Vivianna M Van Deerlin

Publications (45)509.39 Total impact

• Article: GWAS of Cerebrospinal Fluid Tau Levels Identifies Risk Variants for Alzheimer's Disease.

  Carlos Cruchaga, John S K Kauwe, Oscar Harari, Sheng Chih Jin, Yefei Cai, Celeste M Karch, Bruno A Benitez, Amanda T Jeng, Tara Skorupa, David Carrell, [......], Richard Mayeux, Margaret A Pericak-Vance, Lindsay A Farrer, Gerard D Schellenberg, Elaine R Peskind, Douglas Galasko, Anne M Fagan, David M Holtzman, John C Morris, Alison M Goate
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  ABSTRACT: Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ42 are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10(-9) for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10(-8) and p = 3.22 × 10(-9) for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10(-8) for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10(-4), 0.039, 4.86 × 10(-5), respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
  Neuron 04/2013; · 14.74 Impact Factor
• Article: 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
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  ABSTRACT: 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.
  Journal of neurology, neurosurgery, and psychiatry 03/2013; · 4.87 Impact Factor
• Article: Can MRI screen for CSF biomarkers in neurodegenerative disease?

  Corey T McMillan, Brian Avants, David J Irwin, Jon B Toledo, David A Wolk, Vivianna M Van Deerlin, Leslie M Shaw, John Q Trojanoswki, Murray Grossman
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  ABSTRACT: OBJECTIVE: Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) may have overlapping clinical presentations despite distinct underlying neuropathologies, thus making in vivo diagnosis challenging. In this study, we evaluate the utility of MRI as a noninvasive screening procedure for the differential diagnosis of AD and FTLD. METHODS: We recruited 185 patients with a clinically diagnosed neurodegenerative disease consistent with AD or FTLD who had a lumbar puncture and a volumetric MRI. A subset of 32 patients had genetic or autopsy-confirmed AD or FTLD. We used singular value decomposition to decompose MRI volumes and linear regression and cross-validation to predict CSF total tau (tt) and β-amyloid (Aβ(1-42)) ratio (tt/Aβ) in patients with AD and patients with FTLD. We then evaluated accuracy of MRI-based predicted tt/Aβ using 4 converging sources including neuroanatomic visualization and categorization of a subset of patients with genetic or autopsy-confirmed AD or FTLD. RESULTS: Regression analyses showed that MRI-predicted tt/Aβ is highly related to actual CSF tt/Aβ. In each group, both predicted and actual CSF tt/Aβ have extensively overlapping neuroanatomic correlates: low tt/Aβ consistent with FTLD is related to ventromedial prefrontal regions while high tt/Aβ consistent with AD is related to posterior cortical regions. MRI-predicted tt/Aβ is 75% accurate at identifying underlying diagnosis in patients with known pathology and in clinically diagnosed patients with known CSF tt/Aβ levels. CONCLUSION: MRI may serve as a noninvasive procedure that can screen for AD and FTLD pathology as a surrogate for CSF biomarkers.
  Neurology 12/2012; · 8.31 Impact Factor
• Source

  Available from: Joshua William Miller

  Article: Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis.

  David C Whitcomb, Jessica Larusch, Alyssa M Krasinskas, Lambertus Klei, Jill P Smith, Randall E Brand, John P Neoptolemos, Markus M Lerch, Matt Tector, Bimaljit S Sandhu, [......], Frank Ulrich Weiss, C Mel Wilcox, Narcis Octavian Zarnescu, Stephen R Wisniewski, Michael R O'Connell, Michelle L Kienholz, Kathryn Roeder, M Michael Barmada, Dhiraj Yadav, Bernie Devlin
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  ABSTRACT: Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).
  Nature Genetics 11/2012; · 35.53 Impact Factor
• Article: TDP-43 skeins show properties of amyloid in a subset of ALS cases.

  John L Robinson, Felix Geser, Anna Stieber, Mfon Umoh, Linda K Kwong, Vivianna M Van Deerlin, Virginia M-Y Lee, John Q Trojanowski
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  ABSTRACT: Aggregation of TDP-43 proteins to form intracellular inclusions is the primary pathology in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with TDP-43 inclusions (FTLD-TDP). Histologically, in the cerebral cortex and limbic regions of affected ALS and FTLD-TDP patients, these pathologies occur as a variety of cytoplasmic, neuritic and intranuclear TDP-43 inclusions. In the spinal cord and lower brainstem of ALS patients, the lesions form cytoplasmic dashes or complex filamentous and spherical profiles in addition to skein-like inclusions (SLI). Ultrastructurally, the morphology of TDP-43 inclusions is heterogeneous but mainly composed of loose bundles of 10- to 20-nm-diameter straight filaments associated with electron-dense granular material. All of these TDP-43 inclusions are generally described as disordered amorphous aggregations unlike the amyloid fibrils that characterize protein accumulations in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. We here report that Thioflavin-S positive SLI are present in a subset of ALS cases, while TDP-43 inclusions outside the spinal cord lack the chemical properties of amyloid. Further, we examine the differential enrichment of fibrillar profiles in SLI of ALS cases by TDP-43 immuno-electron microscopy (immuno-EM). The demonstration that pathological TDP-43 can be amyloidogenic in situ suggests the following conclusions: (1) the conformational changes associated with TDP-43 aggregation are more complex than previously thought; (2) Thioflavin-S positive SLI may be composed primarily of filamentous ultrastructures.
  Acta Neuropathologica 11/2012; · 9.32 Impact Factor
• Article: Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis.

  David J Irwin, Corey T McMillan, Johannes Brettschneider, David J Libon, John Powers, Katya Rascovsky, Jon B Toledo, Ashley Boller, Jonathan Bekisz, Keerthi Chandrasekaran, [......], John H Woo, Philip A Cook, David A Wolk, Steven E Arnold, Vivianna M Van Deerlin, Leo F McCluskey, Lauren Elman, Virginia M-Y Lee, John Q Trojanowski, Murray Grossman
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  ABSTRACT: 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.
  Journal of neurology, neurosurgery, and psychiatry 10/2012; · 4.87 Impact Factor
• Article: Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease.

  William T Hu, David M Holtzman, Anne M Fagan, Leslie M Shaw, Richard Perrin, Steven E Arnold, Murray Grossman, Chengjie Xiong, Rebecca Craig-Schapiro, Christopher M Clark, [......], Lauren Elman, Jason Karlawish, Alice Chen-Plotkin, Howard I Hurtig, Andrew Siderowf, Frank Swenson, Virginia M-Y Lee, John C Morris, John Q Trojanowski, Holly Soares
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  ABSTRACT: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.
  Neurology 08/2012; 79(9):897-905. · 8.31 Impact Factor
• Article: Prenatal healthcare providers' Gaucher disease carrier screening practices.

  Dana Falcone, Elisabeth McCarty Wood, Michael Mennuti, Sharon X Xie, Vivianna M Van Deerlin
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  ABSTRACT: Purpose:Gaucher disease carrier screening is controversial in the medical community. The goal of this study was to explore current Gaucher disease carrier screening practices of prenatal healthcare providers.Methods:Prenatal healthcare providers were invited by email to complete an electronic-based survey.Results:A total of 1,454 prenatal healthcare providers, including 209 genetic counselors, 450 midwives, and 795 physicians, completed the study. The majority of genetic counselors (n = 208/209, >99%), physicians (n = 415/450, 92%), and midwives (n = 634/795, 80%) currently offer Jewish ancestry disease carrier screening to couples in whom one or both partners are Jewish. Of providers who offer Jewish ancestry disease screening, the majority of genetic counselors (n = 199/208, 96%) and physicians (n = 352/415, 85%) always or sometimes offer Gaucher disease screening whereas the majority of midwives (n = 357/634, 56%) never offer Gaucher disease screening.Conclusion:This study presents the first report of Gaucher disease carrier screening practices of the prenatal healthcare providers in North America. Our results indicate that Gaucher disease carrier screening is being offered at a high rate within the scope of Jewish ancestry-based carrier screening. This may highlight a need to move away from the debate as to whether Gaucher disease carrier screening should be offered and, instead, focus on how best to provide Gaucher disease carrier screening services.Genet Med 2012:14(10):844-851.
  Genetics in medicine: official journal of the American College of Medical Genetics 05/2012; 14(10):844-51. · 3.92 Impact Factor
• Article: Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases.

  Giovanni Coppola, Subashchandrabose Chinnathambi, Jason JiYong Lee, Beth A Dombroski, Matt C Baker, Alexandra I Soto-Ortolaza, Suzee E Lee, Eric Klein, Alden Y Huang, Renee Sears, [......], Jonathan L Haines, Richard Mayeux, Margaret A Pericak-Vance, Lindsay A Farrer, Owen A Ross, Rosa Rademakers, Gerard D Schellenberg, Bruce L Miller, Eckhard Mandelkow, Daniel H Geschwind
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  ABSTRACT: Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
  Human Molecular Genetics 05/2012; 21(15):3500-12. · 7.64 Impact Factor
• Article: Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis.

  Julien Couthouis, Michael P Hart, Renske Erion, Oliver D King, Zamia Diaz, Tadashi Nakaya, Fadia Ibrahim, Hyung-Jun Kim, Jelena Mojsilovic-Petrovic, Saarene Panossian, [......], Robert G Kalb, Virginia M Y Lee, John Q Trojanowski, Garth A Nicholson, Ian P Blair, Nancy M Bonini, Vivianna M Van Deerlin, Zissimos Mourelatos, James Shorter, Aaron D Gitler
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  ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Mutations in related RNA-binding proteins TDP-43, FUS/TLS and TAF15 have been connected to ALS. These three proteins share several features, including the presence of a bioinformatics-predicted prion domain, aggregation-prone nature in vitro and in vivo and toxic effects when expressed in multiple model systems. Given these commonalities, we hypothesized that a related protein, EWSR1 (Ewing sarcoma breakpoint region 1), might also exhibit similar properties and therefore could contribute to disease. Here, we report an analysis of EWSR1 in multiple functional assays, including mutational screening in ALS patients and controls. We identified three missense variants in EWSR1 in ALS patients, which were absent in a large number of healthy control individuals. We show that disease-specific variants affect EWSR1 localization in motor neurons. We also provide multiple independent lines of in vitro and in vivo evidence that EWSR1 has similar properties as TDP-43, FUS and TAF15, including aggregation-prone behavior in vitro and ability to confer neurodegeneration in Drosophila. Postmortem analysis of sporadic ALS cases also revealed cytoplasmic mislocalization of EWSR1. Together, our studies highlight a potential role for EWSR1 in ALS, provide a collection of functional assays to be used to assess roles of additional RNA-binding proteins in disease and support an emerging concept that a class of aggregation-prone RNA-binding proteins might contribute broadly to ALS and related neurodegenerative diseases.
  Human Molecular Genetics 03/2012; 21(13):2899-911. · 7.64 Impact Factor
• Article: Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion.

  Johannes Brettschneider, Vivianna M Van Deerlin, John L Robinson, Linda Kwong, Edward B Lee, Yousuf O Ali, Nathaniel Safren, Mervyn J Monteiro, Jon B Toledo, Lauren Elman, Leo McCluskey, David J Irwin, Murray Grossman, Laura Molina-Porcel, Virginia M-Y Lee, John Q Trojanowski
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  ABSTRACT: C9ORF72-hexanucleotide repeat expansions and ubiquilin-2 (UBQLN2) mutations are recently identified genetic markers in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We investigate the relationship between C9ORF72 expansions and the clinical phenotype and neuropathology of ALS and FTLD. Genetic analysis and immunohistochemistry (IHC) were performed on autopsy-confirmed ALS (N = 75), FTLD-TDP (N = 30), AD (N = 14), and controls (N = 11). IHC for neurodegenerative disease pathology consisted of C9ORF72, UBQLN, p62, and TDP-43. A C9ORF72 expansion was identified in 19.4 % of ALS and 31 % of FTLD-TDP cases. ALS cases with C9ORF72 expansions frequently showed a bulbar onset of disease (57 %) and more rapid disease progression to death compared to non-expansion cases. Staining with C9ORF72 antibodies did not yield specific pathology. UBQLN pathology showed a highly distinct pattern in ALS and FTLD-TDP cases with the C9ORF72 expansion, with UBQLN-positive cytoplasmic inclusions in the cerebellar granular layer and extensive UBQLN-positive aggregates and dystrophic neurites in the hippocampal molecular layer and CA regions. These UBQLN pathologies were sufficiently unique to allow correct prediction of cases that were later confirmed to have C9ORF72 expansions by genetic analysis. UBQLN pathology partially co-localized with p62, and to a minor extent with TDP-43 positive dystrophic neurites and spinal cord skein-like inclusions. Our data indicate a pathophysiological link between C9ORF72 expansions and UBQLN proteins in ALS and FTLD-TDP that is associated with a highly characteristic pattern of UBQLN pathology. Our study indicates that this pathology is associated with alterations in clinical phenotype, and suggests that the presence of C9ORF72 repeat expansions may indicate a worse prognosis in ALS.
  Acta Neuropathologica 03/2012; 123(6):825-39. · 9.32 Impact Factor
• Article: Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

  Elisa Majounie, Alan E Renton, Kin Mok, Elise G P Dopper, Adrian Waite, Sara Rollinson, Adriano Chiò, Gabriella Restagno, Nayia Nicolaou, Javier Simon-Sanchez, [......], Carsten Drepper, Nigel Williams, Janine Kirby, Pamela Shaw, John Hardy, Pentti J Tienari, Peter Heutink, Huw R Morris, Stuart Pickering-Brown, Bryan J Traynor
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  ABSTRACT: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. Full funding sources listed at end of paper (see Acknowledgments).
  The Lancet Neurology 03/2012; 11(4):323-30. · 23.46 Impact Factor
• Article: TDP-43 pathology in a case of hereditary spastic paraplegia with a NIPA1/SPG6 mutation.

  Maria Martinez-Lage, Laura Molina-Porcel, Dana Falcone, Leo McCluskey, Virginia M-Y Lee, Vivianna M Van Deerlin, John Q Trojanowski
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  ABSTRACT: Mutations in NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome) have been described as a cause of autosomal dominant hereditary spastic paraplegia (HSP) known as SPG6 (spastic paraplegia-6). We present the first neuropathological description of a patient with a NIPA1 mutation, and clinical phenotype of complicated HSP with motor neuron disease-like syndrome and cognitive decline. Postmortem examination revealed degeneration of lateral corticospinal tracts and dorsal columns with motor neuron loss. TDP-43 immunostaining showed widespread spinal cord and cerebral skein-like and round neuronal cytoplasmic inclusions. We ruled out NIPA1 mutations in 419 additional cases of motor neuron disease. These findings suggest that hereditary spastic paraplegia due to NIPA1 mutations could represent a TDP-43 proteinopathy.
  Acta Neuropathologica 02/2012; 124(2):285-91. · 9.32 Impact Factor
• Source

  Available from: Jon Toledo

  Article: Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis.

  Johannes Brettschneider, Jon B Toledo, Vivianna M Van Deerlin, Lauren Elman, Leo McCluskey, Virginia M-Y Lee, John Q Trojanowski
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  ABSTRACT: We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity. Microglial pathology was assessed by IHC with 2 different antibodies (CD68, Iba1), myelin loss by Kluver-Barrera staining and myelin basic protein (MBP) IHC, and axonal loss by neurofilament protein (TA51) IHC, performed on 59 autopsy cases of ALS including 9 cases with C9ORF72 repeat expansion. Microglial pathology as depicted by CD68 and Iba1 was significantly more extensive in the corticospinal tract (CST) of ALS cases with a rapid progression of disease. Cases with C9ORF72 repeat expansion showed more extensive microglial pathology in the medulla and motor cortex which persisted after adjusting for disease duration in a logistic regression model. Higher scores on the clinical UMN scale correlated with increasing microglial pathology in the cervical CST. TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease. This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits.
  PLoS ONE 01/2012; 7(6):e39216. · 4.09 Impact Factor
• Article: Genetic testing and Parkinson disease: assessment of patient knowledge, attitudes, and interest.

  Dana Clay Falcone, Elisabeth McCarty Wood, Sharon X Xie, Andrew Siderowf, Vivianna M Van Deerlin
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  ABSTRACT: The most common genetic contributor to late-onset Parkinson disease (PD) is the LRRK2 gene. In order to effectively integrate LRRK2 genetic testing into clinical practice, a strategy tailored to the PD population must be developed. We assessed 168 individuals with PD for baseline knowledge of genetics, perceived risk, and interest and opinions regarding genetic counseling and testing. Most participants felt that they were familiar with general genetics terms but overall knowledge levels were low, with an average score of 55%. The majority of participants thought it was likely they inherited a PD gene (72%), believed genetic testing for PD would be useful (86%), and were interested in genetic testing (59%) and genetic counseling (56%). However, only a few participants had heard of any genetic tests for PD (29%) or LRRK2 (10%). There appears to be a significant level of interest in genetics and genetic testing within the PD population, but a considerable deficit in genetics knowledge and an over-estimation of risk. Genetic education and counseling tools to address these needs were developed to provide patients with the ability to make informed and knowledgeable genetic testing decisions.
  Journal of Genetic Counseling 04/2011; 20(4):384-95. · 1.77 Impact Factor
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  Available from: Joshua William Miller

  Article: Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

  Adam C Naj, Gyungah Jun, Gary W Beecham, Li-San Wang, Badri Narayan Vardarajan, Jacqueline Buros, Paul J Gallins, Joseph D Buxbaum, Gail P Jarvik, Paul K Crane, [......], Deborah Blacker, Debby W Tsuang, Hakon Hakonarson, Walter A Kukull, Tatiana M Foroud, Jonathan L Haines, Richard Mayeux, Margaret A Pericak-Vance, Lindsay A Farrer, Gerard D Schellenberg
  Nature Genetics 04/2011; 43(5):436-441. · 35.53 Impact Factor
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  Available from: María Martínez-Lage

  Article: Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.

  Alice S Chen-Plotkin, Maria Martinez-Lage, Patrick M A Sleiman, William Hu, Robert Greene, Elisabeth McCarty Wood, Shaoxu Bing, Murray Grossman, Gerard D Schellenberg, Kimmo J Hatanpaa, [......], Christine Van Broeckhoven, Thomas D Bird, Nigel J Cairns, Allison Goate, Matthew P Frosch, Peter F Riederer, Nenad Bogdanovic, Virginia M Y Lee, John Q Trojanowski, Vivianna M Van Deerlin
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  ABSTRACT: 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). 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. 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. GRN+ FTLD-TDP differs in key features from GRN- FTLD-TDP.
  Archives of neurology 04/2011; 68(4):488-97. · 6.31 Impact Factor
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  Available from: John S K Kauwe

  Article: Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

  Adam C Naj, Gyungah Jun, Gary W Beecham, Li-San Wang, Badri Narayan Vardarajan, Jacqueline Buros, Paul J Gallins, Joseph D Buxbaum, Gail P Jarvik, Paul K Crane, [......], Deborah Blacker, Debby W Tsuang, Hakon Hakonarson, Walter A Kukull, Tatiana M Foroud, Jonathan L Haines, Richard Mayeux, Margaret A Pericak-Vance, Lindsay A Farrer, Gerard D Schellenberg
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  ABSTRACT: The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.
  Nature Genetics 04/2011; 43(5):436-41. · 35.53 Impact Factor
• Article: Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease.

  Alice S Chen-Plotkin, William T Hu, Andrew Siderowf, Daniel Weintraub, Rachel Goldmann Gross, Howard I Hurtig, Sharon X Xie, Steven E Arnold, Murray Grossman, Christopher M Clark, Leslie M Shaw, Leo McCluskey, Lauren Elman, Vivianna M Van Deerlin, Virginia M-Y Lee, Holly Soares, John Q Trojanowski
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  ABSTRACT: Most people with Parkinson disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma-based biomarkers for CI in PD. A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale-2 (DRS) at baseline and on annual follow-up visits, and baseline plasma levels of 102 proteins were determined with a bead-based immunoassay. Using linear regression, we identified biomarkers of CI in PD, that is, proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow-up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients. Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p < 0.001); many of the other 10 analytes covaried with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an 8-fold greater risk of cognitive decline to dementia-range DRS scores at follow-up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients. Our data suggest that plasma EGF may be a biomarker for progression to CI in PD.
  Annals of Neurology 04/2011; 69(4):655-63. · 11.09 Impact Factor
• Article: Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis.

  Ryan Vass, Emily Ashbridge, Felix Geser, William T Hu, Murray Grossman, Dana Clay-Falcone, Lauren Elman, Leo McCluskey, Virginia M Y Lee, Vivianna M Van Deerlin, John Q Trojanowski, Alice S Chen-Plotkin
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  ABSTRACT: TMEM106B has recently been identified as a genetic risk factor for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). Amyotrophic lateral sclerosis (ALS), like FTLD-TDP, is characterized by pathological TDP-43 inclusions. We therefore investigated whether FTLD-TDP-associated risk genotypes at TMEM106B (1) contribute to risk of developing ALS or (2) modify the clinical presentation in ALS. Detailed clinical and pathological information from 61 postmortem ALS patients was collected by database query, retrospective chart review, and histopathological slide review. DNA from these patients, as well as 24 additional ALS patients, was genotyped for three TMEM106B single nucleotide polymorphisms known to confer increased risk of FTLD-TDP. Associations between TMEM106B genotype and ALS were investigated by comparing TMEM106B genotypes in ALS patients (n = 85) and normal controls (n = 553), and associations between TMEM106B genotype and clinical and pathologic features were explored using linear regression. Multivariate linear models were used to evaluate the contributions of TMEM106B genotype and TDP-43 pathology to cognitive performance in ALS as measured by a phonemic verbal fluency test. We found that TMEM106B genotypes did not differ between ALS patients and normal controls. However, protective alleles at TMEM106B were significantly associated with preserved cognition in ALS patients, with the strongest association seen under a major-allele-dominant genetic model. While lower TDP-43 pathology scores and protective alleles at TMEM106B both correlated with better cognitive scores, these factors were not correlated with each other and demonstrated independent effects. These findings implicate the FTLD-TDP risk gene TMEM106B in the development of cognitive impairment in ALS.
  Acta Neuropathologica 03/2011; 121(3):373-80. · 9.32 Impact Factor