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Dive into the research topics where Elisabeth McCarty Wood is active.

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Featured researches published by Elisabeth McCarty Wood.


Annals of Neurology | 2013

Stages of pTDP-43 pathology in amyotrophic lateral sclerosis

Johannes Brettschneider; Kelly Del Tredici; Jon B. Toledo; John L. Robinson; David J. Irwin; Murray Grossman; EunRan Suh; Vivianna M. Van Deerlin; Elisabeth McCarty Wood; Young Min Baek; Linda Kwong; Edward B. Lee; Lauren Elman; Leo McCluskey; Lubin Fang; Simone Feldengut; Albert C. Ludolph; Virginia M.-Y. Lee; Heiko Braak; John Q. Trojanowski

To see whether the distribution patterns of phosphorylated 43kDa TAR DNA‐binding protein (pTDP‐43) intraneuronal inclusions in amyotrophic lateral sclerosis (ALS) permit recognition of neuropathological stages.


Lancet Neurology | 2007

Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative

Rosa Rademakers; Matt Baker; Jennifer Gass; Jennifer Adamson; Edward D. Huey; Parastoo Momeni; Salvatore Spina; Giovanni Coppola; Anna Karydas; Heather Stewart; Nancy Johnson; Ging Yuek R Hsiung; Brendan J. Kelley; Karen M. Kuntz; Ellen J. Steinbart; Elisabeth McCarty Wood; Chang En Yu; Keith A. Josephs; Eric J. Sorenson; Kyle B. Womack; Sandra Weintraub; Stuart Pickering-Brown; Peter R. Schofield; William S. Brooks; Vivianna M. Van Deerlin; Julie S. Snowden; Christopher M. Clark; Andrew Kertesz; Kevin B. Boylan; Bernardino Ghetti

BACKGROUND The progranulin gene (GRN) is mutated in 5-10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders. METHODS We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene (APOE), and for haplotypes of the microtubule-associated protein tau gene (MAPT). FINDINGS Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimers disease. Range of onset age was 44-69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE epsilon4 allele. INTERPRETATION Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.


Neurology | 2008

CSF biomarkers in frontotemporal lobar degeneration with known pathology

H. Bian; J. C. van Swieten; Susan Leight; Lauren Massimo; Elisabeth McCarty Wood; Peachie Moore; I. de Koning; Christopher M. Clark; Sonia M. Rosso; John Q. Trojanowski; Virginia M.-Y. Lee; Murray Grossman

Objective: To evaluate the diagnostic value of CSF biomarkers in patients with known pathology due to frontotemporal lobar degeneration (FTLD). Background: It is important to distinguish FTLD from other neurodegenerative diseases like Alzheimer disease (AD), but this may be difficult clinically because of atypical presentations. Methods: Patients with FTLD (n = 30) and AD (n = 19) were identified at autopsy or on the basis of genetic testing at University of Pennsylvania and Erasmus University Medical Center. CSF was obtained during a diagnostic lumbar puncture and was analyzed using assays for total tau and amyloid-beta 1-42 (Aβ42). Patients also were assessed with a brief neuropsychological battery. Results: CSF total tau level and the ratio of CSF total tau to Aβ42 (tau/Aβ42) were significantly lower in FTLD than in AD. Receiver operating characteristic curve analyses confirmed that the CSF tau/Aβ42 ratio is sensitive and specific at discriminating between FTLD and AD, and is more successful at this than CSF total tau alone. Although some neuropsychological measures are significantly different in autopsy-proven FTLD and AD, combining these neuropsychological measures with CSF biomarkers did not improve the ability to distinguish FTLD from AD. Conclusions: The ratio of CSF tau/Aβ42 is a sensitive and specific biomarker at discriminating frontotemporal lobar degeneration from Alzheimer disease in patients with known pathology.


Neurology | 2005

Comparison of family histories in FTLD subtypes and related tauopathies

Jill Goldman; Jennifer M. Farmer; Elisabeth McCarty Wood; Julene K. Johnson; Adam L. Boxer; John Neuhaus; Catherine Lomen-Hoerth; Kirk C. Wilhelmsen; Virginia M.-Y. Lee; Murray Grossman; Bruce L. Miller

Pedigrees from 269 patients with frontotemporal lobar degeneration (FTLD), including frontotemporal dementia (FTD), FTD with ALS (FTD/ALS), progressive nonfluent aphasia, semantic dementia (SD), corticobasal degeneration, and progressive supranuclear palsy were analyzed to determine the degree of heritability of these disorders. FTD/ALS was the most and SD the least heritable subtype. FTLD syndromes appear to have different etiologies and recurrence risks.


JAMA Neurology | 2010

The Spectrum of Mutations in Progranulin: A Collaborative Study Screening 545 Cases of Neurodegeneration

Chang En Yu; Bird Td; Lynn M. Bekris; Thomas J. Montine; James B. Leverenz; Ellen J. Steinbart; Nichole M. Galloway; Howard Feldman; Randall L. Woltjer; Carol A. Miller; Elisabeth McCarty Wood; Murray Grossman; Leo McCluskey; Christopher M. Clark; Manuela Neumann; Adrian Danek; Douglas Galasko; Steven E. Arnold; Alice Chen-Plotkin; Anna Karydas; Bruce L. Miller; John Q. Trojanowski; Virginia M.-Y. Lee; Gerard D. Schellenberg; Vivianna M. Van Deerlin

BACKGROUND Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations. OBJECTIVES To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants. DESIGN Case-control study. SETTING Clinical and neuropathology dementia research studies at 8 academic centers. PARTICIPANTS Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/motor neuron disease, corticobasal syndrome/corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease. MAIN OUTCOME MEASURES Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays. RESULTS We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history. CONCLUSIONS Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.


Journal of Neurology, Neurosurgery, and Psychiatry | 2013

Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis

David J. Irwin; Corey T. McMillan; Johannes Brettschneider; D. Libon; John Powers; Katya Rascovsky; Jon B. Toledo; Ashley Boller; Jonathan Bekisz; Keerthi Chandrasekaran; Elisabeth McCarty Wood; Leslie M. Shaw; John H. Woo; Philip A. Cook; David A. Wolk; Steven E. Arnold; Vivianna M. Van Deerlin; Leo McCluskey; Lauren Elman; Virginia M.-Y. Lee; John Q. Trojanowski; Murray Grossman

Background Significant heterogeneity in clinical features of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases with the pathogenic C9orf72 expansion (C9P) have been described. To clarify this issue, we compared a large C9P cohort with carefully matched non-expansion (C9N) cases with a known or highly-suspected underlying TAR DNA-binding protein 43 (TDP-43) proteinopathy. Methods A retrospective case-control study was carried out using available cross-sectional and longitudinal clinical and neuropsychological data, MRI voxel-based morphometry (VBM) and neuropathological assessment from 64 C9P cases (ALS=31, FTLD=33) and 79 C9N cases (ALS=36, FTLD=43). Results C9P cases had an earlier age of onset (p=0.047) and, in the subset of patients who were deceased, an earlier age of death (p=0.014) than C9N. C9P had more rapid progression than C9N: C9P ALS cases had a shortened survival (2.6±0.3 years) compared to C9N ALS (3.8±0.4 years; log-rank λ2=4.183, p=0.041), and C9P FTLD showed a significantly greater annualised rate of decline in letter fluency (4.5±1.3 words/year) than C9N FTLD (1.4±0.8 words/year, p=0.023). VBM revealed greater atrophy in the right frontoinsular, thalamus, cerebellum and bilateral parietal regions for C9P FTLD relative to C9N FTLD, and regression analysis related verbal fluency scores to atrophy in frontal and parietal regions. Neuropathological analysis found greater neuronal loss in the mid-frontal cortex in C9P FTLD, and mid-frontal cortex TDP-43 inclusion severity correlated with poor letter fluency performance. Conclusions C9P cases may have a shorter survival in ALS and more rapid rate of cognitive decline related to frontal and parietal disease in FTLD. C9orf72 genotyping may provide useful prognostic and diagnostic clinical information for patients with ALS and FTLD.


JAMA Neurology | 2011

Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration

Alice Chen-Plotkin; Maria Martinez-Lage; Patrick Sleiman; William T. Hu; Robert Greene; Elisabeth McCarty Wood; Shaoxu Bing; Murray Grossman; Gerard D. Schellenberg; Kimmo J. Hatanpaa; Myron F. Weiner; Charles L. White; William S. Brooks; Glenda M. Halliday; Jillian J. Kril; Marla Gearing; Thomas G. Beach; Neill R. Graff-Radford; Dennis W. Dickson; Rosa Rademakers; Bradley F. Boeve; Stuart Pickering-Brown; Julie S. Snowden; John C. van Swieten; Peter Heutink; Harro Seelaar; Jill R. Murrell; Bernardino Ghetti; Salvatore Spina; Jordan Grafman

OBJECTIVE To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD). PARTICIPANTS AND DESIGN A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)-positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN- FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLD-TDP cases and all of the GRN- FTLD-TDP cases. RESULTS Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN- FTLD-TDP (median, 58.0 vs 61.0 years; P < .001), as was age at death (median, 65.5 vs 69.0 years; P < .001). Concomitant motor neuron disease was much less common in GRN+ FTLD-TDP vs GRN- FTLD-TDP (5.4% vs 26.3%; P < .001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations. CONCLUSION GRN+ FTLD-TDP differs in key features from GRN- FTLD-TDP.


Neurology | 2013

C9ORF72 repeat expansions in cases with previously identified pathogenic mutations

Marka van Blitterswijk; Matt Baker; Mariely DeJesus Hernandez; Roberta Ghidoni; Luisa Benussi; Elizabeth Finger; Ging Yuek R Hsiung; Brendan J. Kelley; Melissa E. Murray; Nicola J. Rutherford; Patricia Brown; Thomas A. Ravenscroft; Peter E.A. Ash; Kevin F. Bieniek; Kimmo J. Hatanpaa; Anna Karydas; Elisabeth McCarty Wood; Giovanni Coppola; Eileen H. Bigio; Carol F. Lippa; Michael J. Strong; Thomas G. Beach; David S. Knopman; Edward D. Huey; M.-Marsel Mesulam; Bird Td; Charles L. White; Andrew Kertesz; Daniel H. Geschwind; Vivianna M. Van Deerlin

Objective: To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases. Methods: A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology. Results: We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations. Conclusions: Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.


FEBS Letters | 2008

A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro

Matthew J. Winton; Vivianna M. Van Deerlin; Linda K. Kwong; Wuxing Yuan; Elisabeth McCarty Wood; Chang En Yu; Gerard D. Schellenberg; Rosa Rademakers; Richard J. Caselli; Anna Karydas; John Q. Trojanowski; Bruce L. Miller; Virginia M.-Y. Lee

TAR DNA‐binding protein‐43 (TDP‐43) is a highly conserved, ubiquitously expressed nuclear protein that was recently identified as the disease protein in frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐U) and amyotrophic lateral sclerosis (ALS). Pathogenic TDP‐43 gene (TARDBP) mutations have been identified in familial ALS kindreds, and here we report a TARDBP variant (A90V) in a FTLD/ALS patient with a family history of dementia. Significantly, A90V is located between the bipartite nuclear localization signal sequence of TDP‐43 and the in vitro expression of TDP‐43‐A90V led to its sequestration with endogenous TDP‐43 as insoluble cytoplasmic aggregates. Thus, A90V may be a genetic risk factor for FTLD/ALS because it predisposes nuclear TDP‐43 to redistribute to the cytoplasm and form pathological aggregates.


Journal of Neurology, Neurosurgery, and Psychiatry | 2013

White matter imaging helps dissociate tau from TDP-43 in frontotemporal lobar degeneration

Corey T. McMillan; David J. Irwin; Brian B. Avants; John Powers; Philip A. Cook; Jon B. Toledo; Elisabeth McCarty Wood; Vivianna M. Van Deerlin; Virginia M.-Y. Lee; John Q. Trojanowski; Murray Grossman

Background Frontotemporal lobar degeneration (FTLD) is most commonly associated with TAR-DNA binding protein (TDP-43) or tau pathology at autopsy, but there are no in vivo biomarkers reliably discriminating between sporadic cases. As disease-modifying treatments emerge, it is critical to accurately identify underlying pathology in living patients so that they can be entered into appropriate etiology-directed clinical trials. Patients with tau inclusions (FTLD-TAU) appear to have relatively greater white matter (WM) disease at autopsy than those patients with TDP-43 (FTLD-TDP). In this paper, we investigate the ability of white matter (WM) imaging to help discriminate between FTLD-TAU and FTLD-TDP during life using diffusion tensor imaging (DTI). Methods Patients with autopsy-confirmed disease or a genetic mutation consistent with FTLD-TDP or FTLD-TAU underwent multimodal T1 volumetric MRI and diffusion weighted imaging scans. We quantified cortical thickness in GM and fractional anisotropy (FA) in WM. We performed Eigenanatomy, a statistically robust dimensionality reduction algorithm, and used leave-one-out cross-validation to predict underlying pathology. Neuropathological assessment of GM and WM disease burden was performed in the autopsy-cases to confirm our findings of an ante-mortem GM and WM dissociation in the neuroimaging cohort. Results ROC curve analyses evaluated classification accuracy in individual patients and revealed 96% sensitivity and 100% specificity for WM analyses. FTLD-TAU had significantly more WM degeneration and inclusion severity at autopsy relative to FTLD-TDP. Conclusions These neuroimaging and neuropathological investigations provide converging evidence for greater WM burden associated with FTLD-TAU, and emphasise the role of WM neuroimaging for in vivo discrimination between FTLD-TAU and FTLD-TDP.

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Murray Grossman

University of Pennsylvania

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Leo McCluskey

University of Pennsylvania

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David J. Irwin

University of Pennsylvania

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Corey T. McMillan

University of Pennsylvania

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Lauren Elman

University of Pennsylvania

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EunRan Suh

University of Pennsylvania

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Jon B. Toledo

University of Pennsylvania

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