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Sporadic AD (sporadic + ad)
Selected AbstractsA, aggregation and possible implications in Alzheimer's disease pathogenesisJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2009Prashant R. Bharadwaj ,,Introduction ,,Amyloid Structure ,,Mechanism of Amyloid aggregation ,,A,: a natively unfolded protein? ,,Ambiguities in synthetic Ab studies ,,Formation of Amyloid plaques ,,Role of Ab in AD Pathogenesis ,,Conclusion Abstract Amyloid , protein (A,) has been associated with Alzheimer's disease (AD) because it is a major component of the extracellular plaque found in AD brains. Increased A, levels correlate with the cognitive decline observed in AD. Sporadic AD cases are thought to be chiefly associated with lack of A, clearance from the brain, unlike familial AD which shows increased A, production. A, aggregation leading to deposition is an essential event in AD. However, the factors involved in A, aggregation and accumulation in sporadic AD have not been completely characterized. This review summarizes studies that have examined the factors that affect A, aggregation and toxicity. By necessity these are studies that are performed with recombinant-derived or chemically synthesized A,. The studies therefore are not done in animals but in cell culture, which includes neuronal cells, other mammalian cells and, in some cases, non-mammalian cells that also appear susceptible to A, toxicity. An understanding of A, oligomerization may lead to better strategies to prevent AD. [source] Design and Implementation of a Multicenter Trial of Vitamin E in Aging Individuals with Down SyndromeJOURNAL OF POLICY AND PRACTICE IN INTELLECTUAL DISABILITIES, Issue 2 2005Paul S. Aisen Abstract, Older individuals with Down syndrome have an extremely high risk of Alzheimer's disease (AD). Advances in understanding the pathophysiology of AD, and the development of effective therapies for individuals with sporadic AD, have raised the possibility that aging Down syndrome individuals may benefit from therapy directed against AD. As no prior large clinical trials had been conducted with this population, the authors launched "A Multicenter Trial of Vitamin E in Aging Individuals with Down Syndrome." The authors describe how they assembled an international group of investigators to develop the infrastructure and methodology for studying the efficacy of therapeutic interventions aimed at slowing the process of AD in Down syndrome. The process of designing and implementing the trial drew together clinical scientists and clinicians from two distinct but overlapping areas: researchers in the areas of Down syndrome and AD therapeutics. The authors review the issues considered and decisions made regarding various aspects of the trial design. [source] Does Alzheimer's disease begin in the brainstem?NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 6 2009G. Simic Although substantial evidence indicates that the progression of pathological changes of the neuronal cytoskeleton is crucial in determining the severity of dementia in Alzheimer's disease (AD), the exact causes and evolution of these changes, the initial site at which they begin, and the neuronal susceptibility levels for their development are poorly understood. The current clinical criteria for diagnosis of AD are focused mostly on cognitive deficits produced by dysfunction of hippocampal and high-order neocortical areas, whereas noncognitive, behavioural and psychological symptoms of dementia such as disturbances in mood, emotion, appetite, and wake,sleep cycle, confusion, agitation and depression have been less considered. The early occurrence of these symptoms suggests brainstem involvement, and more specifically of the serotonergic nuclei. In spite of the fact that the Braak and Braak staging system and National Institutes of Aging , Reagan Institute (NIA-RI) criteria do not include their evaluation, several recent reports drew attention to the possibility of selective and early involvement of raphe nuclei, particularly the dorsal raphe nucleus (DRN), in the pathogenesis of AD. Based on these findings of differential susceptibility and anatomical connectivity, a novel pathogenetic scheme of AD progression was proposed. Although the precise mechanisms of neurofibrillary degeneration still await elucidation, we speculated that cumulative oxidative damage may be the main cause of DRN alterations, as the age is the main risk factor for sporadic AD. Within such a framework, ,-amyloid production is considered only as one of the factors (although a significant one in familial cases) that promotes molecular series of events underlying AD-related neuropathological changes. [source] Return of the cycad hypothesis , does the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health?NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2005P. G. Ince Recently published work provides evidence in support of the cycad hypothesis for Lytico,Bodig, the Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC), based on a new understanding of Chamorro food practices, a cyanobacterial origin of ,-methylaminoalanine (BMAA) in cycad tissue, and a possible mechanism of biomagnification of this neurotoxic amino acid in the food chain. BMAA is one of two cycad chemicals with known neurotoxic properties (the other is cycasin, a proven developmental neurotoxin) among the many substances that exist in these highly poisonous plants, the seeds of which are used by Chamorros for food and medicine. The traditional diet includes the fruit bat, a species that feeds on cycad seed components and reportedly bioaccumulates BMAA. Plant and animal proteins provide a previously unrecognized reservoir for the slow release of this toxin. BMAA is reported in the brain tissue of Guam patients and early data suggest that some Northern American patients dying of Alzheimer's disease (AD) have detectable brain levels of BMAA. The possible role of cyanobacterial toxicity in sporadic neurodegenerative disease is therefore worthy of consideration. Recent neuropathology studies of ALS/PDC confirm understanding of this disorder as a ,tangle' disease, based on variable anatomical burden, and showing biochemical characteristics of ,AD-like' combined 3R and 4R tau species. This model mirrors the emerging view that other neurodegenerative disease spectra comprise clusters of related syndromes, owing to common molecular pathology, with variable anatomical distribution in the nervous system giving rise to different clinical phenotypes. Evidence for ,ubiquitin-only' inclusions in ALS/PDC is weak. Similarly, although there is evidence for ,-synucleinopathy in ALS/PDC, the parkinsonian component of the disease is not caused by Lewy body disease. The spectrum of sporadic AD includes involvement of the substantia nigra and a high prevalence of ,incidental',-synucleinopathy in sporadic AD is reported. Therefore the pathogenesis of Lytico,Bodig appears still to have most pertinence to the ongoing investigation of the pathogenesis of AD and other tauopathies. [source] Cyanobacterial neurotoxin BMAA in ALS and Alzheimer's diseaseACTA NEUROLOGICA SCANDINAVICA, Issue 4 2009J. Pablo Objective,,, The aim of this study was to screen for and quantify the neurotoxic amino acid ,- N -methylamino- l -alanine (BMAA) in a cohort of autopsy specimens taken from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and non-neurological controls. BMAA is produced by cyanobacteria found in a variety of freshwater, marine, and terrestrial habitats. The possibility of geographically broad human exposure to BMAA had been suggested by the discovery of BMAA in brain tissues of Chamorro patients with ALS/Parkinsonism dementia complex from Guam and more recently in AD patients from North America. These observations warranted an independent study of possible BMAA exposures outside of the Guam ecosystem. Methods,,, Postmortem brain specimens were taken from neuropathologically confirmed cases of 13 ALS, 12 AD, 8 HD patients, and 12 age-matched non-neurological controls. BMAA was quantified using a validated fluorescent HPLC method previously used to detect BMAA in patients from Guam. Tandem mass spectrometric (MS) analysis was carried out to confirm the identification of BMAA in neurological specimens. Results,,, We detected and quantified BMAA in neuroproteins from postmortem brain tissue of patients from the United States who died with sporadic AD and ALS but not HD. Incidental detections observed in two out of the 24 regions were analyzed from the controls. The concentrations of BMAA were below what had been reported previously in Chamarro ALS/ Parkinsonism dementia complex patients, but demonstrated a twofold range across disease and regional brain area comparisons. The presence of BMAA in these patients was confirmed by triple quadrupole liquid chromatography/mass spectrometry/mass spectrometry. Conclusions,,, The occurrence of BMAA in North American ALS and AD patients suggests the possibility of a gene/environment interaction, with BMAA triggering neurodegeneration in vulnerable individuals. [source] | ||||||||||