Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases.

Age-related neurodegenerative diseases are associated with mild impairment of oxidative metabolism and accumulation of abnormal proteins. Within the cell, the mitochondria appears to be a dominant site for initiation and propagation of disease processes. Shifts in metabolism in response to mild metabolic perturbations may decrease the threshold for irreversible injury in response to ordinarily sublethal metabolic insults.

A new approach to treating Alzheimer's disease.

It is rational to try to normalize changes that correlate with the severity of the clinical disabilities in Alzheimer's disease (AD) rather than focusing on other of the many abnormalities in end-stage AD brain that relate only theoretically to the clinical manifestations. The neurobiological measure that correlates most closely to the degree of cognitive deterioration is reduction in cerebral metabolic rate. An attempt to treat this abnormality in AD patients is described; it is based, in part, on metabolic control theory.

Admission C-reactive protein does not predict functional outcomes in patients with strokes in a subacute rehabilitation unit.

Objective: Because serum C-reactive protein (CRP) levels correlate with the extent of inflammatory reactions, including acute strokes, we tested whether serum CRP levels on admission to a stroke rehabilitation unit help to predict functional outcome at discharge.

Design: We measured serum CRP level within 72 hrs of admission to an inpatient stroke rehabilitation unit in 102 successive patients transferred to rehabilitation within 4 wks following stroke and who met inclusion criteria.

Results: Patients with normal levels of serum CRP (< or =9.

Increased levels of gamma-glutamylamines in Huntington disease CSF.

Transglutaminases (TGases) catalyze several reactions with protein substrates, including formation of gamma-glutamyl-epsilon-lysine cross-links and gamma-glutamylpolyamine residues. The resulting gamma-glutamylamines are excised intact during proteolysis. TGase activity is altered in several diseases, highlighting the importance of in situ enzymatic determinations.

Randomized clinical stroke trials in 2006.

This article reviews randomized control trials (RCT's) published in 2006 of various medications evaluated for stroke patients. These trials were primarily efficacy studies. These included aggrenox (an antiplatelet agent), magnesium (to treat arterial spasm after an aneurysmal subarachnoid hemorrhage), NXY (a free radical trapping agent) and albumin which were both tested as a neuroprotectant, amphetamine (to aid motor recovery), fluoxetine (an anti-depressant and anxiolytic) and low molecular weight heparin (for prevention of deep vein thrombosis post-stroke).

Randomized clinical stroke trials in 2007.

This article reviews the randomized control trials (RCT's) that were published in 2007 of emerging pharmacotherapies in patients with acute (/= 12 weeks) stroke. A Medline search generated 22 RCT's in stroke in the year 2007 in the English language. These trials were primarily efficacy studies.

Thiamine-dependent processes and treatment strategies in neurodegeneration.

Reductions in brain glucose metabolism and increased oxidative stress invariably occur in Alzheimer's disease (AD) and thiamine (vitamin B1) deficiency. Both conditions cause irreversible cognitive impairment; their behavioral consequences overlap but are not identical. Thiamine-dependent processes are critical in glucose metabolism, and recent studies implicate thiamine in oxidative stress, protein processing, peroxisomal function, and gene expression.

Testing for linkage and association across the dihydrolipoyl dehydrogenase gene region with Alzheimer's disease in three sample populations.

Prior case-control studies from our laboratory of a population enriched with individuals of Ashkenazi Jewish descent suggested that association exists between Alzheimer's disease (AD) and the chromosomal region near the DLD gene, which encodes the mitochondrial dihydrolipoamide dehydrogenase enzyme. In support of this finding, we found that linkage analysis restricted to autopsy-proven patients in the National Institute of Mental Health-National Cell Repository for Alzheimer's Disease (NIMH-NCRAD) Genetics Initiative pedigree data resulted in point-wise significant evidence for linkage (minimum p-value = 0.024) for a marker position close to the DLD locus.

Correlations of disability and biologic alterations in Alzheimer brain and test of significance by a therapeutic trial in humans.

Literature values for the correlations between a number of major neurobiological hallmarks of Alzheimer's disease (AD) and the degree of global cognitive impairment among AD patients have been compared, in an attempt to identify biological abnormalities whose treatment might ameliorate the clinical disabilities. High correlations have been described with impairments of cerebral metabolism at both the level of cerebral metabolic rate in vivo and that of mitochondria. The metabolic abnormality develops even before morphological or symptomatic evidence of the illness.

Mitochondrial aconitase is a transglutaminase 2 substrate: transglutamination is a probable mechanism contributing to high-molecular-weight aggregates of aconitase and loss of aconitase activity in Huntington disease brain.

Transglutaminase activity was found to be present in highly purified non-synaptosomal rat brain mitochondria. A 78-kDa protein in these organelles was shown to be a transglutaminase 2 substrate, and incubation of a non-synaptosomal mitochondrial lysate with transglutaminase 2 yielded high-Mr proteins. The 78-kDa protein was identified as mitochondrial aconitase by MALDI-TOF analysis.

The alpha-ketoglutarate-dehydrogenase complex: a mediator between mitochondria and oxidative stress in neurodegeneration.

Damage from oxidative stress and mitochondrial dysfunction occur together in many common neurodegenerative diseases. The enzymes that form the mitochondrial alpha-ketoglutarate- dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme system of the tricarboxylic acid cycle, might mediate the interaction of these processes. KGDHC activity is reduced in numerous age-related neurodegenerative diseases and is diminished by oxidative stress.

Transglutaminase activity is present in highly purified nonsynaptosomal mouse brain and liver mitochondria.

Several active transglutaminase (TGase) isoforms are known to be present in human and rodent tissues, at least three of which, namely, TGase 1, TGase 2 (tissue transglutaminase), and TGase 3, are present in the brain. TGase activity is known to be present in the cytosolic, nuclear, and extracellular compartments of the brain. Here, we show that highly purified mouse brain nonsynaptosomal mitochondria and mouse liver mitochondria and mitoplast fractions derived from these preparations possess TGase activity.

Mitochondrial abnormalities in Alzheimer brain: mechanistic implications.

Reductions in cerebral metabolism sufficient to impair cognition in normal individuals also occur in Alzheimer's disease (AD). The degree of clinical disability in AD correlates closely to the magnitude of the reduction in brain metabolism. Therefore, we tested whether impairments in tricarboxylic acid (TCA) cycle enzymes of mitochondria correlate with disability.

Mitochondrial enzymes in schizophrenia.

The responses of brain metabolism and blood flow to stimulation are diminished in the dorsolateral prefrontal cortexes (DLPFCs) of schizophrenic patients. Reductions in mitochondrial enzymes underlie diminished metabolism in several neurodegenerative diseases. Thus, we tested whether reductions in selected mitochondrial enzymes could underlie the changes in schizophrenia.

Association of the dihydrolipoamide dehydrogenase gene with Alzheimer's disease in an Ashkenazi Jewish population.

Abundant biochemical evidence links deficient activity of mitochondrial alpha-ketoglutarate dehydrogenase with neuropathologically confirmed Alzheimer's disease (AD). Reduced alpha-ketoglutarate dehydrogenase activity has also been associated with anti-mortem measures of clinical disability. One of the genes encoding this complex, namely, DLD, lies within a chromosome 7 region that is in linkage disequilibrium with AD.

Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology.

Substantial evidence indicates that mitochondria are a major checkpoint in several pathways leading to neuronal cell death, but discerning critical propagation stages from downstream consequences has been difficult. The mitochondrial permeability transition (mPT) may be critical in stroke-related injury. To address this hypothesis, identify potential therapeutics, and screen for new uses for established drugs with known toxicity, 1,040 FDA-approved drugs and other bioactive compounds were tested as potential mPT inhibitors.

Substantial linkage disequilibrium across the dihydrolipoyl succinyltransferase gene region without Alzheimer's disease association.

Association of the candidate gene DLST with late-onset Alzheimer's disease (LOAD) risk has been suggested on the basis of case-control studies. This gene, located on chromosome 14q24.3, encodes a subunit of a mitochondrial component known to be defective in AD, the alpha-ketoglutarate dehydrogenase complex.

Cerebrometabolic abnormalities in Alzheimer's disease.

Extensive, replicated evidence in patients in vivo and in Alzheimer (AD) tissues in vitro indicates that impaired brain metabolism is one of the cardinal and essentially invariable events in AD. The degree of impairment in brain metabolism is proportional to the degree of clinical disability, both in vivo and in vitro. The 'cerebrometabolic lesion' cannot be attributed to 'slower thinking' or 'brain atrophy', because of quantitative considerations and because the metabolic lesion precedes the development of neuropsychological abnormalities or decreases in brain mass detectable by modern imaging techniques.

Alzheimer's disease and Alzheimer's dementia: distinct but overlapping entities.

Much of the controversy about the "amyloid cascade hypothesis" may reflect unrecognized differences in the use of language, including the use of the word "cause." This commentary proposes that the term Alzheimer disease refer to the neuropathological entity and the term Alzheimer dementia to clinical dementia in people who also have Alzheimer neuropathology. The ultimate causes of Alzheimer disease are proposed to be aging, environmental stresses, and genetic predispositions.

Glucose/mitochondria in neurological conditions.

Impairments of glucose and mitochondrial function are important causes of brain dysfunction and therefore of brain disease. Abnormalities have been found in association with disease of the nervous system in most of the components of glucose/mitochondrial metabolism. In many, molecular genetic abnormalities have been defined.

The role of the metabolic lesion in Alzheimer's disease.

This paper discusses the hypothesis that the cerebrometabolic deficiency in Alzheimer's disease(AD) is the proximate cause of the clinical disability. Several sets of observations support this hypothesis. (1) Impaired brain metabolism essentially always occurs in clinically significant AD, and the degree of clinical disability is proportional to the degree of metabolic impairment.