Luca Cravello

Pineal and pituitary-adrenocortical function in physiological aging and in senile dementia

The simultaneous evaluation of the circadian rhythm of plasma melatonin and ACTH and of serum cortisol and DHEAS represents a clinically reliable tool to appreciate the neuroendocrine changes occurring in physiological and pathological brain aging.A selective impairment of the nocturnal melatonin secretion has been observed in elderly subjects, being significantly related either to the age or to the severity of dementia. A significant increase of serum cortisol levels during evening- and night-times was found in elderly subjects, particularly if demented, when compared to young controls. Besides, both the circadian amplitude of cortisol rhythm and the nocturnal cortisol increase were significantly reduced in relation either to age or to cognitive impairment. By comparison to vascular dementia, patients with Alzheimers disease exhibited the highest cortisol concentrations throughout the 24h. The sensitivity of the hypothalamic-pituitary-adrenal axis to the steroid feedback was significantly impaired in old subjects and particularly in the demented ones. The serum DHEAS levels were significantly lower in elderly subjects and even more in demented patients than in young controls. Consequently, a significant increase of the cortisol/DHEAS molar ratio was evident when going from young controls to healthy elderly subjects and to demented patients. In conclusion, the aging process affects many neuroendocrine functions resulting in subtle but clinically relevant consequences; the occurrence of senile dementia seems to play an additive role.

Age-related changes of the adrenal secretory pattern: possible role in pathological brain aging

The biosynthetic dissociation of the adrenocortical secretion occurring with age may have a pathogenetic role in the pathophysiology of brain aging. We studied cortisol and DHEAS secretion in healthy old and young subjects, in senile dementia, in major depression of elderly subjects and in healthy centenarians. A clear age-related decline of DHEAS secretion was well evident in healthy centenarians, and a further decrease in DHEAS concentration was found in old depressed patients and moreover in the demented ones, by comparison with age-matched controls. The circadian profile of serum cortisol was clearly flattened in old subjects, due to the selective increase in the cortisol nocturnal levels, particularly evident in demented subjects; on the other hand, the morning serum cortisol levels were not significantly different among centenarians, young and old controls. The molar ratio between cortisol and DHEAS showed a significant age-related increase; the occurrence of senile dementia and of major depression played an additive role, by comparison to physiological aging. The qualitative and quantitative modifications of the adrenocortical secretion occurring with aging seem mainly dependent on age itself, but the occurrence of pathological conditions may amplify these changes. Since cortisol and DHEAS play opposite effects on the central nervous system, the evaluation of the ratio between cortisol and DHEAS seems to be a good marker of the neuroendocrine features in old subjects.

Stress and dementia: the role of the hypothalamic-pituitary-adrenal axis

Hippocampus plays a crucial role in learning and memory and, in spite of its remarkable plasticity, it is also particularly sensitive to stress hormones due to its high concentration of corticosteroid receptors. Indeed, adrenal steroids modulate hippocampal plasticity, acting on excitability and long term potentiation or depression. By a chronobiological approach, we studied the cortisol and DHEAS secretion in clinically healthy old subjects and in age- matched demented patients, including both the degenerative and the vascular type. When compared to young controls, both clinically healthy elderly subjects and demented patients, particularly those with AD, had significantly higher cortisol levels at night time, i.e. at the moment of the maximal sensitivity of HPA axis to stimulatory or inhibitory inputs. At the same time, a clear age- and disease- dependent reduction of DHEAS secretion was found. Thus the cortisol to DHEAS molar ratio was significantly higher in healthy old subjects, and even more in demented patients, when compared to young controls, and significantly linked to both age and cognitive impairment. Finally, the quantitative and qualitative changes of the adrenal secretory pattern were significantly correlated with the decline of hippocampal volumes, measured by MRI. In conclusion, several lines of evidence deal with a pathogenetic role of stress hormones in the occurrence and progression of cognitive disorders in elderly subjects. The consequent hippocampal neuronal impairment may in turn be responsible for the continuous activation of HPA axis and the increased hypothalamic expression of vaso-pressin and corticotropin releasing hormone.

Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians.

Abstract:  Melatonin secretion is an endogenous synchronizer, and it may possess some anti‐aging properties. Thus we examined melatonin levels in physiological aging, in extreme senescence and in senile dementia. In healthy old (age 66–94 yr) and young subjects (age 23–39 yr) and in demented patients (age 68–91 yr) plasma melatonin was measured by radioimmunoassay in eight serial blood samples. In centenarians (age 100–107 yr) melatonin levels were estimated by assaying urinary 6‐hydroxymelatonin sulfate (aMT6s) in two different urine samples collected from 08:00 to 20:00 hours and from 20:00 to 08:00 hours. These data were compared with the aMT6s excretion of old and young controls. Elderly subjects, demented or not, exhibited a flattened circadian profile of plasma melatonin, because of the suppression of the nocturnal peak. An age‐related decline of the circadian amplitude of the melatonin rhythm occurred in old subjects, especially in demented individuals. Furthermore, the melatonin nocturnal peak was significantly correlated with the severity of the cognitive impairment. aMT6s urinary excretion also declined with age. However, as in young controls, in centenarians the aMT6s excretion was significantly higher at night than during the day. In conclusion, pineal melatonin secretion is affected by age and by the degree of cognitive impairment. In centenarians the maintenance of the circadian organization of melatonin secretion may suggest that the amplitude of the nocturnal peak and/or the persistence of a prevalent nocturnal secretion may be an important marker of biological age and of health status.

Overproduction of IFN-γ and TNF-α from Natural Killer (NK) Cells Is Associated with Abnormal NK Reactivity and Cognitive Derangement in Alzheimer's Disease

Abstract: Alterations of natural killer (NK) function can be involved in the neuroimmune mechanism of neurodegeneration in dementia of the Alzheimers type (DAT). NK cell cytotoxicity (NKCC) and the generation and release of IFN‐γ and TNF‐α (spontaneous and modulated by IL‐2) from pure NK cells (CD 16+, CD 56+, CD 3−) were studied together with circulating IFN‐γ and TNF‐α levels and cognitive function in 22 old patients with DAT and 15 healthy old subjects. Higher (p < 0.001) IL‐2 modulated NKCC (with IL‐2 50 U/mL and 100 U/mL) was demonstrated in DAT patients (+35% and +99% from baseline) than in healthy subjects (+6% and +76% from baseline). Increased spontaneous and IL‐2‐induced release of IFN‐γ and TNF‐α from NK cells were found in DAT patients compared to healthy subjects (p < 0.001), whereas no difference of serum IFN‐γ and TNF‐α was demonstrated between DAT and control groups. Significant negative correlations among the spontaneous release of IFN‐γ and TNF‐α from NK and the decrease of the score of cognitive function (MMSE) were found in patients with DAT. In conclusion, alterations of NKCC control and NK‐derived cytokine release in DAT could be involved in the neuroinflammatory mechanism related to the progression of neurodegeneration and dementia.

Seizure Frequency and Cortisol and Dehydroepiandrosterone Sulfate (DHEAS) Levels in Women with Epilepsy Receiving Antiepileptic Drug Treatment

Summary:  Purpose: Hormonal changes occur in epilepsy because of seizures themselves and of antiepileptic drug (AED) effects on steroid production, binding, and metabolism. Conversely, steroids may influence neuron activity and excitability by acting as neuroactive steroids. This cross‐sectional observational study aimed to evaluating cortisol and dehydroepiandrosterone sulfate (DHEAS) levels in female epilepsy patients with different disease severity, as assessed by a seizure frequency score (SFS).

Antiepileptic drug use and epileptic seizures in elderly nursing home residents: A survey in the province of Pavia, Northern Italy

Some surveys indicate that elderly nursing home residents are extensively prescribed antiepileptic drugs (AEDs). Few studies have evaluated the prevalence of seizure-related diagnoses as a risk factor for AED administration in nursing homes. To assess the prevalence of AED use and of epileptic seizures in the elderly nursing home residents in our country, we considered age and gender data, functional status (measured by the Barthels Index), drugs currently administered on a scheduled basis, clinical diagnoses from the patients chart including possible history of epileptic seizures, of all subjects aged 60 years and over living in 21 federated nursing homes in the province of Pavia, Northern Italy. Data relating to 2.001 subjects (77.5 % females) were collected over a 4-month period (September-December 2000). Eighty-seven of the 2.001 residents (4.3%; 5.3% of all the males and 4.0% of all the females) were taking AEDs and 58 (3.5% of all the males and 2.7% of all the females), all of them under treatment with at least one AED, had epileptic seizures in their history. Both these subgroups had a mean modified Barthels Index score significantly lower than that of the population as a whole. Phenobarbitone was the most frequently prescribed AED, and the penetration of newer AEDs was minimal. Subjects in early old age (60-74 years) were more likely than older subjects to take an AED. Logistic regression indicated a significant association between seizures reports, a younger age and a history of cerebrovascular events, alcohol abuse and meningiomas. The prevalence of AED use in this study was lower than that found by previous U.S. studies: nevertheless, our data confirm male gender and early old age as factors associated with AED taking in elderly nursing home residents. In our series AED users showed a lower level of autonomy. Taken together, our data suggest that an earlier institutionalization of seizure subjects could be facilitated by the clustering of various conditions, such as seizures, cerebrovascular events, other clinical disorders and a possibly inappropriate anticonvulsant treatment.

Long-term heart rate variability as a predictor of patient age

Patients age has been estimated in healthy population by means of the heart rate variability (HRV) parameters to assess the potentiality of HRV indexes as a biomarker of age. A long-term analysis of HRV has been performed, computing linear time and frequency domain parameters as well as non-linear metrics, in a dataset of 113 healthy subjects (age range 20-85 years old). The principal component analysis has been used to capture age-related influence on HRV and then three different models have been applied to predict subjects age: a robust linear regressor (RLR), a feedforward neural network (FFNN) and a radial basis function neural network (RBFNN). A good prediction of patient age has been obtained (using all principal components, the Pearson correlation coefficient between predicted and real age: RLR=0.793; FFNN=0.872; RBFNN=0.829), even if an overestimation in younger subjects and an underestimation in older ones may be observed. The important and complementary contribution of non-linear indexes to aging related HRV modifications has also been underlined.

Serum glucagon concentration and hyperinsulinaemia influence renal haemodynamics and urinary protein loss in normotensive patients with central obesity

OBJECTIVES: Insulin-resistance syndrome and hyperinsulinaemia are linked with cardiovascular disease (CVD) in the obese population. In particular, cardiovascular risk is more frequent in central obesity and is associated with microalbuminuria (MA). MA and changes of glomerular permeability to proteins in obesity might be related with renal haemodynamic modifications (that is glomerular hyperfiltration). Since glucagon is physiologically involved in renal haemodynamic regulation, the purpose of this study was to examine whether changes of circulating glucagon levels might haemodynamically induce MA and proteinuria in patients with central obesity.SUBJECTS: Forty normotensive obese out-patients, 22 with central (CO group) and 18 with peripheral (PO group) body fat distribution and 11 healthy subjects.MEASUREMENTS:Serum insulin and glucagon concentrations (fasting and after oral glucose tolerance test (OGTT)) by radio immuno assay (RIA); glomerular filtration rate (GFR, isotopic); total clearances and urinary excretion rates of albumin (AER), IgG (IgGER) and α1 microglobulin (computerized immunonephelometry).RESULTS: GFR and insulin concentrations (fasting and during OGTT) were higher in the CO than the PO group. Fasting glucagon concentrations were increased, and not physiologically suppressed during OGTT in patients with CO (fasting, P<0.05; OGTT 60 and 120 min, P<0.001 vs PO group). Moreover, glucagon concentrations were significantly correlated with GFR in the CO group (fasting, r=0.49, P<0.05; 60 min after OGTT, r=0.58, P<0.01); whereas no correlations were found in the PO group. Higher AER (P<0.001), IgGER (P<0.001) and α1 microglobulin (P<0.05) urinary concentrations were found in patients with CO than in the PO group.CONCLUSIONS: The increase of serum glucagon concentrations may be associated with the enhancement of GFR in patients with central obesity. Glomerular hyperfiltration might influence the development of MA and of proteinuria by means of a haemodynamic mechanism so contributing to increase the risk of renal microvascular complications and of CVD in central obesity.

Chapter 3.8 – Stress and dementia

Abstract Dementia is a relatively well-defined condition characterized by a progressive decline of cognitive and performances, as a consequence of degenerative and/or vascular brain changes. Although the definition of stress remains still problematic, it is now well known that a chronic exposure to stressors is usually able to disrupt the physiological balance both at the cellular or the organism level, and to play a role in the onset and progression of some pathological conditions. Within this context, at systemic level stress includes all the neurohormonal and metabolic responses of the organism to external stressors; at cellular level, stress, mostly oxidative stress, may instead be a correlate of the aging process itself. The link between stress and cognitive impairment is probably to be found in the hippocampal changes, a crucial as well as vulnerable brain area involved in mood, cognitive and behavioural control, and in the mean time, a site with a very high density of glucocorticoid (GR) and mineralocorticoid (MR) receptors. Therefore, the hippocampal neuronal impairment is responsible for a continuous stress-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis and an increased hypothalamic expression of corticotropin releasing factor (CRF) and vasopressin. Furthermore, the age-related changes of the adrenocortical secretory pattern could play a role in the pathophysiology of brain aging, fostering the brain exposure to a neurotoxic hormonal pattern. In this chapter, we examine particularly the evidence for a link between dementia and HPA activity on the basis of the data in the literature as well as of our personal findings.