson's Disease (PD) have yet to be fully elucidated. Inconsistent findings across studies may be partly due to small sample sizes and heterogeneous analysis methods. Using a multicenter approach and harmonized analysis methods, we aimed to overcome these limitations and shed li...
Article
Introduction: It is unclear how different proteinopathies (tau, transactive response DNA-binding protein 43 [TDP-43], amyloid β [Aβ], and α-synuclein) contribute to atrophy within medial temporal lobe (MTL) subregions in Alzheimer's disease (AD). Methods: We utilized antemortem structural magnetic resonance imaging (MRI) data to measure MTL subs...
Article
Full-text available
The processing of quantifier words such as “many” or “few” is a complex operation supported by a plastic fronto-parietal network predominantly in the left hemisphere. The internal reference criterion defining a quantifier (e.g., ≥50% for “many”) can be modified in a learning paradigm. Most interestingly, changing the criterion for one quantifier al...
Article
Full-text available
Brain aging is a complex process that includes atrophy, vascular injury, and a variety of age-associated neurodegenerative pathologies, together determining an individual's course of cognitive decline. While Alzheimer's disease and related dementias contribute to the heterogeneity of brain aging, these conditions themselves are also heterogeneous i...
Preprint
Amyotrophic lateral sclerosis (ALS) is a multi-system disorder characterized by progressive muscular weakness and, in addition, cognitive/behavioral dysfunction in nearly 50% of patients. The mechanisms underlying risk for cognitive dysfunction, however, remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-lea...
Article
Background Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, a...