Mitochondrial alterations, oxidative stress and neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial disorder characterized by the progressive deterioration of neuronal networks. The primary cause and sequence of its progression are only partially understood but abnormalities in folding and accumulation of insoluble proteins such as beta-amyloid and Tau-protein are both associated with the pathogenesis of AD. Mitochondria play a crucial role in cell survival and death, and changes in mitochondrial structure and/or function are related to many human diseases. Increasing evidence suggests that compromised mitochondrial function contributes to the aging process and thus may increase the risk of AD. Dysfunctional mitochondria contribute to reactive oxygen species which can lead to extensive macromolecule oxidative damage and the progression of amyloid pathology. Oxidative stress and amyloid toxicity leave neurons chemically vulnerable. The mitochondrial toxicity induced by beta-amyloid is still not clear but may include numerous mechanisms, such as the increased permeability of mitochondrial membranes, the disruption of calcium homeostasis, the alteration of oxidative phosphorylation with a consequent overproduction of reactive oxygen species. Other mechanisms have been associated with the pathophysiology of AD. Inflammatory changes are observed in AD brain overall, particularly at the amyloid deposits, which are rich in activated microglia. Once stimulated, the microglia release a wide variety of pro-inflammatory mediators including cytokines, complement components and free radicals, all of which potentially contribute to further neuronal dysfunction and eventually death. Clinically, novel approaches to visualize early neuroinflammation in the human brain are needed to improve the monitoring and control of therapeutic strategies that target inflammatory and other pathological mechanisms. Similarly, there is growing interest in developing agents that modulate mitochondrial function.

Age-related changes of the hypothalamic-pituitary-adrenal axis: pathophysiological correlates.

The aim of this review was to examine the evidence for age-related changes of the hypothalamic-pituitary-adrenal (HPA) axis in both physiological and pathological aging, on the basis of the many data in the literature, as well as of our personal findings. A statistically significant circadian rhythmicity of serum cortisol was maintained in elderly subjects, even if with a reduced amplitude of the 24 h fluctuations and a trend to an increase of the serum levels in the evening and at night-time, in comparison with young controls. Furthermore, an age-related impairment of HPA sensitivity to steroid feedback was present in elderly people. The occurrence of senile dementia amplified the changes already present in physiological aging. While the cortisol secretion was generally well maintained in aging, the adrenal production of dehydroepiandrosterone and of its sulfate (DHEAS) exhibited an age-related decline. Therefore, the cortisol/DHEAS molar ratio was significantly higher in elderly subjects and even more in demented ones, than in young controls. Due to the opposite effects of cortisol and DHEAS on the brain and particularly on the hippocampal region, the imbalance between glucocorticoids and androgens occurring in physiological and even more in pathological aging, may have adverse effects on the function of this region, whose key role in learning and memory is well known.

Dehydroepiandrosterone sulfate decreases the interleukin-2-mediated overactivity of the natural killer cell compartment in senile dementia of the Alzheimer type.

Since dehydroepiandrosterone sulfate (DHEAS) has been involved in the regulation of cellular immunity, the aim of the presence study was to evaluate whether the age-dependent reduction of DHEAS was associated with changes of natural killer (NK) immune function in healthy elderly subjects and in patients with senile dementia of the Alzheimer type (SDAT). Circulating DHEAS was determined throughout 24 h (circadian profile). NK cytotoxic activity was measured as spontaneous and induced cytotoxicity during exposure with DHEAS (10(-7) M), interleukin-2 (IL-2; 100 IU) and IL-2 (100 IU) coincubated with DHEAS (10(-7) M). DHEAS was significantly reduced in healthy elderly subjects (mesor M +/- SD = 2.3 +/- 0.5 micromol/l) and SDAT (1.6 +/- 0.4 micromol/l) patients compared to healthy young subjects (6.7 +/- 0.9 micromol/l; p < 0.001); significant differences were also found when healthy elderly subjects and SDAT patients were compared (p < 0.01). A significant inverse correlation between age and DHEAS levels was demonstrated in SDAT and healthy elderly subjects (p < 0.05). The decrease in 24-hour DHEAS secretion was associated with a higher NK cytotoxic response to DHEAS in the healthy elderly subject group than in healthy subjects of young age (p < 0.01). Increased NK cell activity during IL-2 incubation was found in patients with SDAT in comparison with the healthy elderly subject (p < 0.001). On the contrary, NK cell cytotoxic response of SDAT patients was less pronounced during DHEAS exposure and when DHEAS was coincubated with IL-2 (p < 0.001). These data suggest an immunomodulatory role of DHEAS on NK functional activity in physiological aging and SDAT. The antagonizing effect of DHEAS on NK overactivity during exposure with cytokines might counteract some neuroimmune components related to the pathogenesis and progression of the disease.

Changes in endocrine circadian rhythms as markers of physiological and pathological brain aging.

We studied the circadian rhythm of plasma melatonin, growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), and cortisol in 52 mentally healthy old subjects, 35 old demented patients, and 22 clinically healthy young controls. When compared to young controls, the circadian profile of plasma melatonin of old subjects, both demented or not, was clearly flattened, particularly during the night. The selective impairment of nocturnal melatonin secretion was significantly related to both the age and the severity of mental impairment (Mini Mental State Examination [MMSE] score). The PRL and GH circadian profiles were similar in the three groups during the day, but a significant lowering of the values recorded during the night occurred with aging. The impairment of the nocturnal secretion was related to the subjects' age and, for the GH secretory pattern only, also to the MMSE score. The ACTH circadian profile was similar in the three groups studied, even when old subjects exhibited higher ACTH levels throughout the 24 h cycle, compared to young controls. Significantly higher cortisol values at evening- and nighttime occurred in elderly subjects and particularly in the demented group. Both the mean levels and the nadir values of plasma cortisol were positively related to age and negatively to MMSE score. In order to verify the sensitivity of the hypothalamo-pituitary-adrenal (HPA) axis to the steroid feedback, the circadian profile of plasma cortisol was evaluated also after dexamethasone (DXM) administration (1 mg at 23:00 h); the sensitivity of the HPA axis was significantly impaired in old subjects and particularly in the demented ones. These findings suggest that the neuroendocrine alterations already present in physiological aging, due to both anatomical damages and unbalanced central neurotransmitters, are enhanced in senile dementia.

Chrono-neuroendocrine markers of the aging brain.

The study of the neuroendocrine changes occurring in aging may give information about the CNS functions, and also explain the impaired plasticity of the aged organism. In 16 elderly women and in 14 young controls, the circadian rhythms of plasma melatonin, GH, PRL, ACTH and cortisol, and of oral temperature were simultaneously studied. The plasma cortisol circadian rhythm was also evaluated after DXM administration (1 mg orally at 23:00). The circadian profile of all the bioperiodic functions evaluated was clearly flattened in elderly subjects, and an impairment of the hormonal nocturnal secretion of GH, PRL and melatonin was apparent in elderly subjects when compared to young controls. The plasma ACTH levels throughout the 24-hour cycle were significantly higher in elderly than in young subjects. The cortisol circadian profile exhibited significantly higher values in the evening- and night-time in elderly subjects, compared to young controls; the cortisol nadir values were significantly age-related. A reduction of the sensitivity to DXM inhibition occurred in the elderly group. Both the selective impairment of nocturnal melatonin secretion, and the reduction of hypothalamo-pituitary-adrenal (HPA) sensitivity to steroid feed-back might be considered as markers of aging brain. The neuroendocrine alterations of physiological aging may be ascribable to both the structural and neurochemical changes occurring in the CNS.

Chrono-neuroendocrinological aspects of physiological aging and senile dementia.

The circadian pattern of melatonin and cortisol secretion was evaluated in two groups of elderly subjects (aged 66-90 years), one with Alzheimer's type of multiinfarct dementia (n = 27) and the other without cognitive impairment (n = 16); 13 clinically healthy women aged 20 to 30 years were chosen as controls. All demented patients had severe mental impairment, corresponding to stage 6 of the Global Deterioration Scale. All subjects, either young or aged, were studied as in-patients and were well synchronized with respect to meal timing, diurnal activity and nocturnal rest. At the population mean cosinor analysis (Halberg, 1969) both melatonin and cortisol circadian rhythms reached statistical significance in the three groups of subjects. However, the melatonin circadian profile was clearly flattened in the two groups of elderly subjects by comparison with young controls, due to the selective impairment of melatonin nocturnal secretion. In both elderly groups, but particularly in demented patients, plasma cortisol levels were significantly higher by comparison to young controls, particularly at evening and night time. A significant direct relationship linked the subjects' age and the nadir values of plasma cortisol. Furthermore, the sensitivity of the hypothalamo-pituitary-adrenal axis to dexamethasone (DXM) suppression test (1 mg orally at 2300) was significantly reduced in both elderly groups, and especially in old demented patients, by comparison with young controls. Finally, plasma cortisol response to pulse i.v. injection of a small dose of synthetic corticotropin (Synacthen 2,500 ng) was significantly higher and more prolonged in old demented patients than in mentally healthy old subjects and in young controls.(ABSTRACT TRUNCATED AT 250 WORDS)

O tratamento da síndrome varicosa no idoso: resultados obtidos com aminaftona / Treatment of varicose syndrome in the aged: results obtained with aminaphtone

Foram tratados 40 pacientes idosos acometidos por síndrome varicosa crônica com aminaftona, com dose diária de 225 mg, durante 75 dias. No final do tratamento foi evidenciada uma nítida melhora dos vários parâmetros subjetivos e objetivos tomados em consideraçäo, juntamente a uma perfeita tolerância do medicamento

Beta-endorphin and cold pressor test in the aged.

In 8 young and 8 elderly subjects mean values of plasma beta-endorphin were nearly equal under basal conditions. In all subjects the cold pressor test provoked a marked increase of beta-endorphin, which was more evident in young subjects. Mean values of the areas of endorphin modifications were the same in both young and elderly subjects. These results may suggest that after a short-term stimulus, such as the cold pressor test, no marked differences in pituitary secretion between young and elderly subjects may be evidenced.