Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Percutaneous endoscopic gastrostomy (PEG) is an enteral nutritional assistance technique using a simple device compatible with conventional feeding and thus enabling the patient to be integrated into his or her social and familial surroundings. This inexpensive device is quickly and easily inserted under local anaesthesia. It causes little morbidity and virtually no mortality and has many advantages for patients with amyotrophic lateral sclerosis (ALS). We report the results of PEG in 28 ALS patients with bulbar involvement. Three of these patients developed minor complications during 6 consecutive months of PEG-assisted nutrition (2 had periostomial infection, 1 had mild haematemesis). There were no major complications, and mortality directly ascribable to PEG was nil. All patients put on weight or had their weight stabilized, and GEP was well accepted in all cases.
 ...
PMID:[Role of percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis]. 190 69

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease classically defined by the impairment of the voluntary motor system and ubiquitin-positive intraneuronal aggregates in anterior horn cells. Frontotemporal dementia (FTD) is a common form of neurodegenerative dementia and presents with personality change associated in a significant subgroup of patients with cortical ubiquitin-only neuropathology (FTD-U). Careful study of ALS as well as FTD patient cohorts suggests clinical as well as pathological overlap of ALS with FTD. The idea that this reflects a shared pathogenesis has received strong support from the identification of new genetic loci on chromosome 9p and of mutations in specific genes (CHMP2B and DCN1) in families with co-segregation of ALS and FTD. The identification of two further genetic causes of FTD-U with (rare) ALS (PGRN) or without ALS (VCP) also provides a starting point for exploring the pathways associated with ubiquitin-mediated protein mishandling in FTD-U and ALS. Pure ALS, through ALS with cognitive impairment and ALS-FTD to pure FTD-U, may represent a continuous spectrum of ubiquitin-associated neurodegenerative disease.
 ...
PMID:Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease. 1698 82

The diagnosis of degenerative dementias heavily relies on the identification of neuronal or glial inclusions. Tauopathy is probably the largest group including Alzheimer and Pick disease, mutation of the tau gene, progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease. Lewy bodies, when numerous in the cerebral cortex, are usually associated with the cognitive deficit of Parkinson disease dementia or of dementia with Lewy bodies--both conditions being distinguished by clinical information. The inclusions of the dentate gyrus, only labeled by anti-ubiquitin antibodies, isolate a subgroup of fronto-temporal dementia (FTDu), sometimes familial and sometimes associated with amyotrophic lateral sclerosis. Mutations of the progranulin gene have been recently discovered among a significant proportion of these patients. Neuronal Intermediate Filament Inclusion Disease (NIFID) is a rare, apparently sporadic dementia, characterized by the presence of large inclusions in the cell body of many neurons. These inclusions react with antibodies directed against neurofilaments or against other intermediate filaments (such as alpha-internexin). The diagnostic value of some of these inclusions allowing the classification of the degenerative dementias has been discussed. The link between the inclusions and the pathogenetic mechanism is indeed probably variable. It should however be stressed that whenever their composition has been elucidated, the inclusions have given important clues to the pathogenesis of the disease in which they had been found.
 ...
PMID:[Nosology of dementias: the neuropathologist's point of view]. 1702 59

Work done over the past decade has led to a molecular understanding of frontotemporal lobar degeneration (FTLD), a deadly disease that afflicts patients in mid-life. It is a common cause of dementia, second only to Alzheimer's disease in the population below 65 years of age. Neuroanatomical and neurobiological substrates have been identified for the three major subtypes of FTLD and these discoveries have broadened the FTLD spectrum to include amyotrophic lateral sclerosis (ALS). Mutations in MAPT were found to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), a familial disorder with filamentous tau inclusions in nerve cells and glial cells. FTDP-17 can result in clinical syndromes that closely resemble progressive supranuclear palsy, corticobasal degeneration and Pick's disease. More recently, mutations in three genes (VCP, CHMP2B and PGRN) have been found to cause FTLD with ubiquitin-positive, tau-negative neuronal inclusions (FTLD-U). They explain a large proportion of inherited FTLD-U. It remains to be seen whether dementia lacking distinctive histopathology (DLDH) constitutes a third disease category, as many of these cases are now being reclassified as FTLD-U. Recently, TAR DNA-binding protein-43 (TDP-43) has been identified as a key protein of the ubiquitin inclusions of FTLD-U and ALS. Thus, for familial forms of FTLD and related disorders, we now know the primary etiologies and accumulating proteins. These findings are pivotal for dissecting the pathways by which different etiologies lead to the varied clinicopathological presentations of FTLD.
 ...
PMID:Frontotemporal lobar degeneration: current concepts in the light of recent advances. 1749 44

Frontotemporal lobar degeneration (FTLD) is a common form of dementia that usually afflicts patients in their mid-life. Clinically, patients with FTLD present with changes in behavior and/or language dysfunction. According to their underlying neuropathological substrate, these neurodegenerative conditions can now be classified into two main groups: those with tau pathology (tauopathies), and those without tau pathology. In the majority of nontauopathy disorders the recently identified TAR DNA-binding protein-43 (TDP-43) is found as the major inclusion protein (TDP-43 proteinopathies), and TDP-43 is also present in motor neuron inclusions of amyotrophic lateral sclerosis. Presently, mutations in 4 genes (MAPT, PGRN, VCP, CHMP2B) are known to cause diverse types of FTLD pathology. Here, we summarize the recent neuropathological and genetic advances in FTLD research.
 ...
PMID:Pathology and genetics of frontotemporal lobar degeneration: an update. 1770 95

The clinical disorders associated with frontotemporal lobar degeneration (FTLD) are increasingly recognized as an important cause of early-onset dementia. Patients usually present with progressive changes in personality, behavior, or language, progressing to general cognitive impairment and ultimately death. In the past decade, improved clinical and histopathologic characterization uncovered extensive heterogeneity, and multiple clinical and pathologic FTLD subtypes were defined. Simultaneously, the discovery of four causal FTLD genes emphasized the genetic complexity associated with FTLD. More recently, the field of FTLD has gained increased attention as a result of two major findings. First, mutations in the progranulin gene (PGRN) were recognized as a major cause of FTLD with ubiquitin-positive and tau-negative inclusions (FTLD-U), and subsequently the TAR DNA-binding protein-43 (TDP-43) was identified as a key protein within the ubiquitinated inclusions in FTLD-U and amyotrophic lateral sclerosis (ALS). In this report, we outline the progress made in the study of the genetic etiologies and neuropathologic substrates in FTLD.
 ...
PMID:The genetics of frontotemporal lobar degeneration. 1776 35

TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene (PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate approximately 35 and approximately 25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.
 ...
PMID:Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. 1789 24

The high incidence of amyotrophic lateral sclerosis (ALS) in the residents of Hohara and Kozagawa in the Kii peninsula was reported to have disappeared by early 1980 with its etiology unsolved. However, we found continuous high incidence in Hohara that was neuropathologically characterized by ALS pathology associated with many neurofibrillar tangles (NFTs) similar to Guam ALS. We confirmed existence of neuropathologically-verified parkinsonism-dementia complex (PDC) identical to Guamanian PDC clinically and neuropathologically. The core clinical features consisted of motor neuron signs, parkinsonism and dementia, and patients presented with clinical manifestations of ALS, PDC or PDC followed by ALS. PDC predominated over ALS in incidence. Approximately 70% of patients had family history of ALS/PDC. Neuropathological findings of 12 cases revealed that they were very similar to each others, consisting of many NFTs, no or scanty amyloid plaques, and ALS pathology affecting the upper and lower motor neurons. These findings suggest that ALS and PDC may be different clinical manifestations of a single entity "ALS-parkinsonism-dementia complex". TDP-43 positive inclusions were seen in the neurons of the dentate gyrus and spinal cord in all 6 cases examined. A comparison of age-adjusted prevalence rates in 1967 and 1998 revealed moderate decline of ALS and marked increase of PDC in the latter. The age-adjusted 5-year average incidence rates during 1950 and 2000 showed gradual decline of ALS for 50 years and dramatic increase of PDC after 1990. These findings suggest that the clinical manifestations may have changed in Kii ALS/PDC as in ALS/PDC on Guam, partly because of rapid aging of the population. Gene analyses have so far failed to demonstrate mutations of SOD1, parkin, alpha-synuclein, tau, progranulin, TDP-43 and other genes related to dementia, parkinsonism and motor neuron disease. There have been no differences in drinking water and food between the residents in the high incidence area and those in the neighboring low incidence areas, and none of the patients had habits of eating the cycad, flying fox or any other odd materials. These findings suggest that genetic factors may be etiologically primary and environmental factors may modify the clinical phenotypes.
 ...
PMID:[Revisit to Kii ALS--the innovated concept of ALS-Parkinsonism-dementia complex, clinicopathological features, epidemiology and etiology]. 1796 46

Pathologic TAR-DNA-binding protein 43 (TDP-43) is a disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. We studied the presence, frequency, and distribution of TDP-43 pathology by immunohistochemistry and biochemistry in a series of clinically well-characterized tauopathy patient brains, including 182 Alzheimer disease (AD), 39 corticobasal degeneration, 77 progressive supranuclear palsy, and 12 Pick disease cases and investigated the clinical impact of concomitant TDP-43 pathology in these cases. TAR-DNA-binding protein 43 pathology was found in 25.8% of AD cases. It was restricted to the dentate gyrus and entorhinal cortex in approximately 75% of cases; approximately 25% showed more widespread TDP-43 pathology in frontal and temporal cortices, resembling the FTLD-U subtype associated with progranulin mutations. TAR-DNA-binding protein 43 pathology in AD was associated with significantly longer disease duration, but there was no association with the clinical presentation (148 cases diagnosed as AD and 34 cases diagnosed as frontotemporal lobar degeneration). Progressive supranuclear palsy and Pick disease cases showed no TDP-43 inclusions and no biochemical alterations of TDP-43. There was, however, a unique, predominantly glial TDP-43 pathology with staining of astrocytic plaque-like structures and coiled bodies in 15.4% of corticobasal degeneration cases; this was associated with biochemical TDP-43 changes similar to those in FTLD-U. These findings provide further insight into the burden and clinical significance of TDP-43 pathology in disorders other than FTLD-U and amyotrophic lateral sclerosis.
 ...
PMID:Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. 1852 Jul 74

Major discoveries have been made in the recent past in the genetics, biochemistry and neuropathology of frontotemporal lobar degeneration (FTLD). TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the major pathological protein of FTLD with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Recently, mutations in the TARDBP gene in familial and sporadic ALS have been reported which demonstrate that abnormal TDP-43 alone is sufficient to cause neurodegeneration. Several familial cases of FTLD-U, however, are now known to have mutations in the progranulin (GRN) gene, but granulin is not a component of the TDP-43- and ub-ir inclusions. Further, TDP-43 is found to be a component of the inclusions of an increasing number of neurodegenerative diseases. Other FTLD-U entities with TDP-43 proteinopathy include: FTLD-U with valosin-containing protein (VCP) gene mutation and FTLD with ALS linked to chromosome 9p. In contrast, chromosome 3-linked dementia, FTLD-U with chromatin modifying protein 2B (CHMP2B) mutation, has ub-ir, TDP-43-negative inclusions. In summary, recent discoveries have generated new insights into the pathogenesis of a spectrum of disorders called TDP-43 proteinopathies including: FTLD-U, FTLD-U with ALS, ALS, and a broadening spectrum of other disorders. It is anticipated that these discoveries and a revised nosology of FTLD will contribute toward an accurate diagnosis, and facilitate the development of new diagnostic tests and therapeutics.
 ...
PMID:ALS and FTLD: two faces of TDP-43 proteinopathy. 1868 9


1 2 3 4 5 6 7 8 Next >>