We sought to design a data visualization platform to represent the Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS) item scores in an easy-to-use display without ...modification of the raw data or summary scores. Score items for Parts I, II, and IV were arranged as separate inline blocks, while Part III item blocks were arranged in an anatomical fashion. A color scale was created to represent symptom severity and changes observed from one exam to another. We have found the visualization helpful for quickly defining the most troublesome symptoms and their anatomical location enabling communication of the results and interpretations.
Background/Aims: Accurate diagnosis of sporadic early-onset Alzheimer's disease (EOAD) can be challenging, and cerebrospinal fluid (CSF) biomarkers may assist in this process. We compared CSF indices ...between three EOAD subtypes: amnestic, logopenic progressive aphasia (LPA), and posterior cortical atrophy (PCA). Methods: We identified 21 amnestic EOAD, 20 LPA, and 12 PCA patients with CSF data, which included amyloid β1-42 (Aβ42), total tau (t-tau), phospho-tau181 (p-tau), and Aβ42/t-tau index (ATI) levels. Results: Aβ42 and ATI levels were similar across groups, but t-tau and p-tau levels were significantly lower in PCA patients. Conclusions: The Aβ42 and ATI data confirm the commonality of the Aβ pathology in EOAD. The lower tau indices in PCA patients may reflect differences in the distribution of neurofibrillary tangles or rates of neurodegeneration.
Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, ...although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-β peptide, which is derived from proteolysis of the larger amyloid-β precursor protein (βAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of βAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted βAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to βAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of βAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for βAPP mismetabolism in human IBM.
Cell cycle proteins are elevated in the brain of patients and in transgenic models of Alzheimer's disease (AD), suggesting that aberrant cell cycle re-entry plays a key role in this disorder. ...However, the precise relationship between cell cycle reactivation and the hallmarks of AD, amyloid-beta (Abeta) plaques and tau-laden neurofibrillary tangles, remains unclear. We sought to determine whether cell cycle reactivation initiates in direct response to Abeta and tau accumulation or whether it occurs as a downstream consequence of neuronal death pathways. Therefore, we used a triple transgenic mouse model of AD (3xTg-AD) that develops plaques and tangles, but does not exhibit extensive neuronal loss, whereas to model hippocampal neuronal death a tetracycline-regulatable transgenic model of neuronal ablation (CaM/Tet-DT(A) mice) was used. Cell-cycle protein activation was determined in these two models of neurodegeneration, using biochemical and histological approaches. Our findings indicate that Cdk4, PCNA and phospho-Rb are significantly elevated in CaM/Tet-DT(A) mice following neuronal death. In contrast, no significant activation of cell-cycle proteins occurs in 3xTg-AD mice versus non-transgenic controls. Taken together, our data indicate that neuronal cell cycle reactivation is not a prominent feature induced by Abeta or tau pathology, but rather appears to be triggered by acute neuronal loss.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Most cases of autosomal-dominant familial Alzheimer's disease are linked to mutations in the presenilin genes (PS1 and PS2). In addition to modulating β -amyloid production, presenilin mutations also ...produce highly specific and selective alterations in intracellular calcium signaling. Although the molecular mechanisms underlying these changes are not known, one candidate molecular mediator is calsenilin, a recently identified calcium-binding protein that associates with the C terminus of both PS1 and PS2. In this study, we investigated the effects of calsenilin on calcium signaling in Xenopus oocytes expressing either wild-type or mutant PS1. In this system, mutant PS1 potentiated the amplitude of calcium signals evoked by inositol 1,4,5-trisphosphate and also accelerated their rates of decay. We report that calsenilin coexpression reverses both of these potentially pathogenic effects. Notably, expression of calsenilin alone had no discernable effects on calcium signaling, suggesting that calsenilin modulates these signals by a mechanism independent of simple calcium buffering. Our findings further suggest that the effects of presenilin mutations on calcium signaling are likely mediated through the C-terminal domain, a region that has also been implicated in the modulation of β -amyloid production and cell death.
Proteopathic tau seeding predicts tauopathy in vivo Holmes, Brandon B.; Furman, Jennifer L.; Mahan, Thomas E. ...
Proceedings of the National Academy of Sciences - PNAS,
10/2014, Letnik:
111, Številka:
41
Journal Article
Cell cycle proteins are elevated in the brain of patients and in transgenic models of Alzheimer's disease (AD), suggesting that aberrant cell cycle re-entry plays a key role in this disorder. ...However, the precise relationship between cell cycle reactivation and the hallmarks of AD, amyloid- (A) plaques and tau-laden neurofibrillary tangles, remains unclear. We sought to determine whether cell cycle reactivation initiates in direct response to A and tau accumulation or whether it occurs as a downstream consequence of neuronal death pathways. Therefore, we used a triple transgenic mouse model of AD (3xTg-AD) that develops plaques and tangles, but does not exhibit extensive neuronal loss, whereas to model hippocampal neuronal death a tetracycline-regulatable transgenic model of neuronal ablation (CaM/Tet-DT_{A} mice) was used. Cell-cycle protein activation was determined in these two models of neurodegeneration, using biochemical and histological approaches. Our findings indicate that Cdk4, PCNA and phospho-Rb are significantly elevated in CaM/Tet-DT_{A} mice following neuronal death. In contrast, no significant activation of cell-cycle proteins occurs in 3xTg-AD mice versus non-transgenic controls. Taken together, our data indicate that neuronal cell cycle reactivation is not a prominent feature induced by A or tau pathology, but rather appears to be triggered by acute neuronal loss.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, ...although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease.
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