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Nigel J Cairns - One of the best experts on this subject based on the ideXlab platform.
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laminar distribution of the pathological changes in sporadic frontotemporal lobar degeneration with transactive response tar dna binding protein of 43 kda TDP 43 Proteinopathy a quantitative study using polynomial curve fitting
Neuropathology and Applied Neurobiology, 2013Co-Authors: Richard A. Armstrong, Ronald L Hamilton, Ian R Mackenzie, John C Hedreen, Nigel J CairnsAbstract: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, glial inclusions, neuronal intranuclear inclusions, dystrophic neurites, surviving neurones, abnormally enlarged neurones, and vacuoles in regions of the frontal and temporal lobe. Methods: Changes in density of histological features across cortical gyri were studied in 10 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, neuronal cytoplasmic inclusions, dystrophic neurites and vacuolation were abundant in the upper laminae and glial inclusions, neuronal intranuclear inclusions, abnormally enlarged neurones, 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 10 sporadic cases of FTLD-TDP is heterogeneous and may be accounted for, in part, by disease subtype and disease duration. In addition, the feedforward and feedback cortico-cortical connections may be compromised in FTLD-TDP. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.
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a quantitative study of the neuropathology of 32 sporadic and familial cases of frontotemporal lobar degeneration with TDP 43 Proteinopathy ftld TDP
Neuropathology and Applied Neurobiology, 2012Co-Authors: Richard A. Armstrong, Deborah Carter, Nigel J CairnsAbstract:To further characterize the neuropathology of the heterogeneous molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) Proteinopathy (FTLD-TDP).
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A quantitative study of the neuropathology of 32 sporadic and familial cases of frontotemporal lobar degeneration with TDP‐43 Proteinopathy (FTLD‐TDP)
Neuropathology and applied neurobiology, 2012Co-Authors: Richard A. Armstrong, Deborah Carter, Nigel J CairnsAbstract:To further characterize the neuropathology of the heterogeneous molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) Proteinopathy (FTLD-TDP).
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Spatial patterns of TDP-43 neuronal cytoplasmic inclusions (NCI) in fifteen cases of frontotemporal lobar degeneration with TDP-43 Proteinopathy (FTLD-TDP).
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2011Co-Authors: Richard A. Armstrong, Nigel J CairnsAbstract:Neuronal cytoplasmic inclusions (NCI) immunoreactive for transactive response DNA-binding protein (TDP-43) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 Proteinopathy (FTLD-TDP). We studied the spatial patterns of the TDP-43 immunoreactive NCI in the frontal and temporal cortex of 15 cases of FTLD-TDP. The NCI were distributed parallel to the tissue boundary predominantly in regular clusters 50-400 µm in diameter. In five cortical areas, the size of the clusters approximated to the cells of the cortico-cortical pathways. In most regions, cluster size was smaller than 400 µm. There were no significant differences in spatial patterns between familial and sporadic cases. Cluster size of the NCI was not correlated with disease duration, brain weight, Braak stage, or disease subtype. The spatial pattern of the NCI was similar to that of neuronal inclusions in other neurodegenerative diseases and may reflect a common pattern of degeneration involving the cortico-cortical projections.
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TDP-43 Proteinopathy in familial motor neurone disease with TARDBP A315T mutation: a case report
Neuropathology and applied neurobiology, 2010Co-Authors: Nigel J Cairns, Richard J. Perrin, Robert E. Schmidt, A. Gru, Karen G. Green, Deborah Carter, Lisa Taylor-reinwald, John C. Morris, M. A. Gitcho, R. H. BalohAbstract:Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease (MND), is characterized clinically by progressive motor weakness leading to death within one to five years and neuropathologically by loss of upper and lower motor neurons, corticospinal tract degeneration, gliosis, and ubiquitinated neuronal inclusions in the spinal cord and cerebrum [1,2,3,4]. ALS is largely a sporadic disease but about 10% of cases show an autosomal dominant pattern of inheritance and of these about 20% have mutations in the Cu/Zn superoxide dismutase-1 (SOD1) gene [5,6]. Recently, mutations in two DNA/RNA-binding proteins called TDP-43 (TAR DNA-binding protein of 43 kDa encoded by the TARDBP gene) [7,8,9,10] and FUS (encoded by the fused in sarcoma (FUS) gene) were reported as causes of (~10%) familial and (~2%) sporadic forms of ALS [11,12]. Together, frontotemporal lobar degeneration (FTLD) and ALS form a spectrum of disorders linked by a common molecular pathology called TDP-43 Proteinopathy [13,14]. In cases with combined MND and FTLD, TDP-43-immunoreactive inclusions are found in the spinal cord, brainstem, limbic areas and frontal and temporal lobes. The selective vulnerability of different regions of the neuraxis helps to explain the variability in clinical phenotype associated with TDP-43 Proteinopathy and other proteinopathies. Although most TARDBP mutations have been reported in autosomal dominant ALS, a few cases have included both FTLD-TDP and ALS [15,16]. In only a few cases of ALS/FTLD with a pathogenic TARDBP mutation has neuropathological confirmation of TDP-43 Proteinopathy been demonstrated [17,18,19,20,21]; thus, the contribution of any one mutation to a particular phenotype remains uncertain.
Richard A. Armstrong - One of the best experts on this subject based on the ideXlab platform.
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White matter pathology in sporadic frontotemporal lobar degeneration with TDP-43 Proteinopathy.
Clinical Neuropathology, 2017Co-Authors: Richard A. ArmstrongAbstract:Aims: To characterize white matter pathology in frontotemporal lobar degeneration (FTLD) with TDP-43 Proteinopathy (FTLD-TDP) and its relationship to gray matter pathology. Material: Fiber tracts from frontal and temporal lobes of 10 sporadic cases of FTLD and 8 controls. Method: Density and spatial patterns of vacuolation, glial cell nuclei, and glial inclusions (GI) were studied in 4 fiber tracts from each case. Results: Densities of vacuoles but not glial cells were greater in FTLD-TDP than controls. No GI were observed in controls, while in FTLD-TDP, greatest densities of GI were observed in the cortex of early-onset cases. Vacuoles, glial cell nuclei, and GI were distributed in clusters which were regularly distributed across the tract. Densities of vacuoles in white matter were positively correlated with those in adjacent gray matter, and correlations were also present between GI in white matter and TDP-43-immunoreactive pathology in gray matter. Conclusions: (1) Degeneration of white matter in sporadic FTLD-TDP was characterized by increased vacuolation and GI, (2) pathological changes were topographically distributed, which suggests propagation of pathological TDP-43 in specific groups of fibers, and (3) both white matter pathology and gray matter pathology need to be considered to quantify the pathological "load" in FTLD-TDP.
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White matter pathology in sporadic frontotemporal lobar degeneration with TDP-43 Proteinopathy.
Clinical neuropathology, 2017Co-Authors: Richard A. ArmstrongAbstract:To characterize white matter pathology in frontotemporal lobar degeneration (FTLD) with TDP-43 Proteinopathy (FTLD-TDP) and its relationship to gray matter pathology. Fiber tracts from frontal and temporal lobes of 10 sporadic cases of FTLD and 8 controls. Density and spatial patterns of vacuolation, glial cell nuclei, and glial inclusions (GI) were studied in 4 fiber tracts from each case. Densities of vacuoles but not glial cells were greater in FTLD-TDP than controls. No GI were observed in controls, while in FTLD-TDP, greatest densities of GI were observed in the cortex of early-onset cases. Vacuoles, glial cell nuclei, and GI were distributed in clusters which were regularly distributed across the tract. Densities of vacuoles in white matter were positively correlated with those in adjacent gray matter, and correlations were also present between GI in white matter and TDP-43-immunoreactive pathology in gray matter. (1) Degeneration of white matter in sporadic FTLD-TDP was characterized by increased vacuolation and GI, (2) pathological changes were topographically distributed, which suggests propagation of pathological TDP-43 in specific groups of fibers, and (3) both white matter pathology and gray matter pathology need to be considered to quantify the pathological "load" in FTLD-TDP. .
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Survival in the pre-senile dementia frontotemporal lobar degeneration with TDP-43 Proteinopathy: effects of genetic, demographic and neuropathological variables
Folia neuropathologica, 2016Co-Authors: Richard A. ArmstrongAbstract:Factors associated with survival were studied in 84 neuropathologically documented cases of the pre-senile dementia frontotemporal dementia lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) Proteinopathy (FTLD-TDP). Kaplan-Meier survival analysis estimated mean survival as 7.9 years (range: 1-19 years, SD = 4.64). Familial and sporadic cases exhibited similar survival, including progranulin (GRN) gene mutation cases. No significant differences in survival were associated with sex, disease onset, Braak disease stage, or disease subtype, but higher survival was associated with lower post-mortem brain weight. Survival was significantly reduced in cases with associated motor neuron disease (FTLD-MND) but increased with Alzheimer's disease (AD) or hippocampal sclerosis (HS) co-morbidity. Cox regression analysis suggested that reduced survival was associated with increased densities of neuronal cytoplasmic inclusions (NCI) while increased survival was associated with greater densities of enlarged neurons (EN) in the frontal and temporal lobes. The data suggest that: (1) survival in FTLD-TDP is more prolonged than typical in pre-senile dementia but shorter than some clinical subtypes such as the semantic variant of primary progressive aphasia (svPPA), (2) MND co-morbidity predicts poor survival, and (3) NCI may develop early and EN later in the disease. The data have implications for both neuropathological characterization and subtyping of FTLD-TDP.
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Spatial patterns of phosphorylated TDP-43-immunoreactive cellular inclusions in familial and sporadic frontotemporal lobar degeneration with TDP-43 Proteinopathy
2016Co-Authors: Richard A. ArmstrongAbstract:Abnormal protein aggregates of transactive response (TAR) DNA-binding protein (TDP-43) in the form of neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), neuronal internuclear inclusions (NII), and dystrophic neurites (DN) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 Proteinopathy (FTLD-TDP). To investigate the role of phosphorylated TDP-43 (pTDP-43) in neurodegeneration in FTLD-TDP, the spatial patterns of the pTDP-43-immunoreactive NCI, GI, NII, and DN were studied in frontal and temporal cortex in three groups of cases: (1) familial FTLD-TDP caused by progranulin (GRN) mutation, (2) a miscellaneous group of familial cases containing cases caused by valosin-containing protein (VCP) mutation, ubiquitin associated protein 1 (UBAP1) mutation, and cases not associated with currently known genes, and (3) sporadic FTLD-TDP. In a significant number of brain regions, the pTDP-43-immunoreactive inclusions developed in clusters and the clusters were distributed regularly parallel to the tissue boundary. The spatial patterns of the inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody. The spatial patterns and cluster sizes of the pTDP-43-immunoreactive inclusions were similar in GRN mutation cases, remaining familial cases, and in sporadic FTLD-TDP. Hence, pathological changes initiated by different genetic factors in familial cases and by unknown causes in sporadic FTLD-TDP appear to follow a parallel course resulting in very similar patterns of degeneration of frontal and temporal lobes.
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A comparison of spatial patterns of TDP-43 cellular inclusions in familial and sporadic frontotemporal lobar degeneration with TDP-43 Proteinopathy
2015Co-Authors: Richard A. ArmstrongAbstract:Abnormal protein aggregates of transactive response (TAR) DNA-binding protein (TDP-43) in the form of neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), neuronal internuclear inclusions (NII), and dystrophic neurites (DN) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 Proteinopathy (FTLD-TDP). To investigate the role of phosphorylated TDP-43 (pTDP-43) in neurodegeneration in FTLD-TDP, the spatial patterns of the pTDP-43-immunoreactive NCI, GI, NII, and DN were studied in frontal and temporal cortex in three groups of cases: (1) familial FTLD-TDP caused by progranulin (GRN) mutation, (2) a miscellaneous group of familial cases containing cases caused by valosin-containing protein (VCP) mutation, ubiquitin associated protein 1 (UBAP1) mutation, and cases not associated with currently known genes, and (3) sporadic FTLD-TDP. In a significant number of brain regions, the pTDP-43-immunoreactive inclusions developed in clusters and the clusters were distributed regularly parallel to the tissue boundary. The spatial patterns of the inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody. The spatial patterns and cluster sizes of the pTDP-43-immunoreactive inclusions were similar in GRN mutation cases, remaining familial cases, and in sporadic FTLD-TDP. Hence, pathological changes initiated by different genetic factors in familial cases and by unknown causes in sporadic FTLD-TDP appear to follow a parallel course resulting in very similar patterns of degeneration of frontal and temporal lobes.
John C. Morris - One of the best experts on this subject based on the ideXlab platform.
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TDP-43 Proteinopathy in familial motor neurone disease with TARDBP A315T mutation: a case report
Neuropathology and applied neurobiology, 2010Co-Authors: Nigel J Cairns, Richard J. Perrin, Robert E. Schmidt, A. Gru, Karen G. Green, Deborah Carter, Lisa Taylor-reinwald, John C. Morris, M. A. Gitcho, R. H. BalohAbstract:Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease (MND), is characterized clinically by progressive motor weakness leading to death within one to five years and neuropathologically by loss of upper and lower motor neurons, corticospinal tract degeneration, gliosis, and ubiquitinated neuronal inclusions in the spinal cord and cerebrum [1,2,3,4]. ALS is largely a sporadic disease but about 10% of cases show an autosomal dominant pattern of inheritance and of these about 20% have mutations in the Cu/Zn superoxide dismutase-1 (SOD1) gene [5,6]. Recently, mutations in two DNA/RNA-binding proteins called TDP-43 (TAR DNA-binding protein of 43 kDa encoded by the TARDBP gene) [7,8,9,10] and FUS (encoded by the fused in sarcoma (FUS) gene) were reported as causes of (~10%) familial and (~2%) sporadic forms of ALS [11,12]. Together, frontotemporal lobar degeneration (FTLD) and ALS form a spectrum of disorders linked by a common molecular pathology called TDP-43 Proteinopathy [13,14]. In cases with combined MND and FTLD, TDP-43-immunoreactive inclusions are found in the spinal cord, brainstem, limbic areas and frontal and temporal lobes. The selective vulnerability of different regions of the neuraxis helps to explain the variability in clinical phenotype associated with TDP-43 Proteinopathy and other proteinopathies. Although most TARDBP mutations have been reported in autosomal dominant ALS, a few cases have included both FTLD-TDP and ALS [15,16]. In only a few cases of ALS/FTLD with a pathogenic TARDBP mutation has neuropathological confirmation of TDP-43 Proteinopathy been demonstrated [17,18,19,20,21]; thus, the contribution of any one mutation to a particular phenotype remains uncertain.
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TARDBP 3′-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 Proteinopathy
Acta neuropathologica, 2009Co-Authors: Michael A. Gitcho, Manjari Mishra, Rosa Rademakers, Eileen H Bigio, M.-marsel Mesulam, Sandra Weintraub, Nancy Johnson, Sumi Chakraverty, Carlos Cruchaga, John C. MorrisAbstract:Pathogenic mutations in the gene encoding TDP-43, TARDBP, have been reported in familial amyotrophic lateral sclerosis (FALS) and, more recently, in families with a heterogeneous clinical phenotype including both ALS and frontotemporal lobar degeneration (FTLD). In our previous study, sequencing analyses identified one variant in the 3′-untranslated region (3′-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS. Since that study, brain tissue has become available and provides autopsy confirmation of FTLD-TDP in the proband and ALS in the brother of the bvFTD-ALS family and the neuropathology of those two cases is reported here. The 3′-UTR variant was not found in 982 control subjects (1,964 alleles). To determine the functional significance of this variant, we undertook quantitative gene expression analysis. Allele-specific amplification showed a significant increase of 22% (P < 0.05) in disease-specific allele expression with a twofold increase in total TARDBP mRNA. The segregation of this variant in a family with clinical bvFTD and ALS adds to the spectrum of clinical phenotypes previously associated with TARDBP variants. In summary, TARDBP variants may result in clinically and neuropathologically heterogeneous phenotypes linked by a common molecular pathology called TDP-43 Proteinopathy.
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tardbp 3 utr variant in autopsy confirmed frontotemporal lobar degeneration with TDP 43 Proteinopathy
Acta Neuropathologica, 2009Co-Authors: Michael A. Gitcho, Manjari Mishra, Rosa Rademakers, Eileen H Bigio, M.-marsel Mesulam, Sandra Weintraub, Nancy Johnson, Sumi Chakraverty, Carlos Cruchaga, John C. MorrisAbstract:Pathogenic mutations in the gene encoding TDP-43, TARDBP, have been reported in familial amyotrophic lateral sclerosis (FALS) and, more recently, in families with a heterogeneous clinical phenotype including both ALS and frontotemporal lobar degeneration (FTLD). In our previous study, sequencing analyses identified one variant in the 3′-untranslated region (3′-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS. Since that study, brain tissue has become available and provides autopsy confirmation of FTLD-TDP in the proband and ALS in the brother of the bvFTD-ALS family and the neuropathology of those two cases is reported here. The 3′-UTR variant was not found in 982 control subjects (1,964 alleles). To determine the functional significance of this variant, we undertook quantitative gene expression analysis. Allele-specific amplification showed a significant increase of 22% (P < 0.05) in disease-specific allele expression with a twofold increase in total TARDBP mRNA. The segregation of this variant in a family with clinical bvFTD and ALS adds to the spectrum of clinical phenotypes previously associated with TARDBP variants. In summary, TARDBP variants may result in clinically and neuropathologically heterogeneous phenotypes linked by a common molecular pathology called TDP-43 Proteinopathy.
John Q. Trojanowski - One of the best experts on this subject based on the ideXlab platform.
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Selective Motor Neuron Resistance and Recovery in a New Inducible Mouse Model of TDP-43 Proteinopathy
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2016Co-Authors: Krista Spiller, John Q. Trojanowski, Linda K. Kwong, Claudia Cheung, Clark R. Restrepo, Anna Stieber, Virginia M.-y. LeeAbstract:Motor neurons (MNs) are the neuronal class that is principally affected in amyotrophic lateral sclerosis (ALS), but it is widely known that individual motor pools do not succumb to degeneration simultaneously. Because >90% of ALS patients have an accumulation of cytoplasmic TDP-43 aggregates in postmortem brain and spinal cord (SC), it has been suggested that these inclusions in a given population may trigger its death. We investigated seven MN pools in our new inducible rNLS8 transgenic (Tg) mouse model of TDP-43 Proteinopathy and found striking differences in MN responses to TDP-43 pathology. Despite widespread neuronal expression of cytoplasmic human TDP-43, only MNs in the hypoglossal nucleus and the SC are lost after 8 weeks of transgene expression, whereas those in the oculomotor, trigeminal, and facial nuclei are spared. Within the SC, slow MNs survive to end stage, whereas fast fatigable MNs are lost. Correspondingly, axonal dieback occurs first from fast-twitch muscle fibers, whereas slow-twitch fibers remain innervated. Individual pools show differences in the downregulation of endogenous nuclear TDP-43, but this does not fully account for vulnerability to degenerate. After transgene suppression, resistant MNs sprout collaterals to reinnervate previously denervated neuromuscular junctions concurrently with expression of matrix metalloproteinase 9 (MMP-9), a marker of fast MNs. Therefore, although pathological TDP-43 is linked to MN degeneration, the process is not stochastic and mirrors the highly selective patterns of MN degeneration observed in ALS patients. SIGNIFICANCE STATEMENT Because TDP-43 is the major pathological hallmark of amyotrophic lateral sclerosis (ALS), we generated mice in which mutant human TDP-43 expression causes progressive neuron loss. We show that these rNLS8 mice have a pattern of axonal dieback and cell death that mirrors that often observed in human patients. This finding demonstrates the diversity of motor neuron (MN) populations in their response to pathological TDP-43. Furthermore, we demonstrate that resistant MNs are able to compensate for the loss of their more vulnerable counterparts and change their phenotype in the process. These findings are important because using a mouse model that closely models human ALS in both the disease pathology and the pattern of degeneration is critical to studying and eventually treating progressive paralysis in ALS patients.
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TDP-43 pathology in a case of hereditary spastic paraplegia with a NIPA1/SPG6 mutation
Acta Neuropathologica, 2012Co-Authors: Maria Martinez-lage, Laura Molina-porcel, Dana Falcone, Leo Mccluskey, Vivianna M Van Deerlin, John Q. TrojanowskiAbstract:Mutations in NIPA1 (non-imprinted in Prader–Willi/Angelman syndrome) have been described as a cause of autosomal dominant hereditary spastic paraplegia (HSP) known as SPG6 (spastic paraplegia-6). We present the first neuropathological description of a patient with a NIPA1 mutation, and clinical phenotype of complicated HSP with motor neuron disease-like syndrome and cognitive decline. Postmortem examination revealed degeneration of lateral corticospinal tracts and dorsal columns with motor neuron loss. TDP-43 immunostaining showed widespread spinal cord and cerebral skein-like and round neuronal cytoplasmic inclusions. We ruled out NIPA1 mutations in 419 additional cases of motor neuron disease. These findings suggest that hereditary spastic paraplegia due to NIPA1 mutations could represent a TDP-43 Proteinopathy.
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TDP-43 pathology in a case of hereditary spastic paraplegia with a NIPA1 /SPG6 mutation
Acta Neuropathologica, 2012Co-Authors: Maria Martinez-lage, Laura Molina-porcel, Dana Falcone, Leo Mccluskey, Vivianna M Van Deerlin, John Q. TrojanowskiAbstract:Mutations in NIPA1 (non-imprinted in Prader–Willi/Angelman syndrome) have been described as a cause of autosomal dominant hereditary spastic paraplegia (HSP) known as SPG6 (spastic paraplegia-6). We present the first neuropathological description of a patient with a NIPA1 mutation, and clinical phenotype of complicated HSP with motor neuron disease-like syndrome and cognitive decline. Postmortem examination revealed degeneration of lateral corticospinal tracts and dorsal columns with motor neuron loss. TDP-43 immunostaining showed widespread spinal cord and cerebral skein-like and round neuronal cytoplasmic inclusions. We ruled out NIPA1 mutations in 419 additional cases of motor neuron disease. These findings suggest that hereditary spastic paraplegia due to NIPA1 mutations could represent a TDP-43 Proteinopathy.
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Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies.
Neuropathology : official journal of the Japanese Society of Neuropathology, 2010Co-Authors: Felix Geser, Virginia M.-y. Lee, John Q. TrojanowskiAbstract:It is now established that pathological transactive response DNA-binding protein with a Mr of 43 kD (TDP-43) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis is the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (now known as FTLD-TDP). In fact, the discovery of pathological TDP-43 solidified the idea that these disorders are multi-system diseases and this led to the concept of a TDP-43 Proteinopathy as a spectrum of disorders comprised of different clinical and pathological entities extending from ALS to ALS with cognitive impairment/dementia and FTLD-TDP without or with motor neuron disease (FTLD-MND). These align along a broad disease continuum sharing similar pathogenetic mechanisms linked to pathological TDP-43. We here review salient findings in the development of a concept of TDP-43 Proteinopathy as a novel group of neurodegenerative diseases similar in concept to α-synucleinopathies and tauopathies.
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TDP-43 proteinopathies: neurodegenerative protein misfolding diseases without amyloidosis.
Neuro-Signals, 2007Co-Authors: Linda K. Kwong, John Q. Trojanowski, Kunihiro Uryu, Virginia M.-y. LeeAbstract:In this review, we summarize recent advances in understanding frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders that are collectively known as TDP-43 proteinopathies, since transactive response DNA-binding protein 43 (TDP-43) was recently shown to be the major component of the ubiquitinated inclusions that are their pathological hallmarks. TDP-43 proteinopathies are distinct from most other neurodegenerative disorders because TDP-43 inclusions are not amyloid deposits. Besides TDP-43-positive inclusions, both sporadic and familial forms of FTLD and ALS have the pathologic TDP-43 signature of abnormal hyperphosphorylation, ubiquitination and C-terminal fragments in affected brain and spinal cord, suggesting that they share a common mechanism of pathogenesis. Thus, these findings support the concept that FTLD and ALS represent a clinicopathologic spectrum of one disease, that is, TDP-43 Proteinopathy.
Michael A. Gitcho - One of the best experts on this subject based on the ideXlab platform.
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TARDBP 3′-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 Proteinopathy
Acta neuropathologica, 2009Co-Authors: Michael A. Gitcho, Manjari Mishra, Rosa Rademakers, Eileen H Bigio, M.-marsel Mesulam, Sandra Weintraub, Nancy Johnson, Sumi Chakraverty, Carlos Cruchaga, John C. MorrisAbstract:Pathogenic mutations in the gene encoding TDP-43, TARDBP, have been reported in familial amyotrophic lateral sclerosis (FALS) and, more recently, in families with a heterogeneous clinical phenotype including both ALS and frontotemporal lobar degeneration (FTLD). In our previous study, sequencing analyses identified one variant in the 3′-untranslated region (3′-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS. Since that study, brain tissue has become available and provides autopsy confirmation of FTLD-TDP in the proband and ALS in the brother of the bvFTD-ALS family and the neuropathology of those two cases is reported here. The 3′-UTR variant was not found in 982 control subjects (1,964 alleles). To determine the functional significance of this variant, we undertook quantitative gene expression analysis. Allele-specific amplification showed a significant increase of 22% (P < 0.05) in disease-specific allele expression with a twofold increase in total TARDBP mRNA. The segregation of this variant in a family with clinical bvFTD and ALS adds to the spectrum of clinical phenotypes previously associated with TARDBP variants. In summary, TARDBP variants may result in clinically and neuropathologically heterogeneous phenotypes linked by a common molecular pathology called TDP-43 Proteinopathy.
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tardbp 3 utr variant in autopsy confirmed frontotemporal lobar degeneration with TDP 43 Proteinopathy
Acta Neuropathologica, 2009Co-Authors: Michael A. Gitcho, Manjari Mishra, Rosa Rademakers, Eileen H Bigio, M.-marsel Mesulam, Sandra Weintraub, Nancy Johnson, Sumi Chakraverty, Carlos Cruchaga, John C. MorrisAbstract:Pathogenic mutations in the gene encoding TDP-43, TARDBP, have been reported in familial amyotrophic lateral sclerosis (FALS) and, more recently, in families with a heterogeneous clinical phenotype including both ALS and frontotemporal lobar degeneration (FTLD). In our previous study, sequencing analyses identified one variant in the 3′-untranslated region (3′-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS. Since that study, brain tissue has become available and provides autopsy confirmation of FTLD-TDP in the proband and ALS in the brother of the bvFTD-ALS family and the neuropathology of those two cases is reported here. The 3′-UTR variant was not found in 982 control subjects (1,964 alleles). To determine the functional significance of this variant, we undertook quantitative gene expression analysis. Allele-specific amplification showed a significant increase of 22% (P < 0.05) in disease-specific allele expression with a twofold increase in total TARDBP mRNA. The segregation of this variant in a family with clinical bvFTD and ALS adds to the spectrum of clinical phenotypes previously associated with TARDBP variants. In summary, TARDBP variants may result in clinically and neuropathologically heterogeneous phenotypes linked by a common molecular pathology called TDP-43 Proteinopathy.
