p66(shc) is highly expressed in fibroblasts from centenarians.

p66(shc-/-) mice exhibit prolonged lifespan and increased resistance to oxidative and hypoxic stress. To investigate p66(shc) involvement in human longevity, p66(shc) mRNA and protein were evaluated in fibroblasts from young people, elderly and centenarians, exposed to oxidative or hypoxic stress. Unexpectedly, centenarians showed the highest basal levels of p66(shc). Oxidative stress induced p66(shc) in all samples. At variance, hypoxic stress caused p66(shc) reduction only in cells from centenarians. These changes occurred in absence of any modification of p66(shc) promoter methylation pattern. Intriguingly, in cells from centenarians, p66(shc) induction was affected by p53 codon 72 polymorphism. Thus, cells from centenarians present a peculiar regulation of p66(shc), suggesting that its role in mammalian longevity is more complex than previously thought.

Which target for DBS in Parkinson's disease? Subthalamic nucleus versus globus pallidus internus.

We selected 14 patients with advanced idiopathic Parkinson's disease (PD) and examined the clinical effects of STN DBS versus GPi DBS. Nine patients underwent bilateral STN DBS and five underwent bilateral GPi patients. All patients were followed for at least 12 months. The evaluation was performed on and off drug before surgery; on-drug/on-DBS and off-drug/on-DBS at 1, 3, 6 and 12 months after stereotactic surgery. At 1 and 3 months after surgery in off-drug/on-DBS condition, both groups showed an improvement in motor score (UPDRS III). Nevertheless, the results changed after long-term stimulation in the two groups. Chronic STN DBS is superior to GPi DBS in the amelioration of the clinical features and in the decrease of time spent in the off state. The efficacy in reduction of LID was comparable at 1 and 3 months after surgery, but the results were better in STN DBS after chronic stimulation. The L-dopa dose was reduced only in the STN group.

Intralaminar distribution of neurotransmitter-related enzymes in cerebral cortex of Alzheimer's disease.

The intralaminar distribution of choline acetyltransferase, galactocerebrosides, gangliosides and proteins were determined in frontal (Brodmann's area 9) and temporal (Brodmann's area 22) cortices from subjects with autopsy-proven Alzheimer's disease and controls matched for sex, age and postmortem delay. In normal brain choline acetyltransferase (CAT) activity was higher in the II and IV layers in the temporal cortex, while in frontal cortex CAT activity was relatively high in the II-III layer, appearing as a single peak. The intracortical distribution of galactocerebrosides normally shows a trend to a higher activity from the pial surface to white matter either in frontal or temporal cortices. Higher concentrations of gangliosides were associated with the cell body layers in either frontal or temporal cortices. In either frontal and temporal cortices from 5 patients with Alzheimer's disease the pattern of intralaminar distribution of CAT activity was completely disrupted and it was significantly lower than in all cortical layers of the controls. Galactocerebrosides concentration was significantly decreased in the lower layers (IV, V and VI) in both frontal and temporal cortices and ganglioside sialic acid concentration was also decreased in the Alzheimer brain consistently in the lower (III-IV) layers of the frontal and temporal cortices. These observations indicate a widespread involvement of cholinergic activities through all cortical layers. However, the selective decrease in galactocerebroside concentration in the lower layers (IV-VI) suggests a selective loss of ascending fibers from subcortical nuclei. The decreased concentration of ganglioside sialic acid in lower layers suggests a selective axodendritic degeneration in these laminae of frontal association and temporal cortex in Alzheimer's disease.

Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain.

The activity of the pyruvate dehydrogenase complex (PDHC) was reduced in affected areas of brain from patients with Huntington disease (caudate, putamen) and Alzheimer disease (frontal cortex) where choline acetyltransferase (CAT) activity was low. PDHC was also deficient in an area (Huntington hippocampus) where CAT was not significantly reduced. The activity of fumarase, an inner mitochondrial marker, was normal in all areas examined. The activities of PDHC and CAT correlated well in caudate, putamen, and amygdala but not in hippocampus or frontal cortex. Both total activity and activation of PDHC were below normal in fibroblasts from 4 patients with C-21 trisomy Down syndrome, who are at very high risk to develop Alzheimer disease. However, no abnormality of PDHC was detected in Huntington or Alzheimer fibroblasts. Deficiency of PDHC may play a role in the pathophysiology of Huntington and Alzheimer diseases, although it does not appear to be a primary defect. Loss of tissue oxidative capacity may relate to the reduction in cerebral metabolic rate and blood flow which are characteristic of many dementing illnesses.

Changes in high affinity choline uptake in rat cortex following lesions of the magnocellular forebrain nuclei.

High affinity choline uptake (HACU) and choline acetyltransferase (CAT) were measured in the cerebral cortex of rats 4 and 20 days after placing electrolytic lesions in the magnocellular forebrain nuclei (MFN) or in the pallidum. Four days after MFN lesion a 40-50% decrease in ipsilateral cortical HACU was found and a slightly smaller decrease was found 4 days after the pallidum lesion. Twenty days after the lesion, HACU activity returned to control values in the ipsilateral parietal cortex, its decrease was smaller than 4 days postlesion in the ipsilateral frontal cortex and a significant increase was found in the contralateral cortex. CAT activity showed a 40% decrease in the frontal, parietal and occipital ipsilateral cortex 4 days after MFN lesion. The same decrease was found 20 days postlesion. However, at this time a significant increase in CAT activity was detected in the contralateral cortex. The ipsilateral recovery of HACU activity 20 days after the lesions and the contralateral increase in HACU and CAT activity demonstrate the remarkable and widespread functional adjustment associated with discrete brain lesions. The existence of a large cholinergic pathway projecting to the neocortex from the basal forebrain region is also confirmed.