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

Ubiquitinated cytoplasmic inclusions (Ub-CIs) in superficial frontal cortex and dentate gyrus neurons are the hallmark of frontotemporal degeneration of the motor neuron disease-type (FTD-MND-type). To date, 2 reports have described intranuclear ubiquitinated inclusions (Ub-INIs) in 9 cases of familial FTD-MND-type (without clinical or pathologic motor neuron disease, MND). In the current study we found an additional 11 cases with Ub-INIs. We have identified for the first time among these cases 2 with a negative family history and 3 that have concomitant amyotrophic lateral sclerosis (ALS). The results of the present study i) confirm a previous report of significantly lower average brain weight and longer duration in cases with Ub-INIs, ii) reveal significantly greater striatal neuronal loss and gliosis in cases with intranuclear inclusions, and iii) demonstrate that intranuclear inclusions correlate with cytoplasmic inclusions and dystrophic neurites in frontal cortex and striatum but not in dentate gyrus. In addition, the current study confirms that Ub-INIs are found in familial FTD-MND-type, but also extends the presence of Ub-INIs to familial FTD-MND (with concomitant ALS), and probably also to non-familial FTD-MND-type.
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PMID:Neuronal ubiquitinated intranuclear inclusions in familial and non-familial frontotemporal dementia of the motor neuron disease type associated with amyotrophic lateral sclerosis. 1533 Mar 35

There is increasing recognition of a clinical overlap between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Recent advances in our understanding of the neuropathologic, biochemical, and genetic basis of these conditions provides evidence for a common underlying pathogenesis. The neuropathology in most cases of FTD with ALS is a subtype of frontotemporal lobar degeneration, characterized by neuronal inclusions that are immunoreactive for ubiquitin but not tau (frontotemporal lobar degeneration with ubiquitinated inclusions). These cases show significant pathologic overlap with clinically pure FTD and those with classic ALS. Moreover, the ubiquitinated pathologic protein in all these conditions has recently been identified as TDP-43. A number of families have been reported with autosomal dominant FTD-ALS linked to chromosome 9p and these also have TDP-43-positive frontotemporal lobar degeneration with ubiquitinated inclusions pathology. Together, these findings suggest that FTD-ALS is part of a clinicopathologic spectrum of disease, now identified as TDP-43 proteinopathies.
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PMID:The neuropathology of FTD associated With ALS. 1809 Apr 23

We describe a case of late onset neurodegeneration with brain iron accumulation (NBIA) presenting as frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS). A male patient presented at age 66 with change of personality: disinhibition, emotional blunting, and socially inappropriate behavior, coupled with dysarthria, dystonia, and corticospinal tract involvement. Magnetic resonance imaging showed general cortical atrophy, iron deposits in the globus pallidus, and the "eye of the tiger" sign. Neuropsychologic performance was globally reduced, especially executive functions. Fluorodeoxyglucose positron emission tomography showed hypometabolism predominantly in frontal and temporal areas. Repeated neurophysiologic examinations showed signs of chronic denervation. The patient was diagnosed with NBIA but fulfilled consensus criteria for FTD and had a clinical picture of ALS, without neurophysiologic confirmation. Our finding introduces NBIA as a possible cause of FTD and as a differential diagnosis of the FTD-ALS complex.
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PMID:Frontotemporal dementia-amyotrophic lateral sclerosis complex is simulated by neurodegeneration with brain iron accumulation. 1956 52

Frontotemporal dementia (FTD) is a progressive neurological condition caused by degeneration of the frontal and/or anterior temporal lobes resulting in personality, behavioral, and cognitive changes. Amyotrophic lateral sclerosis (ALS) is caused by degeneration of lower motor and pyramidal neurons, leading to loss of voluntary muscle movement. The common molecular pathological and anatomical overlaps between FTD and ALS suggest that the two disorders are strongly linked. In some patients FTD precedes ALS; in others ALS occurs first, while in still others the two disorders begin simultaneously. The association between ALS and FTD creates unique challenges for family caregivers. This paper provides a guide for healthcare providers caring for patients with FTD-ALS exhibiting behavioral, cognitive, and emotional symptoms. Strategies are suggested to help minimize the impact of negative symptoms.
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PMID:Cognitive and behavioral challenges in caring for patients with frontotemporal dementia and amyotrophic lateral sclerosis. 2022 5

Frontotemporal dementia (FTD) is an important cause of non-Alzheimer's dementia and is the second most common cause of young onset dementia. FTD presents with progressive changes in behavior and personality (behavioral variant FTD) or language deficits (also known as primary progressive aphasia), although both commonly coexist. Patients with progressive aphasia are subclassified according to the pattern of language deficits into those with progressive non-fluent aphasia (PNFA) and semantic dementia (SD). FTD is pathologically heterogeneous, both macroscopically and on a molecular level, with tau positive, TDP-43 positive, and FUS positive intraneuronal inclusions recognized on immunohistochemical analysis. TDP-43 positive inclusions are also a feature of amyotrophic lateral sclerosis pathology, corroborating the observation of overlapping clinical features between the two conditions and reaffirming the FTD-ALS disease spectrum. Most FTD cases are sporadic, but an important minority is inherited in an autosomal dominant fashion, most commonly due to MAPT or progranulin gene mutations. Familial clusters of FTD and amyotrophic lateral sclerosis are also recognized but poorly understood. This paper reviews the clinical phenotypes, assessment and treatment of FTD in light of recent pathological and genetic discoveries.
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PMID:From FUS to Fibs: what's new in frontotemporal dementia? 2041 82

Frontotemporal dementia (FTD) is a clinical entity that comprises at least two distinct diseases: Pick's disease with Pick bodies and frontotemporal lobar degeneration with tau-negative and ubiquitin-positive inclusions (FTLD-U). FTLD-U is now usually referred to as FTLD-TAR DNA binding protein 43 (TDP-43). FTLD-TDP-43, but not Pick's disease with tau-positive Pick bodies, is often associated with motor neuron disease (MND). More than 200 cases of this combined form, i.e., FTD-MND, have been reported in Japan. The neuropathological characteristics of MND in patients with FTD are essentially similar to the MND in patients without dementia. However the other characteristics of the combination of FTD and MND are such that the author has considered this disease a unique clinicopathological entity. These characteristics are as follows: (1) frontotemporal lobe-type dementia with insidious onset, usually in the presenile period; (2) neurogenic muscular wasting during the course of the illness [amyotrophic lateral sclerosis (ALS)]-- or [spinal progressive muscular atrophy (SPMA)]-like symptoms); (3) duration from the onset of illness to death is 2-5 years (average duration, 30.6 months); (4) both extrapyramidal symptoms and definite sensory deficiency are less commonly observed; (5) no characteristic abnormalities in the cerebrospinal fluid (CSF) or on the electroencephalogram (EEG) in screening tests; (6) no known parental consanguinity or familial occurrence; and (7) nonspecific mild-to-slight degenerative changes in the frontotemporal cortex, hypoglossal nuclei, spinal cord, and frequently in the substantia nigra. FTD-MND is characterized by ubiquitin-immunoreactive intraneuronal inclusions in cortical layers II and III and the hippocampal dentate granule cells. The occurrence of ubiquitin-positive, tau-negative and ubiquitinated TDP-43 positive inclusions could be the key to determining the pathological background of this disease. Further studies are required clinicopathological differentiation between FTD-MND and ALS-dementia (ALS-D).
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PMID:[Yuasa-Mitsuyama disease]. 2130 Oct 35

Sixty cases of frontotemporal lobar degeneration (FTLD) were collected over 22 years. Brain weight was negatively correlated with disease duration. The neuronal and/or glial inclusions were labeled by anti-TDP, anti-FUS or anti-TAU antibodies, respectively, in 40, 3 and 12 cases. In the FTLD-TDP group, mutation of the progranulin gene was found in four cases (FTD-GRN), with nuclear, cat eye inclusions and severe neuronal loss in CA1 and subiculum. The motor neurons were involved in 27 cases (fronto-temporal dementia with amyotrophic lateral sclerosis = FTD-ALS). Familial FTD-ALS cases lived longer than sporadic ones. In nine cases, there was no ALS, no GRN mutation (FTD-NAP). The cases in the FTD-ALS and FTD-NAP subgroups were of Sampathu type 2 (TDP-positive inclusions located mostly in cell bodies and short neurites) with the exception of five cases which belonged to type 1 (long TDP-positive neurites in the superficial layers of the cortex). All of the FTLD-FUS of this series cases were affected by neuronal intermediate filament inclusion disease (NIFID). They were young. The survival was short. In the FTLD-tau group, mutations P301P (previously not recognized as pathogenic), P301L and S305N were identified. Pick disease (n = 5) appeared as a homogeneous sporadic disorder. The current nomenclature allows the neuropathological classification of nearly all the cases of FTD. The prevalence of the different types of FTD is tightly linked to the recruitment. This series was enriched in motor neuron disease (explaining the overall predominance of type 2 TDP inclusions).
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PMID:Fronto-temporal lobar degeneration: neuropathology in 60 cases. 2154 71

Investigate how the subventricular proliferation and organisation is modified in a patient with FTLD-ALS. We studied the subventricular zone (SVZ) of a patient with FTLD-ALS immunohistochemical and histologically. We found an increase of Ki-67 positive cells and neuroblast in the subventricular zone, suggesting an activation of proliferating activity in response to FTD-ALS. This proliferation can act as a compensatory mechanism for rapid neuronal death and its modulation could provide a new therapeutic pathway in ALS. These results suggest a modification of neurogenesis in FTD-ALS.
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PMID:Subventricular zone in motor neuron disease with frontotemporal dementia. 2161 25

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer-type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer-type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and the presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but also within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72.
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PMID:Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. 2243 Feb 53

In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 frontotemporal lobar degeneration (FTLD) patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-frontotemporal dementia (FTD) and 2 FTD-amyotrophic lateral sclerosis [ALS]) out of 53 patients and 1 neurologically normal control. Interestingly, 2 of the C9ORF72 expansion carriers also carried 2 novel missense mutations in GRN (Y294C) and in PSEN-2(I146V). Further, 1 of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TAR (trans-activation response) DNA-binding protein (TDP)-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD, or FTD-ALS and occasional comorbid conditions such as Alzheimer's disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples.
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PMID:Screening for C9ORF72 repeat expansion in FTLD. 2245 98


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