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1.  Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy 
Kovacs, Gabor G. | Ferrer, Isidro | Grinberg, Lea T. | Alafuzoff, Irina | Attems, Johannes | Budka, Herbert | Cairns, Nigel J. | Crary, John F. | Duyckaerts, Charles | Ghetti, Bernardino | Halliday, Glenda M. | Ironside, James W. | Love, Seth | Mackenzie, Ian R. | Munoz, David G. | Murray, Melissa E. | Nelson, Peter T. | Takahashi, Hitoshi | Trojanowski, John Q. | Ansorge, Olaf | Arzberger, Thomas | Baborie, Atik | Beach, Thomas G. | Bieniek, Kevin F. | Bigio, Eileen H. | Bodi, Istvan | Dugger, Brittany N. | Feany, Mel | Gelpi, Ellen | Gentleman, Stephen M. | Giaccone, Giorgio | Hatanpaa, Kimmo J. | Heale, Richard | Hof, Patrick R. | Hofer, Monika | Hortobágyi, Tibor | Jellinger, Kurt | Jicha, Gregory A. | Ince, Paul | Kofler, Julia | Kövari, Enikö | Kril, Jillian J. | Mann, David M. | Matej, Radoslav | McKee, Ann C. | McLean, Catriona | Milenkovic, Ivan | Montine, Thomas J. | Murayama, Shigeo | Lee, Edward B. | Rahimi, Jasmin | Rodriguez, Roberta D. | Rozemüller, Annemieke | Schneider, Julie A. | Schultz, Christian | Seeley, William | Seilhean, Danielle | Smith, Colin | Tagliavini, Fabrizio | Takao, Masaki | Thal, Dietmar Rudolf | Toledo, Jon B. | Tolnay, Markus | Troncoso, Juan C. | Vinters, Harry V. | Weis, Serge | Wharton, Stephen B. | White, Charles L. | Wisniewski, Thomas | Woulfe, John M. | Yamada, Masahito | Dickson, Dennis W.
Acta neuropathologica  2015;131(1):87-102.
Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.
doi:10.1007/s00401-015-1509-x
PMCID: PMC4879001  PMID: 26659578
Aging; ARTAG; Tau astrogliopathy; Tau
2.  Primary age-related tauopathy (PART): a common pathology associated with human aging 
Acta neuropathologica  2014;128(6):755-766.
We recommend a new term, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFT) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these “NFT+/Aβ−” brains, for which formal criteria for AD neuropathologic changes are not met, the NFT are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as “tangle-only dementia” and “tangle-predominant senile dementia”, are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
doi:10.1007/s00401-014-1349-0
PMCID: PMC4257842  PMID: 25348064
TPSD; TOD; Braak; Neuropathology; consensus
3.  Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers 
Neurobiology of aging  2014;35(10):2421.e13-2421.e17.
Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are an important cause of both motor neuron disease (MND) and frontotemporal dementia (FTD). Currently, little is known about factors that could account for the phenotypic heterogeneity detected in C9ORF72 expansion carriers. In this study, we investigated four genes that could represent genetic modifiers: ataxin-2 (ATXN2), non-imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1), survival motor neuron 1 (SMN1) and survival motor neuron 2 (SMN2). Assessment of these genes, in a unique cohort of 331 C9ORF72 expansion carriers and 376 controls, revealed that intermediate repeat lengths in ATXN2 possibly act as disease modifier in C9ORF72 expansion carriers; no evidence was provided for a potential role of NIPA1, SMN1 or SMN2. The effects of intermediate ATXN2 repeats were most profound in probands with MND or FTD/MND (2.1% versus 0% in controls, P=0.013), whereas the frequency in probands with FTD was identical to controls. Though intermediate ATXN2 repeats were already known to be associated with MND risk, previous reports did not focus on individuals with clear pathogenic mutations, such as repeat expansions in C9ORF72. Based on our present findings, we postulate that intermediate ATXN2 repeat lengths may render C9ORF72 expansion carriers more susceptible to the development of MND; further studies are needed, however, to validate our findings.
doi:10.1016/j.neurobiolaging.2014.04.016
PMCID: PMC4105839  PMID: 24866401
C9ORF72; ataxin-2; ATXN2; motor neuron disease; amyotrophic lateral sclerosis; frontotemporal dementia; disease modifier
5.  Recent advances in the molecular basis of frontotemporal dementia 
Nature reviews. Neurology  2012;8(8):423-434.
Frontotemporal dementia (FTD) is a clinical syndrome with heterogeneous molecular basis. Until recently, our knowledge was limited to a minority of cases associated with abnormalities of the tau protein or gene (MAPT). However, in 2006, mutations in progranulin (GRN) were discovered as another important cause of familial FTD. That same year, TAR DNA binding protein 43 (TDP-43) was identified as the pathological protein in the most common subtypes of FTD and ALS. Since then, significant efforts have been made to understand the normal functions and regulation of GRN and TDP-43 and their roles in neurodegeneration. More recently, other DNA/RNA binding proteins (FUS, EWS and TAF15) were identified as pathological proteins in most of the remaining cases of FTD. And just six months ago, abnormal expansion of a hexanucleotide repeat in C9ORF72 was found to be the most common genetic cause of both FTD and ALS. With this remarkable progress, it appears that all the common FTD-causing genes have now been discovered and the major pathological proteins identified. This review highlights recent advances in the molecular aspects of FTD, which will provide the basis for improved patient care through the future development of more targeted diagnostic tests and therapies.
doi:10.1038/nrneurol.2012.117
PMCID: PMC3629543  PMID: 22732773
7.  Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p 
Brain  2012;135(3):709-722.
Frontotemporal dementia and amyotrophic lateral sclerosis are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with members affected by frontotemporal dementia, amyotrophic lateral sclerosis or both, which show genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). In the present study, we provide detailed analysis of the clinical features and neuropathology for 16 unrelated families with frontotemporal dementia caused by the C9ORF72 mutation. All had an autosomal dominant pattern of inheritance. Eight families had a combination of frontotemporal dementia and amyotrophic lateral sclerosis while the other eight had a pure frontotemporal dementia phenotype. Clinical information was available for 30 affected members of the 16 families. There was wide variation in age of onset (mean = 54.3, range = 34–74 years) and disease duration (mean = 5.3, range = 1–16 years). Early diagnoses included behavioural variant frontotemporal dementia (n = 15), progressive non-fluent aphasia (n = 5), amyotrophic lateral sclerosis (n = 9) and progressive non-fluent aphasia–amyotrophic lateral sclerosis (n = 1). Heterogeneity in clinical presentation was also common within families. However, there was a tendency for the phenotypes to converge with disease progression; seven subjects had final clinical diagnoses of both frontotemporal dementia and amyotrophic lateral sclerosis and all of those with an initial progressive non-fluent aphasia diagnosis subsequently developed significant behavioural abnormalities. Twenty-one affected family members came to autopsy and all were found to have transactive response DNA binding protein with Mr 43 kD (TDP-43) pathology in a wide neuroanatomical distribution. All had involvement of the extramotor neocortex and hippocampus (frontotemporal lobar degeneration-TDP) and all but one case (clinically pure frontotemporal dementia) had involvement of lower motor neurons, characteristic of amyotrophic lateral sclerosis. In addition, a consistent and relatively specific pathological finding was the presence of neuronal inclusions in the cerebellar cortex that were ubiquitin/p62-positive but TDP-43-negative. Our findings indicate that the C9ORF72 mutation is a major cause of familial frontotemporal dementia with TDP-43 pathology, that likely accounts for the majority of families with combined frontotemporal dementia/amyotrophic lateral sclerosis presentation, and further support the concept that frontotemporal dementia and amyotrophic lateral sclerosis represent a clinicopathological spectrum of disease with overlapping molecular pathogenesis.
doi:10.1093/brain/awr354
PMCID: PMC3286328  PMID: 22344582
frontotemporal dementia; frontotemporal lobar degeneration; amyotrophic lateral sclerosis; C9ORF72, TDP-43
8.  Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p 
Acta Neuropathologica  2012;123(3):409-417.
Two studies recently identified a GGGGCC hexanucleotide repeat expansion in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72) as the cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In a cohort of 231 probands with ALS, we identified the C9ORF72 mutation in 17 familial (27.4 %) and six sporadic (3.6%) cases. Patients with the mutation presented with typical motor features of ALS, although subjects with the C9ORF72 mutation had more frequent bulbar onset, compared to those without this mutation. Dementia was significantly more common in ALS patients and families with the C9ORF72 mutation and was usually early-onset FTD. There was striking clinical heterogeneity among the members of individual families with the mutation. The associated neuropathology was a combination of ALS with TDP-ir inclusions and FTLD-TDP. In addition to TDP-43-immunoreactive pathology, a consistent and specific feature of cases with the C9ORF72 mutation was the presence of ubiquitin-positive, TDP-43-negative inclusions in a variety of neuroanatomical regions, such as the cerebellar cortex. These findings support the C9ORF72 mutation as an important newly-recognized cause of ALS, provide a more detailed characterization of the associated clinical and pathological features and further demonstrate the clinical and molecular overlap between ALS and FTD.
doi:10.1007/s00401-011-0937-5
PMCID: PMC3322555  PMID: 22228244
amyotrophic lateral sclerosis; frontotemporal dementia; frontotemporal lobar degeneration; C9ORF72; TDP-43; chromosome 9p
9.  Frontotemporal dementia and its subtypes: a genome-wide association study 
Ferrari, Raffaele | Hernandez, Dena G | Nalls, Michael A | Rohrer, Jonathan D | Ramasamy, Adaikalavan | Kwok, John B J | Dobson-Stone, Carol | Brooks, William S | Schofield, Peter R | Halliday, Glenda M | Hodges, John R | Piguet, Olivier | Bartley, Lauren | Thompson, Elizabeth | Haan, Eric | Hernández, Isabel | Ruiz, Agustín | Boada, Mercè | Borroni, Barbara | Padovani, Alessandro | Cruchaga, Carlos | Cairns, Nigel J | Benussi, Luisa | Binetti, Giuliano | Ghidoni, Roberta | Forloni, Gianluigi | Galimberti, Daniela | Fenoglio, Chiara | Serpente, Maria | Scarpini, Elio | Clarimón, Jordi | Lleó, Alberto | Blesa, Rafael | Waldö, Maria Landqvist | Nilsson, Karin | Nilsson, Christer | Mackenzie, Ian R A | Hsiung, Ging-Yuek R | Mann, David M A | Grafman, Jordan | Morris, Christopher M | Attems, Johannes | Griffiths, Timothy D | McKeith, Ian G | Thomas, Alan J | Pietrini, P | Huey, Edward D | Wassermann, Eric M | Baborie, Atik | Jaros, Evelyn | Tierney, Michael C | Pastor, Pau | Razquin, Cristina | Ortega-Cubero, Sara | Alonso, Elena | Perneczky, Robert | Diehl-Schmid, Janine | Alexopoulos, Panagiotis | Kurz, Alexander | Rainero, Innocenzo | Rubino, Elisa | Pinessi, Lorenzo | Rogaeva, Ekaterina | George-Hyslop, Peter St | Rossi, Giacomina | Tagliavini, Fabrizio | Giaccone, Giorgio | Rowe, James B | Schlachetzki, J C M | Uphill, James | Collinge, John | Mead, S | Danek, Adrian | Van Deerlin, Vivianna M | Grossman, Murray | Trojanowsk, John Q | van der Zee, Julie | Deschamps, William | Van Langenhove, Tim | Cruts, Marc | Van Broeckhoven, Christine | Cappa, Stefano F | Le Ber, Isabelle | Hannequin, Didier | Golfier, Véronique | Vercelletto, Martine | Brice, Alexis | Nacmias, Benedetta | Sorbi, Sandro | Bagnoli, Silvia | Piaceri, Irene | Nielsen, Jørgen E | Hjermind, Lena E | Riemenschneider, Matthias | Mayhaus, Manuel | Ibach, Bernd | Gasparoni, Gilles | Pichler, Sabrina | Gu, Wei | Rossor, Martin N | Fox, Nick C | Warren, Jason D | Spillantini, Maria Grazia | Morris, Huw R | Rizzu, Patrizia | Heutink, Peter | Snowden, Julie S | Rollinson, Sara | Richardson, Anna | Gerhard, Alexander | Bruni, Amalia C | Maletta, Raffaele | Frangipane, Francesca | Cupidi, Chiara | Bernardi, Livia | Anfossi, Maria | Gallo, Maura | Conidi, Maria Elena | Smirne, Nicoletta | Rademakers, Rosa | Baker, Matt | Dickson, Dennis W | Graff-Radford, Neill R | Petersen, Ronald C | Knopman, David | Josephs, Keith A | Boeve, Bradley F | Parisi, Joseph E | Seeley, William W | Miller, Bruce L | Karydas, Anna M | Rosen, Howard | van Swieten, John C | Dopper, Elise G P | Seelaar, Harro | Pijnenburg, Yolande AL | Scheltens, Philip | Logroscino, Giancarlo | Capozzo, Rosa | Novelli, Valeria | Puca, Annibale A | Franceschi, M | Postiglione, Alfredo | Milan, Graziella | Sorrentino, Paolo | Kristiansen, Mark | Chiang, Huei-Hsin | Graff, Caroline | Pasquier, Florence | Rollin, Adeline | Deramecourt, Vincent | Lebert, Florence | Kapogiannis, Dimitrios | Ferrucci, Luigi | Pickering-Brown, Stuart | Singleton, Andrew B | Hardy, John | Momeni, Parastoo
Lancet neurology  2014;13(7):686-699.
Summary
Background
Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
Methods
We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. All participants had European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) and suggestive single-nucleotide polymorphisms.
Findings
We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8) that encompassed the HLA locus at 6p21.3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC, for the behavioural FTD subtype. Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation incis.
Interpretation
Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and possibly to shed light on the pathomechanisms contributing to FTD.
Funding
The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/ MRC Centre on Parkinson’s disease, Alzheimer’s Research UK, and Texas Tech University Health Sciences Center.
doi:10.1016/S1474-4422(14)70065-1
PMCID: PMC4112126  PMID: 24943344
10.  Expanded GGGGCC hexanucleotide repeat in non-coding region of C9ORF72 causes chromosome 9p-linked frontotemporal dementia and amyotrophic lateral sclerosis 
Neuron  2011;72(2):245-256.
SUMMARY
Several families have been reported with autosomal dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here we report an expansion of a non-coding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43 based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (22.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.
doi:10.1016/j.neuron.2011.09.011
PMCID: PMC3202986  PMID: 21944778
11.  Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation 
Acta Neuropathologica  2011;122(1):87-98.
Mutations in the gene encoding the fused in sarcoma (FUS) protein are responsible for ~3% of familial amyotrophic lateral sclerosis (ALS) and <1% of sporadic ALS (ALS-FUS). Descriptions of the associated neuropathology are few and largely restricted to individual case reports. To better define the neuropathology associated with FUS mutations, we have undertaken a detailed comparative analysis of six cases of ALS-FUS that include sporadic and familial cases, with both juvenile and adult onset, and with four different FUS mutations. We found significant pathological heterogeneity among our cases, with two distinct patterns that correlated with the disease severity and the specific mutation. Frequent basophilic inclusions and round FUS-immunoreactive (FUS-ir) neuronal cytoplasmic inclusions (NCI) were a consistent feature of our early-onset cases, including two with the p.P525L mutation. In contrast, our late-onset cases, that included two with the p.R521C mutation, had tangle-like NCI and numerous FUS-ir glial cytoplasmic inclusions. Double-labeling experiments demonstrated that many of the glial inclusions were in oligodendrocytes. Comparison with the neuropathology of cases of frontotemporal lobar degeneration with FUS-ir pathology showed significant differences and suggests that FUS mutations are associated with a distinct pathobiology.
doi:10.1007/s00401-011-0838-7
PMCID: PMC3319073  PMID: 21604077
fused in sarcoma; FUS; amyotrophic lateral sclerosis; ALS; basophilic inclusions
12.  Baylisascaris procyonis Infection in Elderly Person, British Columbia, Canada 
Emerging Infectious Diseases  2012;18(2):341-342.
doi:10.3201/eid1802.111046
PMCID: PMC3310454  PMID: 22305101
Baylisascaris procyonis; ascarid roundworm; parasites; Alzheimer disease; dementia; elderly person; Canada
13.  TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia 
Acta neuropathologica  2014;127(3):397-406.
Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions (with or without motor neuron disease [MND]; cohort 2), and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls (11.9% versus 19.1%, odds ratio (OR): 0.57, p=0.014; same direction as carriers of GRN mutations). The strongest evidence was provided by FTD patients (OR: 0.33, p=0.009) followed by FTD/MND patients (OR: 0.38, p=0.017), whereas no significant difference was observed in MND patients (OR: 0.85, p=0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR: 0.77, p=0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR: 0.26, p<0.001).
Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations, and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.
doi:10.1007/s00401-013-1240-4
PMCID: PMC3944829  PMID: 24385136
C9ORF72; TMEM106B; frontotemporal dementia; motor neuron disease; amyotrophic lateral sclerosis; disease modifier
14.  FUS GENE MUTATIONS IN FAMILIAL AND SPORADIC AMYOTROPHIC LATERAL SCLEROSIS 
Muscle & nerve  2010;42(2):170-176.
Introduction
Mutations in the fused in sarcoma (FUS) gene have recently been found to cause familial amyotrophic lateral sclerosis (FALS).
Methods
We screened FUS in a cohort of 200 ALS patients [32 FALS and 168 sporadic ALS (SALS)].
Results
In one FALS proband, we identified a mutation (p.R521C) that was also present in her affected daughter. Their clinical phenotype was remarkably similar and atypical of classic ALS, with symmetric proximal pelvic and pectoral weakness. Distal weakness and upper motor neuron features only developed late. Neuropathological examination demonstrated FUS-immunoreactive neuronal and glial inclusions in the spinal cord and many extramotor regions, but no TDP-43 pathology. We also identified a novel mutation (p.G187S) in one SALS patient. Overall, FUS mutations accounted for 3% of our non-SOD1, non-TARDBP FALS cases and 0.6% of SALS.
Discussion
This study demonstrates that the phenotype with FUS mutations extends beyond classical ALS. It suggests there are specific clinicogenetic correlations and provides the first detailed neuropathological description.
doi:10.1002/mus.21665
PMCID: PMC2969843  PMID: 20544928
amyotrophic lateral sclerosis; fused in sarcoma; FUS; translocated in liposarcoma; TLS
15.  Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease 
Acta neuropathologica  2009;118(5):605-616.
Neuronal intermediate filament inclusion disease (NIFID) is an uncommon neurodegenerative condition that typically presents as early-onset, sporadic frontotemporal dementia (FTD), associated with a pyramidal and/or extrapyramidal movement disorder. The neuropathology is characterized by frontotemporal lobar degeneration with neuronal inclusions that are immunoreactive for all class IV intermediate filaments (IF), light, medium and heavy neurofilament subunits and α-internexin. However, not all the inclusions in NIFID are IF-positive and the primary molecular defect remains uncertain. Mutations in the gene encoding the fused in sarcoma (FUS) protein have recently been identified as a cause of familial amyotrophic lateral sclerosis (ALS). Because of the recognized clinical, genetic and pathological overlap between FTD and ALS, we investigated the possible role of FUS in NIFID. We found abnormal intracellular accumulation of FUS to be a consistent feature of our NIFID cases (n = 5). More neuronal inclusions were labeled using FUS immunohistochemistry than for IF. Several types of inclusions were consistently FUS-positive but IF-negative, including neuronal intranuclear inclusions and glial cytoplasmic inclusions. Double-label immunofluorescence confirmed that many cells had only FUS-positive inclusions and that all cells with IF-positive inclusions also contained pathological FUS. No mutations in the FUS gene were identified in a single case with DNA available. These findings suggest that FUS may play an important role in the pathogenesis of NIFID.
doi:10.1007/s00401-009-0581-5
PMCID: PMC2864784  PMID: 19669651
frontotemporal dementia; frontotemporal lobar degeneration; neuronal intermediate filament disease; fused in liposarcoma; translocated in sarcoma
16.  Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene 
Background
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.
Results
We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]).
Conclusions
Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-1326-9-38) contains supplementary material, which is available to authorized users.
doi:10.1186/1750-1326-9-38
PMCID: PMC4190282  PMID: 25239657
C9ORF72; Frontotemporal dementia; Motor neuron disease; Genetic modifier; Repeat expansion
17.  TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia 
Journal of neurochemistry  2013;126(6):781-791.
Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLDTDP). Recently, a genome-wide association study identified the first FTLD-TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD-TDP risk. Intriguingly, the most significant association was in FTLD-TDP patients carrying progranulin (GRN) mutations. Here we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and TMEM106B protein regulation.
First, we confirmed the association of TMEM106B variants with FTLD-TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B-specific antibody for investigation of this protein. Enzyme-linked immunoassay analysis of PGRN levels showed similar effects upon T185 and S185 TMEM106B overexpression. However, overexpression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N-glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD-TDP risk.
doi:10.1111/jnc.12329
PMCID: PMC3766501  PMID: 23742080
TMEM106B; frontotemporal dementia; progranulin; glycosylation
18.  Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS 
Neurobiology of aging  2013;34(9):2235.e11-2235.e13.
The nuclear protein fused in sarcoma (FUS) is found in cytoplasmic inclusions in a subset of patients with the neurodegenerative disorder frontotemporal lobar degeneration (FTLD-FUS). FUS contains a methylated arginine-glycine-glycine domain which is required for transport into the nucleus. Recent findings have shown that this domain is hypomethylated in patients with FTLD-FUS. To determine if the cause of hypomethylation is the result of mutations in protein N-arginine methyltransferases (PRMTs), we selected 3 candidate genes (PRMT1, PRMT3 and PRMT8) and performed complete sequencing analysis and real-time PCR mRNA expression analysis in 20 FTLD-FUS cases. No mutations or statistically significant changes in expression were observed in our patient samples, suggesting that defects in PRMTs are not the cause of FTLD-FUS.
doi:10.1016/j.neurobiolaging.2013.04.004
PMCID: PMC3683824  PMID: 23635657
19.  LAMINAR DISTRIBUTION OF THE PATHOLOGICAL CHANGES IN SPORADIC FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP-43 PROTEINOPATHY: A QUANTITATIVE STUDY USING POLYNOMIAL CURVE FITTING 
Aims
Previous data suggest heterogeneity in laminar distribution of the pathology in the molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP). To study this heterogeneity, we quantified the changes in density across the cortical laminae of neuronal cytoplasmic inclusions (NCI), glial inclusions (GI), neuronal intranuclear inclusions (NII), dystrophic neurites (DN), surviving neurons, abnormally enlarged neurons (EN), and vacuoles in regions of the frontal and temporal lobe.
Methods
Changes in density of histological features across cortical gyri were studied in ten sporadic cases of FTLD-TDP using quantitative methods and polynomial curve-fitting.
Results
Our data suggest that laminar neuropathology in sporadic FTLD-TDP is highly variable. Most commonly, NCI, DN, and vacuolation were abundant in the upper laminae and GI, NII, EN, and glial cell nuclei in the lower laminae. TDP-43-immunoreactive inclusions affected more of the cortical profile in longer duration cases, their distribution varied with disease subtype, but was unrelated to Braak tangle score. Different TDP-43-immunoreactive inclusions were not spatially correlated.
Conclusions
Laminar distribution of pathological features in ten sporadic cases of FTLD-TDL is heterogeneous and may be accounted for, in part, by disease subtype and disease duration. In addition, the feed-forward and feed-back cortico-cortical connections may be compromised in FTLD-TDP.
doi:10.1111/j.1365-2990.2012.01291.x
PMCID: PMC3504185  PMID: 22804696
Frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP); FTLD with ubiquitin-positive inclusions (FTLD-U); Transactive response TAR DNA-binding protein of 43 kDa (TDP-43); Neuronal cytoplasmic inclusions (NCI); Laminar distribution
20.  Anterior brain glucose hypometabolism predates dementia in progranulin mutation carriers 
Neurology  2013;81(15):1322-1331.
Objective:
In this prospective cohort study, we investigated cerebral glucose metabolism reductions on [18F]-fluorodeoxyglucose (FDG)-PET in progranulin (GRN) mutation carriers prior to frontotemporal dementia (FTD) onset.
Methods:
Nine mutation carriers (age 51.5 ± 13.5 years) and 11 noncarriers (age 52.7 ± 9.5 years) from 5 families with FTD due to GRN mutations underwent brain scanning with FDG-PET and MRI and clinical evaluation. Normalized FDG uptake values were calculated with reference to the pons. PET images were analyzed with regions of interest (ROI) and statistical parametric mapping (SPM) approaches.
Results:
Compared with noncarriers, GRN mutation carriers had a lowered anterior-to-posterior (AP) ratio of FDG uptake (0.86 ± 0.09 vs 0.92 ± 0.05) and less left-right asymmetry, consistent with an overall pattern of right anterior cerebral hypometabolism. This pattern was observed regardless of whether they were deemed clinically symptomatic no dementia or asymptomatic. Individual ROIs with lowered FDG uptake included right anterior cingulate, insula, and gyrus rectus. SPM analysis supported and extended these findings, demonstrating abnormalities in the right and left medial frontal regions, right insular cortex, right precentral and middle frontal gyri, and right cerebellum. Right AP ratio was correlated with cognitive and clinical scores (modified Mini-Mental State Examination r = 0.74; Functional Rating Scale r = −0.73) but not age and years to estimated onset in mutation carriers.
Conclusion:
The frontotemporal lobar degenerative process associated with GRN mutations appears to begin many years prior to the average age at FTD onset (late 50s–early 60s). Right medial and ventral frontal cortex and insula may be affected in this process but the specific regional patterns associated with specific clinical variants remain to be elucidated.
doi:10.1212/WNL.0b013e3182a8237e
PMCID: PMC3806924  PMID: 24005336
21.  Frontotemporal Degeneration, the Next Therapeutic Frontier: Molecules and Animal Models for FTD drug development (Part 1 of 2 articles) 
Frontotemporal Degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug’s success in treating FTD may predict efficacy in more common diseases such as Alzheimer’s disease (AD). A variety of regulatory incentives, clinical features of FTD, such as rapid disease progression, and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared to other more common neurodegenerative diseases such as AD. In March 2011, the Frontotemporal Dementia Treatment Study Group (FTSG) sponsored a conference entitled,“ FTD, the Next Therapeutic Frontier,” focused on pre-clinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development, epidemiological, genetic and neuropathological features of FTD, FTD animal models and how best to use them and examples of successful drug-development collaborations in other neurodegenerative diseases.
doi:10.1016/j.jalz.2012.03.002
PMCID: PMC3542408  PMID: 23043900
22.  Frontotemporal lobar degeneration: current perspectives 
The term frontotemporal lobar degeneration (FTLD) refers to a group of progressive brain diseases, which preferentially involve the frontal and temporal lobes. Depending on the primary site of atrophy, the clinical manifestation is dominated by behavior alterations or impairment of language. The onset of symptoms usually occurs before the age of 60 years, and the mean survival from diagnosis varies between 3 and 10 years. The prevalence is estimated at 15 per 100,000 in the population aged between 45 and 65 years, which is similar to the prevalence of Alzheimer’s disease in this age group. There are two major clinical subtypes, behavioral-variant frontotemporal dementia and primary progressive aphasia. The neuropathology underlying the clinical syndromes is also heterogeneous. A common feature is the accumulation of certain neuronal proteins. Of these, the microtubule-associated protein tau (MAPT), the transactive response DNA-binding protein, and the fused in sarcoma protein are most important. Approximately 10% to 30% of FTLD shows an autosomal dominant pattern of inheritance, with mutations in the genes for MAPT, progranulin (GRN), and in the chromosome 9 open reading frame 72 (C9orf72) accounting for more than 80% of familial cases. Although significant advances have been made in recent years regarding diagnostic criteria, clinical assessment instruments, neuropsychological tests, cerebrospinal fluid biomarkers, and brain imaging techniques, the clinical diagnosis remains a challenge. To date, there is no specific pharmacological treatment for FTLD. Some evidence has been provided for serotonin reuptake inhibitors to reduce behavioral disturbances. No large-scale or high-quality studies have been conducted to determine the efficacy of non-pharmacological treatment approaches in FTLD. In view of the limited treatment options, caregiver education and support is currently the most important component of the clinical management.
doi:10.2147/NDT.S38706
PMCID: PMC3928059  PMID: 24600223
review; frontotemporal dementia; frontotemporal lobar degeneration
23.  Inflammation and Alzheimer’s disease 
Neurobiology of aging  2000;21(3):383-421.
Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer’s disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid β peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.
PMCID: PMC3887148  PMID: 10858586
Alzheimer’s disease; Inflammation; Nervous system; Neuroinflammation; Complement; Cytokine; Chemokine; Acute phase protein; Microglia; Astrocyte; Neuron
24.  Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype 
Neurobiology of aging  2012;33(12):2950.e5-2950.e7.
Expansions of the non-coding GGGGCC hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene were recently identified as the long sought-after cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on chromosome 9p. In this study we aimed to determine whether the length of the normal - unexpanded - allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS and 160 FTD-ALS patients and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions and an accurate quantification of the length of the normal alleles in all patients and controls. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or non-mutation carriers.
doi:10.1016/j.neurobiolaging.2012.07.005
PMCID: PMC3617405  PMID: 22840558
Amyotrophic lateral sclerosis; Frontotemporal Dementia; C9ORF72; Repeat-expansion disease; Association study
25.  Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency 
Human Molecular Genetics  2013;23(6):1467-1478.
Progranulin (GRN) mutations causing haploinsufficiency are a major cause of frontotemporal lobar degeneration (FTLD-TDP). Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocytosis and a determinant of plasma PGRN levels portend the development of enhancers targeting the SORT1–PGRN axis. We demonstrate the preclinical efficacy of several approaches through which impairing PGRN's interaction with SORT1 restores extracellular PGRN levels. Our report is the first to demonstrate the efficacy of enhancing PGRN levels in iPSC neurons derived from frontotemporal dementia (FTD) patients with PGRN deficiency. We validate a small molecule preferentially increases extracellular PGRN by reducing SORT1 levels in various mammalian cell lines and patient-derived iPSC neurons and lymphocytes. We further demonstrate that SORT1 antagonists and a small-molecule binder of PGRN588–593, residues critical for PGRN–SORT1 binding, inhibit SORT1-mediated PGRN endocytosis. Collectively, our data demonstrate that the SORT1–PGRN axis is a viable target for PGRN-based therapy, particularly in FTD-GRN patients.
doi:10.1093/hmg/ddt534
PMCID: PMC3929086  PMID: 24163244

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