Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions.
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ABSTRACT:
SUBMITTER: Van Deerlin VM
PROVIDER: S-EPMC2828525 | biostudies-literature | 2010 Mar
REPOSITORIES: biostudies-literature
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Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions.
Van Deerlin Vivianna M VM Sleiman Patrick M A PM Martinez-Lage Maria M Chen-Plotkin Alice A Wang Li-San LS Graff-Radford Neill R NR Dickson Dennis W DW Rademakers Rosa R Boeve Bradley F BF Grossman Murray M Arnold Steven E SE Mann David M A DM Pickering-Brown Stuart M SM Seelaar Harro H Heutink Peter P van Swieten John C JC Murrell Jill R JR Ghetti Bernardino B Spina Salvatore S Grafman Jordan J Hodges John J Spillantini Maria Grazia MG Gilman Sid S Lieberman Andrew P AP Kaye Jeffrey A JA Woltjer Randall L RL Bigio Eileen H EH Mesulam Marsel M Al-Sarraj Safa S Troakes Claire C Rosenberg Roger N RN White Charles L CL Ferrer Isidro I Lladó Albert A Neumann Manuela M Kretzschmar Hans A HA Hulette Christine Marie CM Welsh-Bohmer Kathleen A KA Miller Bruce L BL Alzualde Ainhoa A Lopez de Munain Adolfo A McKee Ann C AC Gearing Marla M Levey Allan I AI Lah James J JJ Hardy John J Rohrer Jonathan D JD Lashley Tammaryn T Mackenzie Ian R A IR Feldman Howard H HH Hamilton Ronald L RL Dekosky Steven T ST van der Zee Julie J Kumar-Singh Samir S Van Broeckhoven Christine C Mayeux Richard R Vonsattel Jean Paul G JP Troncoso Juan C JC Kril Jillian J JJ Kwok John B J JB Halliday Glenda M GM Bird Thomas D TD Ince Paul G PG Shaw Pamela J PJ Cairns Nigel J NJ Morris John C JC McLean Catriona Ann CA DeCarli Charles C Ellis William G WG Freeman Stefanie H SH Frosch Matthew P MP Growdon John H JH Perl Daniel P DP Sano Mary M Bennett David A DA Schneider Julie A JA Beach Thomas G TG Reiman Eric M EM Woodruff Bryan K BK Cummings Jeffrey J Vinters Harry V HV Miller Carol A CA Chui Helena C HC Alafuzoff Irina I Hartikainen Päivi P Seilhean Danielle D Galasko Douglas D Masliah Eliezer E Cotman Carl W CW Tuñón M Teresa MT Martínez M Cristina Caballero MC Munoz David G DG Carroll Steven L SL Marson Daniel D Riederer Peter F PF Bogdanovic Nenad N Schellenberg Gerard D GD Hakonarson Hakon H Trojanowski John Q JQ Lee Virginia M-Y VM
Nature genetics 20100214 3
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 ...[more]
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Project description:TAR DNA-binding protein 43 (TDP-43) is a major pathological protein of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. We performed ubiquitin and TDP-43 immunohistochemistry on 193 cases of familial and sporadic FTLD with or without MND. On selected cases, immunoelectron microscopy and biochemistry were performed. Clinically defined frontotemporal dementias (FTDs) included four groups: 1) familial FTD with mutations in progranulin (n = 36), valosin-containing protein (n = 5), charged multivesicular body protein 2B (n = 4), and linked to chromosome 9p (n = 7); 2) familial cases of FTD with unknown gene association (n = 29); 3) sporadic FTD (n = 72); and 4) familial and sporadic FTD with MND (n = 40). Our studies confirm that the spectrum of TDP-43 proteinopathies includes most cases of sporadic and familial FTLD-U with and without MND and expand this disease spectrum to include reported families with FTD linked to chromosome 9p but not FTD with charged multivesicular body protein 2B mutations. Thus, despite significant clinical, genetic, and neuropathological heterogeneity of FTLD-U, TDP-43 is a common pathological substrate underlying a large subset of these disorders, thereby implicating TDP-43 in novel and unifying mechanisms of FTLD pathogenesis.
| S-EPMC1941578 | biostudies-literature
Project description:Neuronal cytoplasmic and intranuclear aggregates of RNA-binding protein TDP-43 are a hallmark feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). ALS and FTLD show a considerable clinical and pathological overlap and occur as both familial and sporadic forms. Though missense mutations in TDP-43 cause rare forms of familial ALS, it is not yet known whether this is due to loss of TDP-43 function or gain of aberrant function. Moreover, the role of wild-type (WT) TDP-43, associated with the majority of familial and sporadic ALS/FTLD patients, is also currently unknown. Generating homozygous and hemizygous WT human TDP-43 transgenic mouse lines, we show here a dose-dependent degeneration of cortical and spinal motor neurons and development of spastic quadriplegia reminiscent of ALS. A dose-dependent degeneration of nonmotor cortical and subcortical neurons characteristic of FTLD was also observed. Neurons in the affected spinal cord and brain regions showed accumulation of TDP-43 nuclear and cytoplasmic aggregates that were both ubiquitinated and phosphorylated as observed in ALS/FTLD patients. Moreover, the characteristic approximately 25-kDa C-terminal fragments (CTFs) were also recovered from nuclear fractions and correlated with disease development and progression in WT TDP-43 mice. These findings suggest that approximately 25-kDa TDP-43 CTFs are noxious to neurons by a gain of aberrant nuclear function.
| S-EPMC2840518 | biostudies-literature
Project description:AimsTo assess the burden of transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions in a unique cohort of old-age patients with genetic frontotemporal lobar degeneration (gFTLD-TDP) and compare these patients with sporadic old-age individuals with TDP-43, either in the presence of Alzheimer's disease (AD-TDP) or in isolation (pure-TDP).MethodsThe brain bank at Mayo Clinic-Jacksonville was searched for cases ≥75 years old at death with TDP-43 extending into middle frontal cortex. Cases were split into the following groups: (1) gFTLD-TDP (n = 15) with progranulin (GRN)/C9ORF72 mutations; (2) AD-TDP (n = 10)-cases with median Braak neurofibrillary tangle (NFT) stage VI, Thal phase V; (3) pure-TDP (n = 10)-cases with median Braak NFT stage I, Thal phase I. Clinical data were abstracted; TDP-43 burden was calculated using digital pathology.ResultsAmnestic Alzheimer's dementia was the clinical diagnosis in ≥50% patients in each group. The distribution of TDP-43 burden in gFTLD-TDP and AD-TDP, but not pure-TDP, was limbic-predominant targeting CA1 and subiculum. Patients with gFTLD-TDP had higher burden in entorhinal cortex compared to AD-TDP. TDP-43 burden in middle frontal cortex did not differ between the three groups.ConclusionsIn old age it is challenging to clinically and pathologically differentiate gFTLD-TDP from AD-TDP and pure-TDP-43 based on burden. Like AD-TDP, old age gFTLD-TDP have a limbic predominant TDP-43 distribution. The finding that amnestic Alzheimer's dementia was the most common clinical diagnosis regardless of group suggests that TDP-43 directly and indirectly targets limbic regions.
| S-EPMC8576062 | biostudies-literature
Project description:AimsAccumulating evidence suggests that patients with frontotemporal lobar degeneration (FTLD) can have pathologic accumulation of multiple proteins, including tau and TDP-43. This study aimed to determine the frequency and characteristics of concurrent tau pathology in FTLD with TDP-43 pathology (FTLD-TDP).MethodsThe study included 146 autopsy-confirmed cases of FTLD-TDP and 55 cases of FTLD-TDP with motor neuron disease (FTLD-MND). Sections from the basal forebrain were screened for tau pathology with phosphorylated-tau immunohistochemistry. For cases with tau pathology on the screening section, additional brain sections were studied to establish a diagnosis. Genetic analysis of C9orf72, GRN and MAPT was performed on select cases.ResultsWe found 72 cases (36%) with primary age-related tauopathy (PART), 85 (42%) with ageing-related tau astrogliopathy (ARTAG), 45 (22%) with argyrophilic grain disease (AGD) and 2 cases (1%) with corticobasal degeneration (CBD). Patients with ARTAG or AGD were significantly older than those without these comorbidities. One of the patients with FTLD-TDP and CBD had C9orf72 mutation and relatively mild tau pathology, consistent with incidental CBD.ConclusionThe coexistence of TDP-43 and tau pathologies was relatively common, particularly PART and ARTAG. Although rare, patients with FTLD can have multiple neurodegenerative proteinopathies. The absence of TDP-43-positive astrocytic plaques may suggest that CBD and FTLD-TDP were independent disease processes in the two patients with both tau and TDP-43 pathologies. It remains to be determined if mixed cases represent a unique disease process or two concurrent disease processes in an individual.
| S-EPMC9300011 | biostudies-literature
Project description:ImportanceBiomarkers are lacking that can discriminate frontotemporal lobar degeneration (FTLD) associated with tau (FTLD-tau) or TDP-43 (FTLD-TDP).ObjectiveTo test whether plasma biomarkers glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), or their ratio (GFAP/NfL) differ between FTLD-tau and FTLD-TDP.Design, setting, and participantsThis retrospective cross-sectional study included data from 2009 to 2020 from the University of Pennsylvania Integrated Neurodegenerative Disease Database, with a median (IQR) follow-up duration of 2 (0.3-4.2) years. The training sample was composed of patients with autopsy-confirmed and familial FTLD; nonimpaired controls were included as a reference group. The independent validation sample included patients with FTD with a clinical diagnosis of progressive supranuclear palsy syndrome (PSPS) associated with tau (PSPS-tau) or amytrophic lateral sclerosis (ALS) associated with TDP-43 (ALS-TDP). In patients with FTLD with autopsy-confirmed or variant-confirmed pathology, receiver operating characteristic (ROC) curves tested the GFAP/NfL ratio and established a pathology-confirmed cut point. The cut point was validated in an independent sample of patients with clinical frontotemporal dementia (FTD). Data were analyzed from February to July 2022.ExposuresClinical, postmortem histopathological assessments, and plasma collection.Main outcomes and measuresROC and area under the ROC curve (AUC) with 90% CIs evaluated discrimination of pure FTLD-tau from pure FTLD-TDP using plasma GFAP/NfL ratio; the Youden index established optimal cut points. Sensitivity and specificity of cut points were assessed in an independent validation sample.ResultsOf 349 participants with available plasma data, 234 met inclusion criteria (31 controls, 141 in the training sample, and 62 in the validation sample). In the training sample, patients with FTLD-tau were older than patients with FTLD-TDP (FTLD-tau: n = 46; mean [SD] age, 65.8 [8.29] years; FTLD-TDP: n = 95; mean [SD] age, 62.3 [7.82] years; t84.6 = 2.45; mean difference, 3.57; 95% CI, 0.67-6.48; P = .02) but with similar sex distribution (FTLD-tau: 27 of 46 [59%] were male; FTLD-TDP: 51 of 95 [54%] were male; χ21 = 0.14; P = .70). In the validation sample, patients with PSPS-tau were older than those with ALS-TDP (PSPS-tau: n = 31; mean [SD] age, 69.3 [7.35] years; ALS-TDP: n = 31; mean [SD] age, 54.6 [10.17] years; t54.6 = 6.53; mean difference, 14.71; 95% CI, 10.19-19.23; P < .001) and had fewer patients who were male (PSPS-tau: 9 of 31 [29%] were male; ALS-TDP: 22 of 31 [71%] were male; χ21 = 9.3; P = .002). ROC revealed excellent discrimination of FTLD-tau from FTLD-TDP by plasma GFAP/NfL ratio (AUC = 0.89; 90% CI, 0.82-0.95; sensitivity = 0.73; 90% CI, 0.65-0.89; specificity = 0.89; 90% CI, 0.78-0.98), which was higher than either GFAP level alone (AUC = 0.65; 90% CI, 0.54-0.76) or NfL levels alone (AUC = 0.75; 90% CI, 0.64-0.85). In the validation sample, there was sensitivity of 0.84 (90% CI, 0.66-0.94) and specificity of 0.81 (90% CI, 0.62-0.91) when applying the autopsy-derived plasma GFAP/NfL threshold.Conclusions and relevanceThe plasma ratio of GFAP/NfL may discriminate FTLD-tau from FTLD-TDP.
| S-EPMC9552044 | biostudies-literature
Project description:TAR DNA-binding protein of 43 kDa (TDP-43) is a major component of intracellular aggregates formed in brains of the patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), which are correctively referred to as TDP-43 proteinopathies. A link between Ataxin-2 (ATXN2) and TDP-43 proteinopathies was established when intermediate CAG repeat expansions of ATXN2 gene were found to be associated with ALS and it was shown that ATXN2 modifies TDP-43 toxicity. Although ATXN2's contribution to TDP-43 proteinopathies has been mostly studied in ALS, recent studies have shown that intermediate repeat expansions of ATXN2 also influence the phenotype of FTLD by an unknown mechanism. To address this issue, we immunohistochemically and biochemically analyzed the intracellular dynamics of ATXN2 in brains of normal controls and FTLD-TDP cases. The immunohistochemical studies revealed that ATXN2 localized in the neuronal cytoplasm and proximal dendrites, and expressed widely and uniformly in normal human brains. A semi-quantitative immunofluorescent analysis of normal brains revealed that the cytoplasmic ATXN2 strongly associates with ribosomal protein S6 and poly-A binding protein 1 and partially overlaps with the endoplasmic reticulum marker Calnexin, suggesting a major role of ATXN2 in protein synthesis. The results of immunohistochemical and biochemical analyses of brains from FTLD-TDP cases showed the colocalization of ATXN2 and phosphorylated TDP-43 in the dystrophic neurites and the neuronal cytoplasmic inclusions in the hippocampal region, and a significant reduction of ATXN2 protein compared to controls. These results suggest that ATXN2 is involved in the pathological process of FTLD-TDP. It remains to be clarified whether reduced ATXN2 expression induces neurodegeneration by impairing protein synthesis or plays a neuroprotective role by attenuating the toxicity of TDP-43 aggregates in FTLD-TDP and other TDP-43 proteinopathies.
| S-EPMC7594343 | biostudies-literature
Project description:TAR-DNA binding protein-43 (TDP-43) proteinopathy is seen in multiple brain diseases. A standardized terminology was recommended recently for common age-related TDP-43 proteinopathy: limbic-predominant, age-related TDP-43 encephalopathy (LATE) and the underlying neuropathological changes, LATE-NC. LATE-NC may be co-morbid with Alzheimer's disease neuropathological changes (ADNC). However, there currently are ill-defined diagnostic classification issues among LATE-NC, ADNC, and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). A practical challenge is that different autopsy cohorts are composed of disparate groups of research volunteers: hospital- and clinic-based cohorts are enriched for FTLD-TDP cases, whereas community-based cohorts have more LATE-NC cases. Neuropathological methods also differ across laboratories. Here, we combined both cases and neuropathologists' diagnoses from two research centres-University of Pennsylvania and University of Kentucky. The study was designed to compare neuropathological findings between FTLD-TDP and pathologically severe LATE-NC. First, cases were selected from the University of Pennsylvania with pathological diagnoses of either FTLD-TDP (n = 33) or severe LATE-NC (mostly stage 3) with co-morbid ADNC (n = 30). Sections from these University of Pennsylvania cases were cut from amygdala, anterior cingulate, superior/mid-temporal, and middle frontal gyrus. These sections were stained for phospho-TDP-43 immunohistochemically and evaluated independently by two University of Kentucky neuropathologists blinded to case data. A simple set of criteria hypothesized to differentiate FTLD-TDP from LATE-NC was generated based on density of TDP-43 immunoreactive neuronal cytoplasmic inclusions in the neocortical regions. Criteria-based sensitivity and specificity of differentiating severe LATE-NC from FTLD-TDP cases with blind evaluation was ∼90%. Another proposed neuropathological feature related to TDP-43 proteinopathy in aged individuals is 'Alpha' versus 'Beta' in amygdala. Alpha and Beta status was diagnosed by neuropathologists from both universities (n = 5 raters). There was poor inter-rater reliability of Alpha/Beta classification (mean κ = 0.31). We next tested a separate cohort of cases from University of Kentucky with either FTLD-TDP (n = 8) or with relatively 'pure' severe LATE-NC (lacking intermediate or severe ADNC; n = 14). The simple criteria were applied by neuropathologists blinded to the prior diagnoses at University of Pennsylvania. Again, the criteria for differentiating LATE-NC from FTLD-TDP was effective, with sensitivity and specificity ∼90%. If more representative cases from each cohort (including less severe TDP-43 proteinopathy) had been included, the overall accuracy for identifying LATE-NC was estimated at >98% for both cohorts. Also across both cohorts, cases with FTLD-TDP died younger than those with LATE-NC (P < 0.0001). We conclude that in most cases, severe LATE-NC and FTLD-TDP can be differentiated by applying simple neuropathological criteria.
| S-EPMC7526723 | biostudies-literature
Project description: Not available
| S-EPMC10564657 | biostudies-literature
Project description: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).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.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.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.
| S-EPMC3737288 | biostudies-other
Project description:The G4C2 hexanucleotide repeat expansion mutation in the C9orf72 gene is the most common genetic cause underlying both amyotrophic lateral sclerosis and frontotemporal dementia. Pathologically, these two neurodegenerative disorders are linked by the common presence of abnormal phosphorylated TDP-43 neuronal cytoplasmic inclusions. We compared the number and size of phosphorylated TDP-43 inclusions and their morphology in hippocampi from patients dying with sporadic versus C9orf72-related amyotrophic lateral sclerosis with pathologically defined frontotemporal lobar degeneration with phosphorylated TDP-43 inclusions, the pathological substrate of clinical frontotemporal dementia in patients with amyotrophic lateral sclerosis. In sporadic cases, there were numerous consolidated phosphorylated TDP-43 inclusions that were variable in size, whereas inclusions in C9orf72 amyotrophic lateral sclerosis/frontotemporal lobar degeneration were quantitatively smaller than those in sporadic cases. Also, C9orf72 amyotrophic lateral sclerosis/frontotemporal lobar degeneration homogenized brain contained soluble cytoplasmic TDP-43 that was largely absent in sporadic cases. To better understand these pathological differences, we modelled TDP-43 inclusion formation in fibroblasts derived from sporadic or C9orf72-related amyotrophic lateral sclerosis/frontotemporal dementia patients. We found that both sporadic and C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia patient fibroblasts showed impairment in TDP-43 degradation by the proteasome, which may explain increased TDP-43 protein levels found in both sporadic and C9orf72 amyotrophic lateral sclerosis/frontotemporal lobar degeneration frontal cortex and hippocampus. Fibroblasts derived from sporadic patients, but not C9orf72 patients, demonstrated the ability to sequester cytoplasmic TDP-43 into aggresomes via microtubule-dependent mechanisms. TDP-43 aggresomes in vitro and TDP-43 neuronal inclusions in vivo were both tightly localized with autophagy markers and, therefore, were likely to function similarly as sites for autophagic degradation. The inability for C9orf72 fibroblasts to form TDP-43 aggresomes, together with the observations that TDP-43 protein was soluble in the cytoplasm and formed smaller inclusions in the C9orf72 brain compared with sporadic disease, suggests a loss of protein quality control response to sequester and degrade TDP-43 in C9orf72-related diseases.
| S-EPMC6788139 | biostudies-literature