High plasma homocysteine levels predict the progression from mild cognitive impairment to dementia.

High levels of blood homocysteine (HCy), a well-known cardiovascular risk factor and promoter of oxidative stress, have been associated with the incidence of cognitive impairment and dementia. Nonetheless, contrasting data are still present on its involvement in the progression from Mild Cognitive Impairment (MCI) to overt dementia. In this study we aimed to observe whether blood HCy level are associated with the evolution from MCI, divided into amnestic MCI (aMCI) and non-amnestic MCI (naMCI), to dementia. Blood HCy was measured in 311 MCI subjects (aMCI: 64%, naMCI: 36%) followed-up for a median of 33 months (range 10-155 months). At follow-up, 137 individuals converted to dementia (naMCI, n = 34; aMCI, n = 103). Based on HCy distribution, subjects in the highest tertile had a greater risk to convert to dementia compared to tertile I (Hazard Ratio (95% confidence interval): 2.25 (1.05-4.86); p = 0.04). aMCI subjects did not show increased risk to convert to dementia with increasing HCy concentration, but was significant in naMCI (p = 0.04). We observed a non-significant increase in the risk of progression to dementia from naMCI/low HCy (reference group, HCy cutoff value = 16 µmol/L) to naMCI/high HCy, but it was significant from aMCI/low HCy (HR: 2.73; 95%CI: 1.06-7.0; p:0.03), to aMCI/high HCy (HR: 3.24; 95%CI: 1.17-8.47; p:0.02). Our results suggest that HCy levels are associated with the progression from MCI to dementia. This association seems significant only for the naMCI group, indirectly supporting the notion that hyperhomocysteinemia damages the nervous system through its role as a vascular risk factor.

Cerebral Blood Flow in Alzheimer's Disease: A Meta-Analysis on Transcranial Doppler Investigations.

BACKGROUND: Cerebrovascular hemodynamic impairment has been reported in Alzheimer's disease (AD). We performed a systematic review and meta-analysis to investigate changes in cerebral blood flow (CBF) in AD patients. METHODS: Data were obtained by searching MEDLINE and Scopus for all investigations published between 1 January 2011 and 1 November 2021, comparing the cerebrovascular hemodynamic between AD patients and cognately healthy age-matched controls, using transcranial Doppler (TCD) ultrasound. RESULTS: Twelve studies, based on 685 patients [395 with AD and 290 age-matched cognitively healthy controls, with a mean age of 71.5 and 72.1 years, respectively] were included in the analysis. A random effect model revealed that AD patients, in the proximal segments of the middle cerebral artery (MCA), have a significantly lower CBF velocity, compared to controls (MD: -7.80 cm/s, 95%CI: -10.78 to -5.13, p < 0.0001, I2 = 71.0%). Due to a significant Egger's test (t = 3.12, p = 0.008), a trim-and-fill analysis was performed, confirming the difference (MD: -11.05 cm/s, 95%CI: -12.28 to -9.82, p < 0.0001). Meta-regression analysis demonstrated that the mean CBF at the proximal MCA was directly correlated with arterial hypertension (p = 0.03) and MMSE score (p < 0.001), but inversely correlated with age (p = 0.01). In AD patients, the pulsatility index was significantly higher compared to controls (MD: 0.16, 95%CI: 0.07 to 0.25, p < 0.0001, I2: 84.5%), while the breath-holding index test results were significant lower (MD: -1.72, 95%CI: -2.53 to -0.91, p < 0.001, I2: 85.4%). CONCLUSIONS: AD patients have a significant impairment in relation to their cerebrovascular perfusion, suggesting that cerebrovascular hemodynamic deterioration, evaluated using TCD, may be a useful diagnostic tool.

Variability in Alzheimer's disease mortality from European vital statistics, 2012-2020.

OBJECTIVE: Data regarding the trends in Alzheimer's disease (AD) mortality in the modern European Union (EU-27) member states are lacking. We assess the sex- and age-specific trends in AD mortality in the EU-27 member states between years 2012 and 2020. METHODS: Data on cause-specific deaths and population numbers by sex for each country of the EU-27 were retrieved through publicly available European Statistical Office (EUROSTAT) dataset from 2012 to 2020. AD-related deaths were ascertained when the ICD-10 code G30 was listed as the primary cause of death in the medical death certificate. To calculate annual trends, we assessed the average annual percent change (AAPC) with relative 95% confidence intervals (CIs) using Joinpoint regression. RESULTS: During the study period, 751,493 deaths (1.7%, 233,271 males and 518,222 females) occurred in the EU-27 because of AD. Trends in the proportion of AD-related deaths per 1000 total deaths slightly increased from 16.8% to 17.5% (p for trend <0.001). The age-adjusted mortality rate was higher in women over the entire study period. Joinpoint regression analysis revealed a stagnation in age-adjusted AD-related mortality from 2012 to 2020 among EU-27 Member States (AAMR: -0.1% [95% CI: -1.8-1.79], p = 0.94). Stratification by Country showed relevant regional disparities, especially in the Northern and Eastern EU-27 member states. CONCLUSIONS: Over the last decade, the age-adjusted AD-related mortality rate has plateaued in EU-27. Important disparities still exist between Western and Eastern European countries.

Acetyl-cholinesterase-inhibitors reconsidered. A narrative review of post-marketing studies on Alzheimer's disease.

The real efficacy of Acetyl-cholinesterase-inhibitors (AChEI) has been questioned. In this narrative review we evaluated their effect on cognitive decline, measured by Mini Mental State Examination (MMSE), and on total mortality rates in patients with Alzheimer's disease (AD) recruited into post-marketing open/non-randomized/retrospective studies. In AD patients treated with AChEI, the mean MMSE loss ranged from 0.2 to 1.37 points/years, compared with 1.07-3.4 points/years in non-treated patients. Six studies also reported data about survival; a reduction in total mortality relative risk between 27% and 42% was observed, over a period of 2-8 years. The type of studies and the use of MMSE to assess cognitive decline, may have introduced several biases. However, the clinical effects of AChEI seem to be of the same order of magnitude as the drugs currently used in most common chronic disorders, as regards progression of the disease and total mortality. In the absence of long-term randomized trials on "standard" unselected AD outpatients, open/retrospective studies and health databases represent the best available evidence on the possible effect of AChEI in the real-word setting. Our data support the clinical benefit of AChEI in older patients affected by AD.

Interleukin-18 Is a Potential Biomarker Linking Dietary Fatty Acid Quality and Insulin Resistance: Results from a Cross-Sectional Study in Northern Italy.

Dietary lipids are pivotal in modulating metabolic inflammation. Among the inflammatory mediators characterizing metabolic inflammation, interleukin 18 (IL-18) has been consistently associated with obesity and insulin resistance. This study aims to evaluate whether the quality of lipid intake impacts upon IL-18 plasma levels and the implications on insulin resistance computed by the homeostatic model assessment for insulin resistance (HOMA-IR). Using a cross-sectional design, this study confirmed that IL-18 correlated positively with insulin resistance and individuals with a HOMA-IR ≥ 2.5 displayed higher circulating IL-18 levels compared with their insulin-sensitive counterparts. In terms of the effect of the quality of dietary lipids on IL-18 circulating levels, the ratio between monounsaturated, omega-3, polyunsaturated and saturated fatty acids as well as the intake of eicosapentaenoic and docosahexaenoic acids correlated negatively with IL-18. Despite this, IL-18 circulating levels, but not dietary fatty acid quality, predicted insulin resistance. Nevertheless, the ratio between omega 3 and saturated fatty acids was a predictor of IL-18 plasma levels. Thus, the downregulation of IL-18 may underpin, at least partially, the beneficial metabolic effects of substituting omega 3 for saturated fatty acids with this cytokine potentially representing a biomarker linking dietary lipids and metabolic outcomes.

Dementia and Related Comorbidity: Analysis of 2 Years of Admissions to Italian Hospitals.

BACKGROUND: The aim of the present study was to examine the prevalence of dementia, related comorbidities, and mortality rates in hospitalized elderly patients in Italy. METHODS: Data were obtained from the Italian Ministry of Health and included all discharge records from Italian hospitals concerning subjects aged 65 years or above admitted to acute Internal Medicine during 2 years (n=3,695,278 admissions). Discharge diagnoses were re-classified into 24 clusters, each including homogeneous diseases by the ICD-9-CM code classification. Dementia was identified by the presence of ICD-9-CM codes 290, 294, or 331 series. RESULTS: Patients with dementia represented 7.5% of the sample; compared with those without dementia, they were older and more often female, had a greater length of hospital stay and higher mortality rate. Besides delirium [odds ratio (OR): 54.20], enthesopaties (OR: 2.19), diseases of fluids and electrolytes (OR:1.96), diseases of arteries (OR: 1.69), skin diseases (OR: 1.64), and pneumonia and pleurisy (OR: 1.53) were the diseases more strongly associated with the diagnosis of dementia, independent of other clusters, age, sex, and length of stay. CONCLUSIONS: Some comorbidities are specifically associated with the diagnosis of dementia among hospitalized elderly patients. Overall, these comorbidities describe the typical clinical profile of the patient with advanced dementia and could be treated in the context of the primary care, since they do not require specific skills belonging to hospital settings.

Orthostatic hypotension and vitamin D deficiency in older adults: systematic review and meta-analysis.

BACKGROUND: Over the latest years different studies have investigated the possible relationship between D deficiency and occurrence of orthostatic hypotension (OH), often reaching controversial results. We perform an update meta-analysis providing an update overview on the association between hypovitaminosis D and orthostatic hypotension (OH) in older adults. METHODS: Data extraction was independently performed by two authors and based upon predefined criteria. The meta-analysis was performed using a random-effects model. Statistical heterogeneity between groups was measured using the Higgins I2 statistic. RESULTS: Eight investigations enrolling 16.326 patients (mean age 75.5 years) met the inclusion criteria and were considered for the analysis. Patients with vitamin D deficiency were more likely to have OH compared to those without (OR: 1.36, 95% CI 1.14-1.63, p = 0.0001, I2 = 43.6%). A further sub-analysis, based on three studies, estimating the risk of OH in patients with hypovitaminosis D receiving antihypertensive treatment, did not reach the statistical significance (OR: 1.40, 95% CI 0.61-3.18, p = 0.418, I2 = 53.3%). Meta-regression performed using age (p = 0.12), BMI (p = 0.73) and gender (p = 0.62) as moderators did not reveal any statistical significance in influencing OH. Conversely, physical activity, Vitamin D supplementation and use of radioimmunoassay for the measurement of vitamin D serum levels showed a significant inverse relationship towards the risk of OH (Coeff.-0.09, p = 0.002, Coeff. - 0.12, p < 0.001 and Coeff. - 0.08, p = 0.03, respectively) among patients with hypovitaminosis D. A direct correlation between the administration of antihypertensive treatment and the risk of OH in older patients with low vitamin D level was observed (Coeff. 0.05, p < 0.001). CONCLUSIONS: Hypovitaminosis D is significantly associated with OH in older adults and directly influence by the administration of antihypertensive drugs. Conversely, physical activity, vitamin D supplementation and use of radioimmunoassay as analytic method inversely correlated with the risk of OH in older patients.

Physical capacities and leisure activities are related with cognitive functions in older adults.

BACKGROUND: This study aimed to evaluate the relationship between physical activity habits, physical performance and cognitive capacity in older adults' population of Italy and Slovenia. METHODS: Anthropometric characteristics and body composition bioelectrical impedance analysis were evaluated in 892 older adults (60-80 y). Aerobic capacity was measured using the 2-km walk test and handgrip and flexibility tests were performed. Physical activity habits and cognitive functions were evaluated by the Global-Physical-Activity-Questionnaires (GPAQ) and by Montreal-Cognitive-Assessment (MoCA) questionnaires, respectively. RESULTS: GPAQ scores were associated with lower BMI (r=-0.096; P=0.005), lower percentage of fat-mass (r=-0.138; P=0.001), better results in the 2-km walk test (r=-0.175; P=0.001) and a higher percentage of fat-free mass (r=0.138; P=0.001). We also evaluated that a higher MoCA Score correlates with age (r=-0.208; P=0.001), 2-km walk test (r=-0.166; P=0.001), waist-hip ratio (r=-0.200; P=0.001), resting heart-rate (r=-0.087; P=0.025) and heart-rate at the end of 2-km walk test (r=0.189; P=0.001). CONCLUSIONS: Older adults with a higher level of daily physical activity showed reduction in fat-mass and BMI, and higher aerobic fitness; these characteristics have a protection effect on cognitive function.

Dementia and in-hospital mortality: retrospective analysis of a nationwide administrative database of elderly subjects in Italy.

AIMS:  To evaluate the relationship between comorbidity and in-hospital mortality in elderly patients affected by dementia. METHODS: Data were obtained from the Italian Ministry of Health and included all discharge records from Italian hospitals concerning subjects aged ≥ 65 years admitted to acute Internal Medicine or Geriatrics wards between January 2015 and December 2016 (3.695.278 admissions). The variables analyzed included age, sex, and in-hospital death. Twenty-five homogeneous clusters of diseases were identified in discharge codes according to the ICD-9-CM classification. RESULTS: Patients with dementia represented 7.5% of the sample (n. 278.149); they were older, more often males (51.9%), and had a higher in-hospital mortality (24.3%) compared to patients without dementia (9.7%). Dementia per se doubled the odds of death (OR 1.98; 95% CI 1.95-2.00), independent of age, sex, and comorbidities. Seven clusters of disease (pneumonia, heart failure, kidneys disease, cancer, infectious diseases, diseases of fluids/electrolytes and general symptoms) were associated with increased in-hospital mortality, independent of the presence/absence of dementia. Among patients with dementia, heart failure, pneumonia and kidney disease on their own substantially doubled/tripled mortality risk. The risk increased from 10.1% (none of selected conditions), up to 28.9% when only one of selected comorbidities was present, rising to 52.3% (OR: 9.34; p < 0.001) when two or more comorbidities were simultaneously diagnosed, besides general symptoms. CONCLUSIONS: Our study confirmed an important increase of in-hospital mortality in older subjects with dementia. Despite a different comorbidity, the conditions associated with in-hospital mortality were substantially the same in patients with or without dementia. Heart failure, pneumonia, and kidney disease identified a high risk of in-hospital mortality among subjects with dementia.

Serum beta-secretase 1 (BACE1) activity increases in patients with mild cognitive impairment.

Beta-secretase 1 (BACE1) is considered as the key enzyme in amyloid-ß formation. Previous works suggest that high BACE1 activity may be present in brain, cerebrospinal fluid and serum of patients with late-onset Alzheimer's disease (LOAD) as well as mild cognitive impairment (MCI). Therefore, we evaluated whether serum BACE1 activity increases in MCI patients and is associated with the progression from MCI to dementia. BACE1 activity was measured in the serum of 259 MCI patients (162 amnestic-aMCI, 97 non-amnestic-naMCI) and 204 healthy Controls. After a median follow-up of 32 months (range: 10-153), 116 MCI progressed to dementia (87 aMCI and 29 naMCI). Serum BACE1 activity was higher in MCI compared with Controls (p < 0.001), and in aMCI with brain atrophy compared with naMCI without brain atrophy (p = 0.04). No difference in BACE1 activity emerged between converter and non-converter MCI, and this was true for both aMCI and naMCI. However, among aMCI with better cognitive performance (n. 163, MMSE score ≥24/30) those converting to dementia had higher BACE1 activity compared to stable ones (p = 0.05). This was not associated with an increased risk to develop dementia (hazard ratio: 1.65; 95% confidence interval: 0.67-4.01). In conclusion, serum BACE1 activity significantly increased in MCI patients (both amnestic and non-amnestic) compared with Controls. Moreover, higher serum BACE1 activity was observed only among aMCI with a better cognitive performance who progressed to dementia, suggesting that a dysregulation of this enzyme might be an early event primarily associated with neurodegeneration.

Serum Apo J as a potential marker of conversion from mild cognitive impairment to dementia.

BACKGROUND: Apolipoprotein J (ApoJ) is present in both plasma and tissues, including brain. Growing evidence suggest that this protein may play an early role on the development of the two most common forms of dementia, Alzheimer's disease (AD) and vascular dementia (VD). OBJECTIVE: To evaluate whether serum ApoJ levels might be able to predict the progression to AD, VD, or mixed dementia (AD&VD) in individuals with mild cognitive impairment (MCI). METHODS: Serum ApoJ was measured in 196 MCI subjects (aged ≥60 years) with a median follow up of 2.9 years. RESULTS: One hundred thirty-two of the enrolled MCI subjects converted to dementia. Among these, 45% developed AD, 33% mixed dementia, 13% VD (VD), and 9% other forms of dementia. A significant trend toward a progressive reduction in the incidence of dementia, regardless of the type, from tertile I (83.1%), to tertile II (63.1%), to tertile III (56.1%) was observed (p = 0.003). After adjustment for potential confounders, a twofold increase in the risk of conversion to dementia was found in subjects belonging to tertile I of Apo J compared with tertile III; the risk increased after two years of follow up, while no differences emerged within the first 2 years. CONCLUSIONS: Our results suggest that in MCI subjects, low APOJ levels may be associated with increased risk of developing dementia.

Clinical and demographic parameters predict the progression from mild cognitive impairment to dementia in elderly patients.

OBJECTIVES: To evaluate the possibility of predicting the risk of progression from mild cognitive impairment (MCI) to dementia using a combination of clinical/demographic parameters. METHODS: A total of 462 MCI elderly patients (follow-up: 33 months). Variable measured included cognitive functions, age, gender, MCI type, education, comorbidities, clinical chemistry, and functional status. RESULTS: Amnestic type (aMCI) represented 63% of the sample, non-amnestic (naMCI) 37%; 190 subjects progressed to dementia, 49% among aMCI, and 28% among naMCI. At Cox multivariate regression analysis, only MMSE (one point increase HR 0.84; 95% CI 0.79-0.90), aMCI (HR 2.35; 95% CI 1.39-3.98), and age (1 year increase HR 1.05; 95% CI 1.01-1.10) were independently associated with progression to dementia. A score was created based on these dichotomized variables (score 0-3): age (≥ or < 78 years), MMSE score (≥ or < 25/30) and aMCI type. The conversion rate progressed from 6% in subjects with score 0 (negative predictive value: 0.94), to 31% in individuals with score 1, to 53% in subjects with score 2, to 72% in individuals with score 3 (positive predictive value: 0.72). ROC curve analysis showed an area under the curve of 0.72 (95% CI 0.66-0.75, p 0.0001). CONCLUSIONS: We have described a simple score, based on previously recognized predictors such as age, MMSE, and MCI type, which may be useful for an initial stratification of the risk of progression to dementia in patients affected by MCI. The score might help the clinicians to evaluate the need for more expansive/invasive examinations and for a closer follow-up in MCI patients.

Autophagy and mitophagy biomarkers are reduced in sera of patients with Alzheimer's disease and mild cognitive impairment.

Dementia is a neurocognitive disorder characterized by a progressive memory loss and impairment in cognitive and functional abilities. Autophagy and mitophagy are two important cellular processes by which the damaged intracellular components are degraded by lysosomes. To investigate the contribution of autophagy and mitophagy in degenerative diseases, we investigated the serum levels of specific autophagic markers (ATG5 protein) and mitophagic markers (Parkin protein) in a population of older patients by enzyme-linked immunosorbent assay. Two hundred elderly (≥65 years) outpatients were included in the study: 40 (20 F and 20 M) with mild-moderate late onset Alzheimer's disease (AD); 40 (20 F and 20 M) affected by vascular dementia (VAD); 40 with mild cognitive impairment (MCI); 40 (20 F and 20 M) with "mixed" dementia (MD); 40 subjects without signs of cognitive impairment were included as sex-matched controls. Our data indicated that, in serum samples, ATG5 and Parkin were both elevated in controls, and that VAD compared with AD, MCI and MD (all p < 0.01). Patients affected by AD, MD, and MCI showed significantly reduced circulating levels of both ATG5 and Parkin compared to healthy controls and VAD individuals, reflecting a significant down-regulation of autophagy and mitophagy pathways in these groups of patients. The measurement of serum levels of ATG5 and Parkin may represent an easily accessible diagnostic tool for the early monitoring of patients with cognitive decline.

Uric acid within the "normal" range predict 9-year cardiovascular mortality in older individuals. The InCHIANTI study.

BACKGROUND AND AIMS: Increased uric acid levels correlate with cardiovascular disease and cardiovascular/overall mortality. To identify a uric acid threshold above which cardiovascular mortality rises, we studied the relationship between uric acid concentration and overall/cardiovascular mortality. METHODS AND RESULTS: We analyzed data from the InCHIANTI study, a cohort study of Italian community-dwelling people with 9 years of follow-up. We selected a sample of 947 individuals over 64 years of age, free from cardio-cerebrovascular disease and with available uric acid measurement at baseline. The sample was divided according to plasma uric acid tertiles. The Hazard ratio (HR) for mortality was calculated by multivariate Cox proportional hazard model. Mean age of participants was 75.3 ± 7.3 years; the mean value of uric acid was 5.1 ± 1.4 mg/dl. Over 9-years of follow-up, 342 (36.1%) participants died, 143 deaths (15.1%) were due to cardiovascular disease. Subjects with higher uric acid concentrations presented a higher cardiovascular mortality [II (4.6-5.5 mg/dl) vs I (1.8-4.5 mg/dl) tertile HR: 1.98, 95%C.I. 1.22-3.23; III (≥5.6 mg/dl) vs I tertile HR: 1.87, 95%C.I. 1.13-3.09]. We found a non-linear association between uric acid concentrations and cardiovascular mortality with the lowest mortality for values of about 4.1 mg/dl and a significant risk increment for values above 4.3 mg/dl. CONCLUSION: In community-dwelling older individuals free from cardio-cerebrovascular events, the lowest 9-year cardiovascular mortality was observed for uric acid values far below current target values. If confirmed, these data might represent the background for investigating the efficacy of uric acid levels reduction in similar populations.

Hand grip strength assessment in older people: is the supine position valid and reliable?

PURPOSE: Muscle strength evaluation is important in older people's functional assessment. We investigated the validity of grip strength measurement in a supine position as compared to the traditional one. METHODS: Cross-sectional study conducted in older people hospitalized in a medical unit. Patients underwent measurements of grip strength in both supine and sitting positions. Agreement between results was evaluated using Pearson correlation and Infraclass correlation coefficient. The two measurements techniques were graphically compared with Bland-Altman plot. RESULTS: Forty four participants enrolled (21 females), mean age 80.6. Correlation coefficients demonstrated a strong positive relationship between the two different measurement positions (all values greater than 0.9). Results were consistent and similar across gender, body side and were not affected by cognitive impairment. Infraclass correlation analyses demonstrate a very good inter-rate reliability. CONCLUSIONS: Grip strength assessed in the supine position can be considered a valid alternative in bedridden individuals.

Association of Anticholinergic Drug Burden with Cognitive and Functional Decline Over Time in Older Inpatients: Results from the CRIME Project.

BACKGROUND: Medications with anticholinergic properties, although widely used, may negatively affect cognitive and functional status in older patients. To date there is still no standardized method to quantify anticholinergic exposure. We analyzed the relationship of two different tools for the evaluation of the anticholinergic drug burden with cognitive and functional impairment in a sample of older hospitalized patients. METHODS: A retrospective and longitudinal analysis with 1-year follow-up of 1123 older hospitalized patients enrolled in seven Italian acute care wards was conducted. We assessed anticholinergic burden with the Anticholinergic Cognitive Burden (ACB) and Anticholinergic Risk Scale (ARS). Cognitive and functional status were evaluated at hospital discharge and during follow-up (3, 6, 12 months) using the Mini Mental State Examination (MMSE) and five basic activities of daily living (ADLs). Associations between anticholinergic burden and cognitive decline and incident disability were estimated using linear regression models for repeated measures and logistic models, respectively. RESULTS: The mean age of the study population was 81 ± 7.5 years. ACB and ARS classifications showed low correlation (Spearman's rho = 0.39-0.43). Anticholinergic burden increased during hospitalization and was associated with cognitive and functional status. Patients with an ARS of ≥ 1 at discharge had  significantly lower baseline MMSE scores (ARS = 0: 23.1; ARS ≥ 1: 20.8; p = 0.002) and during follow-up presented a  significantly steeper MMSE score decline (- 0.15/month). Moreover, patients with an ACB of ≥ 1 at discharge had an almost threefold increased risk of developing disability (odds ratio 2.77, 95% confidence interval 1.39-5.54). CONCLUSIONS: ACB and ARS have only a moderate degree of correlation. Use of drugs with anticholinergic properties in elderly patients is independently associated with cognitive and functional decline.

Lower Plasma Klotho Concentrations Are Associated with Vascular Dementia but Not Late-Onset Alzheimer's Disease.

BACKGROUND: The protein Klotho is involved in biological processes related to longevity, cardiovascular health, and cognition. Serum Klotho levels have been associated with better cognition in animal models; moreover, lower Klotho concentrations in cerebrospinal fluid from subjects with late-onset Alzheimer's disease (LOAD) have been reported. OBJECTIVE: Our study aimed to examine the possible relationship between Klotho plasma concentrations and cognitive status in the elderly. METHODS: We evaluated plasma Klotho levels in a sample of 320 elderly patients admitted to a Memory Clinic. Four groups of subjects were enrolled, including cognitively intact individuals complaining about memory loss (controls) and patients affected by LOAD, mild cognitive impairment, or vascular dementia (VD). The sample was stratified by plasma Klotho tertiles. RESULTS: Lower levels of plasma Klotho (1st tertile) were associated with older age, higher prevalence of VD, single/multiple lacunar infarcts and leukoaraiosis, coronary heart disease and stroke, and higher levels of creatinine, homocysteine, and high-sensitivity C-reactive protein. On multivariate logistic regression analysis, the risk of VD was 3- and 4-fold in subjects belonging to the 1st tertile (≤514.8 pg/mL, OR 3.54, 95% CI 1.05-11.93) and 2nd tertile (> 514.8, < 659.1 pg/mL, OR 4.28, 95% CI 1.30-14.06) compared to the 3rd tertile (≥659.1 pg/mL). A significantly increased VD risk was found for Klotho values < 680 pg/mL. CONCLUSION: In a sample of elderly individuals, we found a significant association between low plasma Klotho levels and VD, but not LOAD. This finding suggests that, although these 2 forms of dementia might overlap, some physiopathological mechanisms related to VD and LOAD remain distinct.

Low-grade systemic inflammation is associated with functional disability in elderly people affected by dementia.

The decline in basic and instrumental activities of daily living (BADLs and IADLs, respectively) is a well-established clinical hallmark of dementia. Growing evidence has shown that systemic subclinical inflammation may be related to functional impairment. We evaluated the possible association between low-grade systemic inflammation and functional disability in older individuals affected by dementia. We explored the association between high-sensitivity C-reactive protein (hs-CRP) levels and BADLs/IADLs in older individuals affected by late onset Alzheimer's disease (LOAD; n 110), "mixed" dementia (n 135), or mild cognitive impairment (MCI; n 258), and compared them with 75 normal Controls. Independent of age, gender, comorbidity, and other potential confounders, higher hs-CRP was significantly associated with poorer BADLs (loss ≥ 1 function) in people with LOAD (odds ratio [OR] 3.14, 95% confidence interval [CI], 1.33-7.33) and mixed dementia (OR 2.48, 95%CI 1.12-5.55), but not in those with MCI (OR 1.38, 95%CI 0.83-2.45) or Controls (OR 2.98, 95%CI 0.54-10.10). No association emerged between hs-CRP and IADLs in any of the sub-group. Our data suggest that systemic low-grade inflammation may contribute to functional disability in older patients with dementia.

Serum Soluble Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Levels in Older Subjects with Dementia and Mild Cognitive Impairment.

BACKGROUND: The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been involved in both physiological and pathological conditions, including vascular pathologies and pathologies of the central nervous system. Nonetheless, the knowledge about the role of systemic TRAIL in patients affected by different types of dementia and mild cognitive impairment (MCI) is still limited. OBJECTIVE: We assessed serum TRAIL levels in a large cohort of older individuals (n = 644) including patients with late-onset Alzheimer's disease (LOAD), vascular dementia (VAD), 'mixed' dementia (MIX), MCI, and healthy controls. METHODS: Circulating TRAIL was measured by ELISA. RESULTS: At univariate analysis, TRAIL levels were higher in VAD, MIX, and MCI patients compared with LOAD patients and controls. Using the multiple linear regression model, we found that TRAIL levels were associated with VAD and MCI, but not MIX, independent of potential confounding factors. CONCLUSION: The finding of high levels of circulating TRAIL in VAD and MCI seems to suggest that both of these conditions are characterized by a significant vascular damage with respect to LOAD.

The relationship between hyperhomocysteinemia and neurodegeneration.

Homocysteine (Hcy) is a key junction in methionine metabolism. In inherited forms of hyperhomocysteinemia patients develop early vascular damage and cognitive decline. Hyperhomocysteinemia is a common consequence of dietary, behavioral and pathological conditions and is epidemiologically related to different diseases, among them neurodegenerative ones are receiving progressively more attention in the last years. Several detrimental mechanisms that see in Hcy a possible promoter seem to be implicated in neurodegeneration (protein structural and functional modifications, oxidative stress, cellular metabolic derangements, epigenetic modifications, pathological aggregates deposition, endothelial damage and atherothrombosis). Interventional studies exploring B group vitamins administration in terms of prevention of Hcy-related cognitive decline and cerebrovascular involvement have shown scant results. In this review, current and possible alternative/complementary approaches are discussed.