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Published online 12 November 2008 | Nature | doi:10.1038/456161a
Neuroscience: The plaque plan
Neuroscientists are pretty sure they know what causes Alzheimer's disease, but their theory has not yet given rise to effective drugs. Alison Abbott asks what's wrong.
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Not a single sentence in this article mentions what likely is the root cause of most neurodegenerative disorders, including AD: cerebral hypoperfusion. Alois himself commented on the nature and pathology of blood vessels in AD more than 100 years ago. However, rather than being secondary to the "neurocentric" view of AD, an inexorable decline in adequate cerebral perfusion could explain the defect in proper Abeta clearance as well as poor neuronal function. It is time for a more "vascular-centric" outlook on AD and other ND disorders.
The pessimistic tendency in this article towards both the diagnostic potential of modern biomarkers and current treatment trials have not been confirmed by recent publications. Data fusion of different modern biomarkers (both CSF and MRI) have been shown to reduce the diagnostic error to less than 6.9% (CM Clark et al, Neurosignals 2008;16:11-8). Whereas several unsuccessful Alzheimer therapy trials are cited, no mention is given to positive results of others, e.g., a randomized controlled trial of the non-selective antihistamine dimebon in 183 subjects (RS Doody et al, Lancet 2008;372:207-15). Another placebo-controlled double-blind trial in 332 patients from the UK and Singapore used methylthioninium chloride (RemberTM), that after 24 weeks (60mg 3x/day) showed significant efficacy in modest AD and a 50 week stabilization of disease progression (CM Wischik, ICAD, Chicago, July 2008). The substance acts as a tau aggregation inhibitor in a cellular model and reversed tau pathology in tg models of AD (Harrington et al, ICAD, Chicago, July 2008). It is time for a more optimistic outlook on the diagnosis and therapy of AD.
Aging- and chronical diseases- associated protein modification may have a universal mechanisms -- oxidative/carbonyl stresses. For a general resolution of such aging-related protein accumulation, one may recommented to a review paper published on "Free Radic Biol Med" 1996,21; 871-888, entitled "Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores." Dazhong Yin