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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
[show abstract]
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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
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Christina Sundal,
Jay A Van Gerpen,
Alexandra M Nicholson,
Christian Wider,
Elizabeth A Shuster,
Jan Aasly, Salvatore Spina,
Bernardino Ghetti,
Sigrun Roeber,
James Garbern, [......],
Shinsuke Fujioka,
Michael G Heckman,
Ryan J Uitti,
Keith A Josephs,
Matt Baker,
Oluf Andersen,
Rosa Rademakers,
Dennis W Dickson,
Daniel Broderick,
Zbigniew K Wszolek
[show abstract]
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ABSTRACT: To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5.
We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0-57) for each MRI scan.
Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10-33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology.
Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion.
Neurology 07/2012; 79(6):566-74. · 8.31 Impact Factor
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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
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Ian R. A. Mackenzie,
Manuela Neumann,
Eileen H. Bigio,
Nigel J. Cairns,
Irina Alafuzoff,
Jillian Kril,
Gabor G. Kovacs,
Bernardino Ghetti,
Glenda Halliday,
Ida E. Holm, [......],
Wouter Kamphorst,
Tamas Revesz,
Annemieke J. M. Rozemuller,
Samir Kumar-Singh,
Haruhiko Akiyama,
Atik Baborie, Salvatore Spina,
Dennis W. Dickson,
John Q. Trojanowski,
David M. A. Mann
Acta Neuropathologica 04/2012; 119(1):1-4. · 9.32 Impact Factor
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Rosa Rademakers,
Matt Baker,
Alexandra M Nicholson,
Nicola J Rutherford,
NiCole Finch,
Alexandra Soto-Ortolaza,
Jennifer Lash,
Christian Wider,
Aleksandra Wojtas,
Mariely DeJesus-Hernandez, [......],
Jay A Van Gerpen,
James F Meschia,
Shawn Levy,
Daniel F Broderick,
Neill Graff-Radford,
Owen A Ross,
Bradley B Miller,
Russell H Swerdlow,
Dennis W Dickson,
Zbigniew K Wszolek
[show abstract]
[hide abstract]
ABSTRACT: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.
Nature Genetics 12/2011; 44(2):200-5. · 35.53 Impact Factor
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ABSTRACT: This chapter describes the various aspects of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) associated with mutations in the microtubule-associated protein tau (MAPT) gene. The main sections are devoted to the clinical, neuropathological, biochemical and molecular genetic characteristics of this disorder. The clinical phenotypes may vary in presentation and age at onset. A table is shown indicating the predominant symptomatology associated with the mutations. The neuropathological changes associated with each mutation are described in detail. The mechanisms associated with tau phosphorylation and tau filament formation as well as pathogenetic mechanisms associated with intronic and exonic mutations are explained.
09/2011: pages 110 - 134; , ISBN: 9781444341256
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ABSTRACT: To report the rare but distinct clinical and neuropathological phenotype of non-familial, rapidly progressive parkinsonism and dementia associated with frontotemporal lobar degeneration with motor neuron disease (FTLD-MND).
Subjects included two 70-year-old women presenting with rapidly progressive severe postural instability, axial-predominant parkinsonism, oculomotor dysfunction and frontal-predominant dementia with language impairment and pseudobulbar palsy. One had diffuse weakness without signs of lower motor neuron disease. Post-mortem evaluations included immunohistochemistry with antiphospho-TAR DNA-binding protein 43 (TDP-43) and genetic analysis of the TARDBP and PGRN genes.
Subjects died within 14 months from symptom onset. TDP-43-positive neuronal intracytoplasmic inclusions were prominent in the primary motor cortex, granule cell layer of the hippocampus, and several cranial and spinal cord nuclei. TDP-43 globular glial inclusions (GGI) were identified in one case. There were no mutations in PGRN or TARDBP genes.
FTLD-MND due to TDP-43-proteinopathy should be considered in patients with rapidly progressive parkinsonism and dementia phenotype, especially when aphasia and/or weakness are also present.
Journal of neurology, neurosurgery, and psychiatry 07/2011; 82(7):751-3. · 4.87 Impact Factor
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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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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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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
[show abstract]
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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
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Vivianna M Van Deerlin,
Patrick M A Sleiman,
Maria Martinez-Lage,
Alice Chen-Plotkin,
Li-San Wang,
Neill R Graff-Radford,
Dennis W Dickson,
Rosa Rademakers,
Bradley F Boeve,
Murray Grossman, [......],
M Cristina Caballero Martínez,
David G Munoz,
Steven L Carroll,
Daniel Marson,
Peter F Riederer,
Nenad Bogdanovic,
Gerard D Schellenberg,
Hakon Hakonarson,
John Q Trojanowski,
Virginia M-Y Lee
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ABSTRACT: Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
Nature Genetics 02/2010; 42(3):234-9. · 35.53 Impact Factor
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Ian R A Mackenzie,
Manuela Neumann,
Eileen H Bigio,
Nigel J Cairns,
Irina Alafuzoff,
Jillian Kril,
Gabor G Kovacs,
Bernardino Ghetti,
Glenda Halliday,
Ida E Holm, [......],
Wouter Kamphorst,
Tamas Revesz,
Annemieke J M Rozemuller,
Samir Kumar-Singh,
Haruhiko Akiyama,
Atik Baborie, Salvatore Spina,
Dennis W Dickson,
John Q Trojanowski,
David M A Mann
Acta Neuropathologica 11/2009; 119(1):1-4. · 9.32 Impact Factor
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ABSTRACT: To determine the brain areas associated with specific components of ideomotor apraxia (IMA) in corticobasal syndrome (CBS).
Case-control and cross-sectional study.
Forty-eight patients with CBS and 14 control subjects. Intervention Administration of the Test of Oral and Limb Apraxia.
Differences between patients with CBS and healthy controls and associations between areas of gray matter volume and IMA determined by voxel-based morphometry in patients with CBS.
Overall, IMA was associated with decreased gray matter volume in the left supplemental motor area, premotor cortex, and caudate nucleus of patients with CBS. The overall degree of apraxia was independent of the side of motor impairment. Praxis to imitation (vs command) was particularly impaired in the patients with CBS. Patients demonstrated equal impairment in transitive and intransitive praxis.
In patients with CBS, IMA is associated with left posterior frontal cortical and subcortical volume loss. Despite showing left frontal volume loss associated with IMA, patients with CBS have particularly impaired imitation of gestures. These findings suggest either that the IMA of CBS affects a route of praxis that bypasses motor engrams or that motor engrams are affected but that they exist in areas other than the inferior parietal cortex.
Archives of neurology 10/2009; 66(10):1274-80. · 6.31 Impact Factor
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ABSTRACT: TDP-43 has been identified as the pathological protein in the majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). TARDBP mutations have so far been uniquely associated with familial and sporadic ALS. We describe clinicopathological and genetic findings in a carrier of the novel K263E TARDBP variation, who developed frontotemporal dementia, supranuclear palsy, and chorea, but no signs of motor neuron disease. Neuropathologic examination revealed neuronal and glial TDP-43-immunoreactive deposits, predominantly in subcortical nuclei and brainstem. This is the first report of a TARDBP variation associated with a neurodegenerative syndrome other than ALS.
Movement Disorders 08/2009; 24(12):1843-7. · 4.51 Impact Factor
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Xiangzhu Xiao,
Leticia Miravalle,
Jue Yuan,
John McGeehan,
Zhiqian Dong,
Robert Wyza,
Gregory T MacLennan,
Alan M Golichowski,
Geoff Kneale,
Nicholas King,
Qingzhong Kong, Salvatore Spina,
Ruben Vidal,
Bernardino Ghetti,
Karen Roos,
Pierluigi Gambetti,
Wen-Quan Zou
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ABSTRACT: The vertical transmission of a prion disease from infected mothers to their offspring is believed to be one of the routes for the natural spread of animal prion diseases. Supporting this notion is the observation that prion infectivity occurs in the placenta of infected ewes. Furthermore, the prion protein (PrP), both in its cellular form (PrP(C)) and its pathological isoform (PrP(Sc)), has been observed at the fetal-maternal interface of scrapie-infected sheep. However, whether these features of prion infectivity also hold true for human prion diseases is currently unknown. To begin to address such an important question, we examined PrP in the uterus as well as gestational tissues, including the placenta and amniotic fluid, in a pregnant woman with sporadic Creutzfeldt-Jakob disease (CJD). Although the proteinase K (PK)-resistant prion protein, PrP27-30, was present in the brain tissues of the mother, the PrP detected in the uterus, placenta, and amniotic fluid was sensitive to PK digestion. Unlike PrP(C) in the brain and adjacent cerebrospinal fluid, the predominant PrP species in the reproductive and gestational tissues were N-terminally truncated, similar to urine PrP. Our study did not detect abnormal PrP in the reproductive and gestational tissues in this case of CJD. Nevertheless, examination by a highly sensitive bioassay is ongoing to ascertain possible prion infectivity from CJD in the amniotic fluid.
American Journal Of Pathology 05/2009; 174(5):1602-8. · 4.89 Impact Factor
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Chera L Maarouf,
Ian D Daugs, Salvatore Spina,
Ruben Vidal,
Tyler A Kokjohn,
R Lyle Patton,
Walter M Kalback,
Dean C Luehrs,
Douglas G Walker,
Eduardo M Castaño,
Thomas G Beach,
Bernardino Ghetti,
Alex E Roher
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ABSTRACT: Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter gamma-secretase activity to promote accumulation of toxic Abeta42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-beta precursor protein (AbetaPP), Notch, N-cadherin and Erb-B4 by gamma-secretase. In addition, the levels of Abeta40/42 peptides were quantified by ELISA.
We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Abeta40 over Abeta42. The AbetaPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations.
These observations imply that missense mutations in PSEN genes can alter a range of key gamma-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.
Molecular Neurodegeneration 12/2008; 3:20. · 4.28 Impact Factor
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Ian R A Mackenzie,
Manuela Neumann,
Eileen H Bigio,
Nigel J Cairns,
Irina Alafuzoff,
Jillian Kril,
Gabor G Kovacs,
Bernardino Ghetti,
Glenda Halliday,
Ida E Holm, [......],
Wouter Kamphorst,
Tamas Revesz,
Annemieke J M Rozemuller,
Samir Kumar-Singh,
Haruhiko Akiyama,
Atik Baborie, Salvatore Spina,
Dennis W Dickson,
John Q Trojanowski,
David M A Mann
Acta Neuropathologica 12/2008; 117(1):15-8. · 9.32 Impact Factor
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Gabor G Kovacs,
Katalin Majtenyi, Salvatore Spina,
Jill R Murrell,
Ellen Gelpi,
Romana Hoftberger,
Graham Fraser,
R Anthony Crowther,
Michel Goedert,
Herbert Budka,
Bernardino Ghetti
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ABSTRACT: Frontotemporal lobar degenerations are a group of disorders characterized by circumscribed degeneration of the frontal and temporal lobes and diverse histopathologic features. We report clinical, neuropathologic, ultrastructural, biochemical, and genetic data on 7 individuals with a 4-repeat tauopathy characterized by the presence of globular glial inclusions (GGIs) in brain white matter. Clinical manifestations were compatible with the behavioral variant of frontotemporal dementia and included motor neuron symptoms; there was prominent neuronal loss in the frontal and temporal cortex, subiculum, and amygdala. The surrounding white matter showed abundant GGIs composed of abnormal filaments present mostly in oligodendrocytes. The severity of white matter tau abnormalities correlated with a reduction in myelin and axons and with microglial activation. Western blotting of sarkosyl-insoluble tau demonstrated the presence of 2 major tau bands of 64 and 68 kd. No mutations in the microtubule-associated protein tau gene were detected in 2 affected individuals. We propose that 4-repeat tau-immunoreactive GGIs are the neuropathologic hallmark of a distinct sporadic tauopathy with variable clinical presentations that include frontotemporal dementia and occasionally upper motor neuron disease. This type of tauopathy with GGIs expands the group of neurodegenerativedisorders in which oligodendroglial pathology predominates, beyond the synucleinopathy multiple system atrophy disorders.
Journal of Neuropathology and Experimental Neurology 10/2008; 67(10):963-75. · 4.26 Impact Factor
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ABSTRACT: Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is associated with mutations in the Microtubule-Associated Protein Tau(MAPT) gene or the Progranulin(PGRN) gene. MAPT mutations lead to widespread deposition of hyperphosphorylated tau protein (FTDP-17T). PGRN mutations are associated with ubiquitin- and TDP-43-positive inclusions in the frontotemporal cortex, striatum and hippocampus (FTDP-17U). Despite the differences, FTDP-17T and FTDP-17U share a largely overlapping clinical phenotype.
To determine whether neuroimaging studies may allow an in vivo early differentiation between FTDP-17T and FTDP-17U.
We studied 25 individuals affected with FTDP-17T associated with either the exon 10+3 (24 subjects) or the G335S (1 subject) MAPT mutation, as well as 3 FTDP-17U individuals, who were carriers of the A9D, IVS6-2A>G or R493X PGRN mutation. Neuroimaging studies, obtained along the course of the disease, were compared to the neuropathologic findings.
FTDP-17T cases were associated with symmetric frontotemporal atrophy. Behavioral changes constituted the predominant clinical presentation. Conversely, an asymmetric degenerative process was seen in all 3 PGRN cases, who presented with either corticobasal syndrome (A9D) or frontotemporal dementia and language deterioration (IVS6-2A>G and R493X).
Neuroimaging data, in the early disease stage of FTDP-17, may offer the possibility of an early differentiation of FTDP-17T and FTDP-17U phenotypes, independent of the genetic analysis.
Neurodegenerative Diseases 02/2008; 5(3-4):215-7. · 3.06 Impact Factor
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Salvatore Spina,
Martin R Farlow,
Frederick W Unverzagt,
David A Kareken,
Jill R Murrell,
Graham Fraser,
Francine Epperson,
R Anthony Crowther,
Maria G Spillantini,
Michel Goedert,
Bernardino Ghetti
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ABSTRACT: Multiple system tauopathy with presenile dementia (MSTD) is an inherited disease caused by a (g) to (a) transition at position +3 in intron 10 of Tau. It belongs to the spectrum of frontotemporal dementia and parkinsonism linked to chromosome 17 with mutations in Tau (FTDP-17T). Here we present the longitudinal clinical, neuropsychological, neuroimaging, neuropathological, biochemical and genetic characterization of the MSTD family. Presenting signs were consistent with the behavioural variant of frontotemporal dementia in 17 of 21 patients. Two individuals presented with an atypical form of progressive supranuclear palsy and two others with either severe postural imbalance or an isolated short-term memory deficit. Memory impairment was present at the onset in 15 patients, with word finding difficulties and stereotyped speech also being common. Parkinsonism was first noted 3 years after the onset of symptoms. Neuroimaging showed the most extensive grey matter loss in the hippocampus, parahippocampal gyrus and frontal operculum/insular cortex of the right hemisphere and, to a lesser extent, in the anterior cingulate gyrus, head of the caudate nucleus and the posterolateral orbitofrontal cortex and insular cortex bilaterally. Neuropathologically, progressive nerve cell loss, gliosis and coexistent neuronal and/or glial deposits consisting mostly of 4-repeat tau were present in frontal, cingulate, temporal and insular cortices, white matter, hippocampus, parahippocampus, basal ganglia, selected brainstem nuclei and spinal cord. Tau haplotyping indicated that specific haplotypes of the wild-type allele may act as modifiers of disease presentation. Quantitative neuroimaging has been used to analyse the progression of atrophy in affected individuals and for predicting disease onset in an asymptomatic mutation carrier. This multidisciplinary study provides a comprehensive description of the natural history of disease in one of the largest known families with FTDP-17T.
Brain 02/2008; 131(Pt 1):72-89. · 9.46 Impact Factor
