The increased cortisol levels with preserved rhythmicity in aging and its relationship with dementia and metabolic syndrome.

BACKGROUND: In the aging process, the cumulative exposure to stress with increased cortisol levels is considered to be associated to the senescence itself and its related disorders. AIMS: To evaluate the role of cortisol in elderly subjects, with or without dementia, by the means of the AGICO study. METHODS: The AGICO study enrolled patients from ten Geriatric Units in Italy in 2012-2017 (Study Director Prof Paolo Falaschi, S. Andrea Hospital of Rome). Every subject received a comprehensive geriatric assessment (including the Mini-Mental State Examination, MMSE), the neurological examination (with a computed tomography scan or magnetic resonance imaging of the brain), the assessment of the metabolic syndrome (MetS), the evaluation of the cortisol activity by two consecutive urine collections (diurnal and nocturnal). RESULTS: The MMSE was inversely related to the standardized diurnal and nocturnal urinary cortisol levels (p < 0.025 and p < 0.01, respectively) and the age was positively related (p < 0.01 and p < 0.001, respectively). The ratio between the standardized diurnal and nocturnal urinary cortisol levels was 1.50 ± 1.2 (mean ± standard deviation) and it was not modified by the age or dementia. The standardized diurnal and nocturnal urinary cortisol levels were significantly higher in patients with dementia (MMSE < 24) (p < 0.01). In the analysis of the subgroups with MetS, the highest concentrations of diurnal and nocturnal cortisol were found in patients with both dementia and MetS (p < 0.025 and p < 0.01, respectively). DISCUSSION: The AGICO study showed that the stress response significantly and progressively increases with age. CONCLUSION: The cortisol increase in aging is related to the presence of both dementia and metabolic syndrome.

Bacterial DNAemia in Alzheimer's Disease and Mild Cognitive Impairment: Association with Cognitive Decline, Plasma BDNF Levels, and Inflammatory Response.

Microbial dysbiosis (MD) provokes gut barrier alterations and bacterial translocation in the bloodstream. The increased blood bacterial DNA (BB-DNA) may promote peripheral- and neuro-inflammation, contributing to cognitive impairment. MD also influences brain-derived neurotrophic factor (BDNF) production, whose alterations contribute to the etiopathogenesis of Alzheimer's disease (AD). The purpose of this study is to measure BB-DNA in healthy elderly controls (EC), and in patients with mild cognitive impairment (MCI) and AD to explore the effect on plasma BDNF levels (pBDNF), the inflammatory response, and the association with cognitive decline during a two-year follow-up. Baseline BB-DNA and pBDNF were significantly higher in MCI and AD than in EC. BB-DNA was positively correlated with pBDNF in AD, plasma Tumor necrosis factor-alpha (TNF-α), and Interleukin-10 (IL-10) levels in MCI. AD patients with BB-DNA values above the 50th percentile had lower baseline Mini-Mental State Examination (MMSE). After a two-year follow-up, AD patients with the highest BB-DNA tertile had a worse cognitive decline, while higher BB-DNA levels were associated with higher TNF-α and lower IL-10 in MCI. Our study demonstrates that, in early AD, the higher the BB-DNA levels, the higher the pBDNF levels, suggesting a defensive attempt; BB-DNA seems to play a role in the AD severity/progression; in MCI, higher BB-DNA may trigger an increased inflammatory response.

Study of the effects of adapted Tango and multidimensional intervention in pREvention of dementia in agiNG: developing healTHy lifestyle programs (STRENGTH Project)-the experimental protocol of a prospective randomised controlled trial.

BACKGROUND: Dementia represents a key health issue for older adults, with negative consequences on psycho-social and functional status. Treatments that counteract cognitive deficits in mild cognitive impairment (MCI) are needed to prevent or delay it. AIM: To describe the experimental protocol of the STRENGTH Project. This study investigates a multimodal intervention in older adults with MCI to improve cognitive, functional, biochemical and psycho-social aspects. METHODS: The prospective randomised controlled trial will enrol 300 subjects with MCI (age ≥ 60 years). Participants will be randomly assigned to: (a) the experimental group, which will undergo sessions of adapted tango, music therapy, engagement in social activities, cognitive intervention and psycho-education for 6 months or (b) the control group, which will receive psycho-education and advice on healthy lifestyle for 6 months. All outcomes will be analysed before intervention (baseline), immediately after termination (follow-up 1), after 6 months (follow-up 2) and after 2 years (follow-up 3). DISCUSSION: We expect that the findings of this multidisciplinary study will be useful to optimize clinical and psycho-social interventions for improving cognitive and functional status of subjects with MCI. CONCLUSIONS: This project could have a meaningful impact on National Health Systems by providing clues on multidisciplinary management of older adults affected by cognitive decline to prevent dementia.

Coronary flow response to remote ischemic preconditioning is preserved in old cardiac patients.

BACKGROUND: The effect of remote ischemic preconditioning (RIPC) on coronary flow in elderly cardiac patients has not been investigated yet. Thus, we aimed to study the change of coronary flow subsequent to RIPC in old patients with heart diseases and to identify its main correlates. METHODS: Ninety-five elderly patients (aged ≥ 65 years) accessing cardiac rehabilitation ward underwent transthoracic ultrasound evaluation of peak diastolic flow velocity of left anterior descending artery. Measurements of coronary flow velocity were performed on baseline and after an RIPC protocol (three cycles of 5 min ischemia of right arm alternating 5 min reperfusion). Differences between subjects with coronary flow velocity change over or equal the 75° percentile (high-responders) and subjects with a coronary flow velocity change under the 75° percentile (low-responders) were assessed. RESULTS: In enrolled elderly heart patients, coronary flow velocity significantly augmented from baseline after RIPC [0.23 m/s (0.18-0.28) vs 0.27 m/s (0.22-0.36); p < 0.001 by Wilcoxon test]. High-responders to RIPC were significantly younger and in better functional status than low-responders. Heart failure resulted as the main variable associated with impairment of RIPC responsiveness (R 2 = 0.202; p = 0.002)]. CONCLUSIONS: Our sample of old cardiac patients presented a significant median increment of coronary flow velocity after RIPC. The magnitude of the observed change of coronary flow velocity was comparable to that previously described in healthy subjects. The coronary response to RIPC was attenuated by heart failure. Further research should define whether such RIPC responsiveness is associated with cardioprotection and carries prognostic implications.

Subjective memory complaints in Italian elderly with mild cognitive impairment: implication of psychological status.

Subjective cognitive and memory complaints (SMC) are common in later life and are considered an indicator for progression to cognitive decline. The aim of the present study was to identify the relationship among SMC, neuropsychiatric symptoms and psychological aspects in elderly subjects with mild cognitive impairment (MCI) as well as to analyse the effect on SMC of a comprehensive cognitive training. Data from a sample of 94 patients enrolled in 'My Mind Project' (Grant No. 154/GR-2009-1584108) were collected. The study evidenced that depression was a significant predictor of SMC and that after the training, the number of subjects with SMC was significantly reduced in the experimental group in comparison to the control one. These results suggest that the participation in cognitive stimulation protocols may improve the perception of SMC in subjects with MCI.

Prognostic Interplay of Functional Status and Multimorbidity Among Older Patients Discharged From Hospital.

OBJECTIVES: The purpose of this study was to investigate the prognostic weight of multimorbidity and functional impairment over long-term mortality among older patients discharged from acute care hospitals. DESIGN: A prospective multicenter observational study. SETTING AND PARTICIPANTS: Our series consisted of 1967 adults aged ≥65 years consecutively admitted to acute care wards in Italy, in the context of the Report-AGE project. METHODS: After signing a written informed consent, all patients underwent comprehensive geriatric assessment by Inter-RAI Minimum Data Set acute care. The primary endpoint of the present study was long-term mortality. Patients were grouped into 3 functional clusters and 3 disease clusters using the K-medians cluster analysis. The association of functional clusters, disease clusters, and Charlson score categories with long-term mortality was investigated through Cox regression analysis and the intercluster classification agreement was further estimated. Finally, the additive effect of either disease clusters or Charlson score on predictive ability of functional clusters was assessed by using changes in Harrell's C-index and categorical Net Reclassification Index (NRI). RESULTS: Functional clusters, disease clusters, and Charlson score were significant predictors of long-term mortality, but the interclassification agreement was poor. Functional clusters predicted mortality with greater accuracy [C-index 0.66, 95% confidence interval (CI) 0.65-0.68] compared with disease clusters (C-index 0.54, 95% CI 0.53-0.56), and Charlson score (C-index 0.58, 95% CI 0.56-0.59). Adding multimorbidity (NRI 0.23, 95% CI 0.14-0.31) or Charlson score (NRI 0.13, 95% CI 0.03-0.20) to functional cluster model slightly improved the accuracy of prediction. CONCLUSIONS AND IMPLICATIONS: Functional impairment may better predict prognosis compared with multimorbidity, which may be relevant to optimally address individuals' needs and to design tailored preventive interventions.

Preadmission Functional Decline Predicts Functional Improvement Among Older Patients Admitted to Acute Care Hospital.

Background: Functional decline from preadmission to admission may represent an important predictor of functional trajectories during hospitalization among older patients. Therefore, we aimed at describing the impact of preadmission decline on functional trajectories among older hospitalized patients. Methods: Our series consisted of 2,011 patients aged 65 years or more consecutively admitted to four acute care wards of Geriatric Medicine participating to a multicenter observational study. Enrolled patients underwent comprehensive geriatric assessment (CGA) by Inter-RAI Minimum Data Set. Main outcomes were functional decline or improvement from hospital admission to discharge based on Activities of Daily Living (ADL) scale. The main exposure variable was ADL decline during the preadmission period (ie, 3 days before the onset of acute illness), and its impact on functional trajectories during stay was investigated by Cox regression models after adjusting for potential confounders. Results: After adjusting for potential confounders, preadmission functional decline was significantly associated with functional improvement during stay (hazard ratio [HR] = 6.65; 95% confidence interval [CI] = 5.01-8.84), but not with functional decline. Severe cognitive impairment (HR = 0.28, 95% CI = 0.13-0.60), visual impairment (HR = 0.60, 95% CI = 0.41-0.89), and weight loss (HR = 0.67, 95% CI = 0.47-0.94) were associated with functional improvement during stay. Hearing impairment (HR = 1.94, 95% CI = 1.17-3.23) and mild (HR = 2.54, 95% CI = 1.41-4.58) or severe cognitive impairment (HR = 2.72, 95% CI = 1.13-6.56) were associated with functional decline during stay. Conclusions: Patients experiencing recent preadmission functional decline should be considered as those for which the geriatric approach may lead to the better functional result in the acute care setting. CGA allows to individuate risk factors to be addressed in the acute care setting.

Oxidative Stress in Elderly with Different Cognitive Status: My Mind Project.

BACKGROUND: Biomarkers of oxidative stress have been associated with cognitive status in humans and have been proposed to guide prognosis/treatment in Alzheimer's disease (AD) and mild cognitive impairment (MCI). OBJECTIVE: The aim of this study was to compare oxidative stress status in the plasma of mild-moderate AD, MCI, and healthy elderly with normal cognition (HE) undergoing a non-pharmacological intervention including multi-modal cognitive training ("My Mind Project"). METHODS: A prospective randomized trial involving 321 elderly people enrolled in Marche Region, Italy. Each subject was randomly assigned to an experimental (cognitive training) or to a control group. Cognitive performances and biomarkers have been analyzed before intervention (baseline), immediately after termination (follow-up 1), after 6 months (follow-up 2), and after 2 years (follow-up 3). The biological antioxidant potential (BAP) to Diacron reactive oxygen metabolites (d-ROM) ratio has been used as an indicator of oxidative stress status and as outcome variable. RESULTS: We have found no differences in the oxidative status among AD, MCI, and HE. Neither did we find a significant effect of the intervention within experimental groups. Gender was the sole factor with a strong significant effect on BAP/d-ROM. CONCLUSIONS: Based on these results, the utility of biomarkers of oxidative stress to guide prognosis/treatment in AD or MCI seems to be limited by lack of specificity, large interindividual variability, and gender bias.

Effect of a Comprehensive Intervention on Plasma BDNF in Patients with Alzheimer's Disease.

A comprehensive intervention (CI) on patients with Alzheimer's disease was assessed by measuring plasmabrain-derived neurotrophic factor (pBDNF) and ADAS-Cog score (ADAS-Cogscore) before, immediately after (FU1), and 6 (FU2) and 24 months (FU3) after the CI. Baseline pBDNF was higher in patients with moderate AD (but not mild AD) than in healthy controls. At FU1, pBDNF and ADAS-Cogscore decreased significantly. At FU2 and FU3, patients' cognitive status worsened and pBDNF further increased versus baseline, suggesting that CI interruption may be a stress event that prevents return to homeostasis. CI exerted positive short-term effects, but more information is needed on long-term consequences.

Association between Cognitive Status and Physical Activity: Study Profile on Baseline Survey of the My Mind Project.

BACKGROUND: The incidence of people with dementia is expected to increase significantly in the coming years, but it seems that there is a relationship between an active lifestyle and cognitive decline. The present study aimed to compare the characteristics and engagement in the physical activity (PA) of three groups of Italian elderly with different cognitive statuses at baseline phase. METHODS: Data were examined using the results from the "My Mind Project" on 305 community-dwelling Italians. The sample was comprised of 93 subjects with Alzheimer's disease (AD), 109 with mild cognitive impairment (MCI) and 103 healthy elderly (HE). RESULTS: Classification of subjects on the basis of Physical Activity Scale for the Elderly (PASE) score showed that 47% of HE performed the highest level of physical activity while 40% of AD performed the lowest level. MCI subjects were distributed quite homogeneously across the levels (p < 0.001). Physical activity such as walking and light sports was carried out mainly and more frequently by HE as compared to the others (p < 0.05). As regards functional status, AD presented worse conditions in basic and instrumental activities of daily living than the other groups (p < 0.001). CONCLUSIONS: Our results evidenced that subjects with cognitive decline had the tendency to engage in PA less than HE. In particular, age and education negatively affected engagement in PA.

The Effects of Cognitive Training for Elderly: Results from My Mind Project.

Cognitive decline and dementia represent very important public health problems that impact the ability to maintain social function and independent living. The aim of this study was to investigate the effects of a nonpharmacological intervention consisting of comprehensive cognitive training in elderly people having one of three different cognitive statuses. In all, 321 elderly people with a diagnoses of mild-moderate Alzheimer's disease (AD), with mild cognitive impairment (MCI) and without cognitive decline were randomly assigned to two groups: experimental group (EG, who underwent intervention) and control group (CG), according to a prospective randomized intervention study. In the three groups, immediately after the end of the intervention, we observed a significant effect on some cognitive and noncognitive outcomes in the EGs. At the end of the intervention, we found an intermediate intervention effect on the Alzheimer's Disease Assessment Scale (ADAS) score of subjects with AD, as well as on functional status, as measured by using the Instrumental Activities of Daily Living scale. A significant intervention effect was also observed on enhancement of auditory verbal short-term memory and subjective memory complaints of subjects with MCI. The group of subjects without cognitive decline obtained a significant intervention effect on subjective complaints outcomes. The obtained results demonstrated that participation in the intervention could improve performance with respect to specific cognitive functions and psychological statuses. The role of healthy lifestyle programs, such as the use of comprehensive interventions, has been shown to be efficient for enhancing memory and other abilities in aged individuals with and without cognitive decline.

Cardioprotection by Conditioning Mimetic Drugs.

BACKGROUND: At present, ischemic heart disease (IHD) is one of the main causes of morbidity and mortality world-wide. An important insight into both IHD pathophysiology and cardioprotection was achieved in 1986 when Murry et al. described for the first time the ischemic preconditioning (IP). IP can be defined as an innate phenomenon by which brief episodes of ischemia confer protection to a tissue from a subsequent more protracted ischemic insult. Suggested mechanisms explaining IP comprise the action of circulating substances (e.g. adenosine, bradykinin, nitric oxide). These mediators are released after a prolonged ischemic stress, causing activation of molecular pathways that induce favorable posttranslational changes of proteins and adaptive modifications in genetic expression. PURPOSE: Briefly review evidences from clinical studies on drugs that exert their effects by mimicking IP, discussing their therapeutic properties and the potential clinical employment in order to obtain cardioprotection. METHODS: Literature regarding IP mimicking pharmacological agents was searched in Medline and Google Scholar. Authors reviewed relevant researches in English language including both clinical studies and reviews of clinical studies published from 1986 to 2016. RESULTS: Several pharmacological agents reproducing IP protective actions have been evaluated in many clinical trials. Examined molecules include adenosine, nicorandil and atrial natriuretic peptide. Interestingly IP mimicking effects of drugs have been also analyzed perioperatively in the context of ischaemia-reperfusion heart injury. Moreover evidences suggest that also some anaesthetic drugs (especially volatile agents) are able to provide myocardial protection by inducing IP. CONCLUSION: Drugs capable of mimicking IP exhibit a high therapeutic potential because of their properties of eliciting an effective cardioprotective signaling. Future studies should clarify the optimal doses and timing of administration of IP mimetic agents in order to favor the advent of new cardioprotective strategies beyond available reperfusive therapies.

Cognitive Stimulation Modulates Platelet Total Phospholipases A2 Activity in Subjects with Mild Cognitive Impairment.

We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activity (tPLA2A) in patients with mild cognitive impairment (MCI_P). At baseline, tPLA2A negatively correlated with Mini-Mental State Examination score (MMSE_s): patients with MMSE_s <26 (Subgroup 1) had significantly higher activity than those with MMSE_s ≥26 (Subgroup 2), who had values similar to the healthy elderly. Regarding CS effect, Subgroup 1 had a significant tPLA2A reduction, whereas Subgroup 2 did not significantly changes after training. Our results showed for the first time that tPLA2A correlates with the cognitive conditions of MCI_P, and that CS acts selectively on subjects with a dysregulated tPLA2A.

Contribution of non-reference alleles in mtDNA of Alzheimer's disease patients.

Many observations suggest that mutations of mitochondrial DNA (mtDNA) could be responsible for the neurodegenerative changes of Alzheimer's disease (AD). Here we examined the signal intensity of the four alleles of each mtDNA nucleotide position (np) in whole blood of AD patients and age-matched controls using MitoChip v2.0 array. Our analysis identified 270 significantly different nps which, with one exception, showed an increased contribution of non-reference alleles in AD patients. Principal component analysis (PCA) and cluster analysis showed that five of these nps could discriminate AD from control subjects with 80% of cases correctly classified. Our data support the hypothesis of mtDNA alterations as an important factor in the etiology of AD.

Social isolation risk factors in older hospitalized individuals.

BACKGROUND: Elderly people are particularly vulnerable to the effects of social reduction, so there is an urgent need to identify the risks associated with social isolation. The aim of this paper was to analyze associations between psychological, socio-demographic, functional aspects on the risk of social isolation, mortality and re-hospitalization in older persons. METHODS: This is a longitudinal study on 580 hospitalized elderly sample aged ≥70yrs recruited from 2005 to 2007 in the Geriatrics Operative Unit of INRCA in Fermo, Italy. The comprehensive geriatric assessment (CGA) was used. Outcome measures included 36-month mortality and re-hospitalization. RESULTS: In all patients, approximately 20% (n=112) of the subjects were socially isolated. Women perceived their social support significantly worse than men (77.7 vs. 22.3%; p<0.001). A multiple logistic regression analysis (goodness of fit χ(2)=102.86, p<0.001) with risk of social isolation as the dependent variable, showed that women were at a greater risk than men for social isolation (OR=1.99, 95% CI=1.13-3.50). Furthermore, patients with a higher number of family components (OR=0.72, 95% CI=0.59-0.88) and good parameters of quality of life (PCS-12: OR=0.94, 95% CI=0.91-0.98; MCS-12: OR=0.94, 95% CI=0.92-0.97) were less likely to be socially isolated. Cox regression models adjusted for gender, quality of life and number of family components, showed that the social isolation did not predict mortality (HR=1.44, 95% CI=0.84-2.46, p=0.19), but was associated with higher re-hospitalization rates (HR=1.28, 95% CI=1.02-1.59, p=0.03). CONCLUSIONS: Our findings highlight several aspects related to the risk of social isolation and re-hospitalization in a specific group of older persons.

Prevalence of aging-associated cognitive decline in an Italian elderly population: results from cross-sectional phase of Italian PRoject on Epidemiology of Alzheimer's disease (IPREA).

BACKGROUND AND AIMS: The prevalence of the preclinical phase of dementia varies greatly, according to the diagnostic criteria and assessment procedures applied. The purpose of this study was to estimate the prevalence of cognitive impairment according to the Aging-Associated Cognitive Decline (AACD) diagnostic criteria in an Italian elderly population. METHODS: In a multicenter community-based prospective study, 4785 Italian subjects aged 65-84 years, randomly selected from the registries of 12 Italian municipalities, were assessed by personal and informant interviews, physical and neurological examinations and an extensive neuropsychological battery. RESULTS: Of these older subjects, 274 (9.2%) fulfilled all the AACD criteria, whereas 561 (18.8%) fulfilled only 3 of them (AACD-3). When the two groups diagnosed according to AACD criteria (AACD and AACD- 3) were merged, the prevalence was 28.0% (28.3% for men, 27.6% for women). Two other groups of subjects were also identified: a) Subjects with Objective evidence of Cognitive Decline without cognitive complaints (OCD), 508 (17.0%), i.e., subjects with documented neuropsychological deficits, although neither subjects nor informants reported cognitive complaints; and b) Subjects with Cognitive Complaints without objective demonstrable cognitive deficits (CC), 44 (1.5%), i.e., subjects and/or informants reported cognitive complaints without evidence of neuropsychological deficits. Thus, taking into account the additional OCD group, a total of 1343 persons with cognitive impairment without dementia (45.0%) was identified. CONCLUSIONS: On the basis of our results, we estimate that 45% of our population-based Italian sample aged 65-84 years had some kind of cognitive deficits without dementia.

Cerebrovascular and brain microanatomy in spontaneously hypertensive rats with streptozotocin-induced diabetes.

The influence of hypertension associated with diabetes on cerebrovascular and frontal cortex or hippocampus microanatomy was investigated in 20-week-old spontaneously hypertensive rats (SHR) in which diabetes was induced by treatment with streptozotocin (STZ) and in control or STZ-diabetic age-matched normotensive Wistar Kyoto (WKY) rats. At the beginning of experiment, systolic pressure values were similar in WKY rats either control, or exposed to STZ and remarkably higher in control or STZ-treated SHR. Systolic pressure values increased in the different animal groups examined along the course of experiment. Blood glucose levels were increased in either STZ-WKY rats or -SHR compared to WKY rats and SHR respectively. The main changes occurring in pial and intracerebral arteries of SHR and STZ-SHR were thickening of the arterial wall accompanied by luminal narrowing. In medium sized pial arteries of STZ-WKY rats luminal narrowing and a decreased thickness of arterial wall were noticeable. Intracerebral arteries of STZ-WKY diabetic rats showed a not homogeneous sensitivity of different sized branches. The volume of zones III and IV of frontal cortex was decreased in SHR and STZ-SHR compared to control WKY rats. The number of nerve cells in these cerebrocortical layers was decreased to a similar extent in SHR. STZ-WKY rats or STZ-SHR compared to control WKY rats. In dentate gyrus, followed by the CA1 subfield of hippocampus, decreased volume and number of neurons were found in SHR and STZ-SHR compared to control WKY rats. The occurrence of astrogliosis was observed in hypertensive, diabetic or hypertensive plus diabetic rats. The above findings indicate the occurrence of cerebrovascular and brain microanatomical changes in SHR and to a lesser extent in STZ-diabetic rats compared to control normotensive and normoglicemic WKY rats. Association of hypertension and diabetes caused more pronounced changes than in the single disease models. These results support the view that hypertension and diabetes affect the structure of cerebrovascular tree and of brain and that association of the two diseases results in an increased risk of target-organ damage, involving brain.