Brain metabolism and brain disease: Is metabolic deficiency the proximate cause of Alzheimer dementia?

The potential of impairments in oxidative/energy metabolism to cause diseas es of the brain had been proposed even before the major pathways of oxidati ve/energy metabolism were described. Deficiencies associated with disease a re known in all the pathways of oxidative/energy metabolism and are associa ted with some of the most common disorders of the nervous system, including Alzheimer's disease (AD) and Parkinson's disease. A common mechanism in th ese conditions appears to be a downward mitochondrial spiral, involving abn ormalities in energy metabolism, calcium metabolism, and free radicals (rea ctive oxygen and nitrogen species). In AD, the spiral appears to interact w ith abnormalities in the metabolism of the Alzheimer amyloid precursor prot ein (APP) and its A beta fragment. Several lines of evidence indicate that the mitochondrial spiral may be a proximate cause of the clinical disabilit ies in AD. Decreases in cerebral metabolic rate (CMR) characteristically oc cur in AD and in other dementias. Inducing decreases in CMR leads to clinic al disabilities characteristically associated with AD and with analogous pr oblems in experimental animals. Treatments directed toward normalizing CMR appear to help at least some patients. Further studies of this possibility and of treatments designed to ameliorate the mitochondrial spiral may prove useful for treating AD and perhaps some other dementing disorders. (C) 200 1 Wiley-Liss, Inc.