Articles: amyotrophic-lateral-sclerosis-pathology.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive death of motor neurons. Although the pathogenesis of ALS remains unclear, several cellular processes are known to be involved, including apoptosis. A previous study revealed the apoptosis-related gene c-Abl to be upregulated in sporadic ALS motor neurons. ⋯ The present results suggest that c-Abl is a potential therapeutic target for ALS and that the c-Abl inhibitor dasatinib has neuroprotective properties in vitro and in vivo.
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Using clinical information, it was investigated whether lesions in sporadic amyotrophic lateral sclerosis (sALS) spread contiguously from an onset site to the another regions in domino-like manner as hypothesized by prion-like propagation of pathogenic proteins. First, the data from medical records of 53 sALS patients with bulbar or lower limb onset showed that the symptom has noncontiguously spread from the bulbar region to the lower limbs or vice versa, skipping the upper limbs, in 18.9% of the patients. ⋯ The two parameters should be positively correlated, if the lesion propagates contiguously from an initially affected motoneuron to the neighbouring ones within the same motoneuron pool (local progression) and then propagates to the another motoneuron pools (regional spread). However, the statistically significant correlation was not found, suggesting that there may be the different mechanisms between local progression and regional spread of ALS lesions.
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Amyotrophic lateral sclerosis as a system failure is a concept supported by the finding of consistent extramotor as well as motor cerebral pathology. The functional correlates of the structural changes detected using advanced magnetic resonance imaging techniques such as diffusion tensor imaging and voxel-based morphometry have not been extensively studied. A group of 25 patients with amyotrophic lateral sclerosis was compared to healthy control subjects using a multi-modal neuroimaging approach comprising T(1)-weighted, diffusion-weighted and resting-state functional magnetic resonance imaging. ⋯ An integrated structural and functional connectivity approach therefore identified apparently dichotomous processes characterizing the amyotrophic lateral sclerosis cerebral network failure, in which there was increased functional connectivity within regions of decreased structural connectivity. Patients with slower rates of disease progression showed connectivity measures with values closer to healthy controls, raising the possibility that functional connectivity increases might not simply represent a physiological compensation to reduced structural integrity. One alternative possibility is that increased functional connectivity reflects a progressive loss of inhibitory cortical influence as part of amyotrophic lateral sclerosis pathogenesis, which might then have relevance to future therapeutic strategies.
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Acta neuropathologica · Dec 2011
Comparative StudyClinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72.
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. ⋯ 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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FDG-PET in ALS most typically demonstrates a primary (and sometimes also supplementary) motor cortex hypometabolism, often associated with more diffuse cortical hypometabolism involving mostly the dorsolateral prefrontal cortex, the medial and lateral premotor cortices, and the bilateral insular cortex involvement. In ALS-FTD, extensive temporal hypometabolism is seen in addition to severe diffuse frontal hypometabolism. ⋯ In ALS, more diffuse frontal and temporal FDG-PET hypometabolism was seen than earlier reported, with the anterolateral area as the best preserved part of the frontal lobe. In ALS-FTD, relatively preserved perirolandic metabolism was seen, associated with severe frontal and temporal hypometabolism.