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Mild cognitive decline and brain aging in physiological conditions Torna agli editoriali

Anna Giulia Cattaneo, M.D.
Dipartimento di Scienze e Tecnologie Biomediche (DBSM), Università dell'Insubria.

Brain aging apparently not related to defined disease appears to be an elusive matter of discussion that requires psychiatric competence for diagnosis and treatment. Clinical trials proposing different test to evaluate the degree of the cognitive decline have been performed on the basis of the loss of selective functions: declarative memory, fluid intelligence or "back working memory" among others. A comprehensive review has appeared in recent years (Journal of American Geriatric Society, 2000, 48, 431-441), in which types of memory loss, cerebral morphological and physiological changes present in other ways normally older population have been classified and analysed in order to propose valuable diagnostic criteria and principle for pharmacological treatment.
A wide number of causative or superimposing factors and diseases (depression, inflammatory or cardiac disease, as an example) can affect cognitive function, that on the other hand can dramatically improve by curing or removing companion causes of distress.
In addition to mild cognitive decline and memory loss, aging can be associated with increased threshold for all form of sensory input, only partially dependent on peripheral alterations, like retinal changes, degeneration of cochlear hair cells, loss of skin Meissner corpuscles.
The aging but other ways healthy human brain seems to undergo an average loss of 50,000 neurons per day and appears reduced in size at imaging diagnostic procedures. Alterations in mitochondrial function and organization are reported and discussed, increased mutations in mtDNA among the most frequent. Leukoariariosis is frequently seen at the MRI, an alteration of the paracallosal white matter that seems to be a marker of brain aging, not associated to any cognitive or behavioural modification.

Several endocrine functions have been regarded as associated and even responsible for brain aging.

A molecule of interest is the melatonin and its urinary metabolite, 6-hydroxymelatonin sulphate. Old age is accompanied by blunted nocturnal peak of melatonin, and cognitive impairment has an additive effect. However, the concentration of metabolite in urine produced during the day in comparison with that produced by night show a generally conserved pattern even in centenarians, limiting the significance of this molecule to a generic marker of wellness.

After 1985, when the recombinant molecule of human growth hormone (hGH) became disposable, possible implications of the decline of secretion of GH in a great variety of paraphysiological conditions has been actively investigated. The decline of amplitude of pulsatile growth hormone (GH) secretion and production of insulin-like growth factor-1 observed late in adulthood and in elderly has been posed into relation with the generalized decline in fitness, both psychological and physical, observed in aged people. GH administration has been claimed a powerful means to prevent and even reverse alterations in cardiovascular function, loss of memory and changes in body composition frequently observed in aged people. However, a final statement of benefits of GH in treating age-dependent defects, and even its association with physiological aging is lacking. At the present this parameter remains one of most intriguing phenomena to tentatively explain the great variety of phenotypic aging in humans.

A promising field of interest is represented by neurotransmitters, and the role of so-called "neurosteroids" should be remembered. The term applies to steroids whose synthesis in the brain is not dependent from peripheral glands, and that play a role similar to that of neurotransmitters. An index of modulation of hypothalamus-pituitary-adrenal axis, the cortisol-to-dehydroepiandrosterone ratio (C/DHEA), is strongly enhanced during the physiological aging process, predominantly due to the great decrease of DHEA. Mild symptoms of cognitive decline follow the reduction of C/DHEA, depression and true dementia playing an additive role. The action seems to be mediated trough modulation of signal transduction mechanisms, such as that involving the protein kinase C. Poor regulation of cortisol secretion and cardiovascular function response to a mental stress seem to be associated to poor performance when old but otherwise healthy persons have been tested for declarative memory and matrix reasoning. Exogenous administration of DHEA has not been proved to be effective, probably because the action on cerebral aging is due to local concentration of neurosteroid.

When the attention is focused on neurotransmitters, it should be remembered that synaptic loss, reactive gliosis and altered interaction between neurons and astrocytes following deranged production of the glial acidic fibrillary protein are among the most important alterations seen in an aging brain, under a functional point of view are. Cerebral deafferentation is important even in determining the generalized reduction of sensitive function seen in the elderly. The brain areas playing a major role in mild cognitive decline are the hippocampus, centre for selected form of learning and memory, the dentate nucleus responsible for neurogenesis, the hypothalamus as a centre of the endocrine axis, the forebrain areas playing a role in behaviour (attention, cognition, autosomal activity). GABA receptors appear to be increased in the aging brain, and the phenomenon could be compensatory for the synaptic loss. Neurotransmitters production and specialized functions, like calcium homeostasis and channels seems to be functions most affected by aging. The hypothesis that their sacrifice is the more convenient manner to face the loss of oxygen influx in the aging brain has been proposed. The proposed role for cytokines has not been proved. Even the frequently remembered role played by reactive oxygen species (ROS) seems to be dual, in brain. The oxidative stress can damage intracellular macromolecules, membranes lipids, nucleic acids and enzymes, on one hand. However ROS, the reactive molecules mainly responsible for oxidative damage, are essential components for signal transduction, and play a role as messenger in long term potentiation, a form of synaptic plasticity mediating the learning and memory functions in the hippocampus. ROS and antioxidant enzymes seem to regulate in a complex manner, variable during the lifespan, the hippocampal long-term potentiation in mice over expressing antioxidating enzymes.

Studies of genes expressed in "normal" aging and the biostatistical analysis of genotypic and phenotypic aging variations in human populations could reach to a more understandable amount of know ledges in the near future.
At the present, measures to prevent at the best dramatic loss of cognitive faculties later in life comprise a number of behavioural measures (choosing better dietary habits, enhancing physical activity, avoiding smoking and exposure to pollutants, between other) are highly recommendable. Pharmaceutical prevention and treatment for cerebral decline seems to be a measure more appropriate for patients suffering from true disease, with the exception of addition of anti-oxidant agents to the diet, like vitamin and microelements, omega-3 fatty acids, and equilibrate caloric restriction seems to be the best anti-aging agents. Melatonin and HGH exogenous administration should be reserved to selected cases, eventually during a controlled experimental trial.

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