miRNAs Plasma Profiles in Vascular Dementia: Biomolecular Data and Biomedical Implications.

Vascular dementia (VaD) is a pathogenetically heterogeneous neuropsychiatric syndrome, mainly characterized by cognitive impairment. Among dementias, it is second by incidence after Alzheimer's dementia (AD). VaD biomolecular bases have been poorly characterized, but vascular-linked factors affecting the CNS and its functions are generally hypothesized to perform a major role, together with cardiovascular and immunological factors. miRNAs, which perform critically important biomolecular roles within cell networks, are also found in biological fluids as circulating miRNAs (cmiRNAs). We hypothesized that differentially expressed (DE) cmiRNAs in plasma from VaD patients could be applied to diagnose VaD through liquid biopsies; these profiles also could allow to start investigating VaD molecular bases. By exploiting TaqMan Low-Density Arrays and single TaqMan assays, miR-10b*, miR29a-3p, and miR-130b-3p were discovered and validated as significantly downregulated DE cmiRNAs in VaD patients compared to unaffected controls (NCs). These miRNAs also were found to be significantly downregulated in a matched cohort of AD patients, but miR-130b-3p levels were lower in AD than in VaD. A negative correlation was detected between miR-29a and miR-130b expression and cognitive impairment in VaD and AD, respectively. Receiver operating characteristic curves demonstrated that decreased plasma levels of miR-10b*, miR29a-3p, and miR-130b-3p allow to discriminate VaD and AD patients from NCs. Furthermore, the concurrent downregulation of both miR-10b* and miR-130b-3p in VaD showed an area under the curve (AUC) of 0.789 (p < 0.0001) with 75% of sensitivity and 72% of specificity, whereas an AUC of 0.789 (p < 0.0001) with 92% of sensitivity and 81% of specificity was found for both in AD. The miRNAs profiles reported in this paper pave the way to translational applications to molecular VaD diagnosis, but they also should allow to further investigate on its molecular bases.

"Postural first" principle when balance is challenged in elderly people.

Human cognitive processing limits can lead to difficulties in performing two tasks simultaneously. This study aimed to evaluate the effect of cognitive load on both simple and complex postural tasks. Postural control was evaluated in 128 noninstitutionalized elderly people (mean age = 73.6 ± 5.6 years) using a force platform on a firm support in control condition (CC) and mental counting condition (MCC) with eyes open (EO) and eyes closed (EC). Then, the same tests were performed on a foam support. Sway path traveled and area covered by the center of foot pressure were recorded, low values indicating efficient balance. On firm support, sway path was higher in MCC than in CC both in EO and EC conditions (p < 0.001). On foam support, sway path was higher in CC than in MCC in EC condition (p < 0.001), area being higher in CC than in MCC both in EO (p < 0.05) and EC (p < 0.001) conditions. The results indicate that cognitive load alters balance control in a simple postural task (i.e. on firm support), which is highlighted by an increase of energetic expenditure (i.e. increase of the sway path covered) to balance. Awareness may not be increased and the attentional demand may be shared between balance and mental task. Conversely, cognitive load does not perturb the realization of a new complex postural task. This result showed that postural control is prioritized ("postural first" principle) when seriously challenged.

Biological determinants of postural disorders in elderly women.

Postural control impairments and dizziness, which are major health problems with high secondary morbidity and mortality, increase with aging. Elevated homocysteine (Hcy) level is an age-related metabolic disorder, known to be involved in cardiovascular, neurological, and multisensory dysfunctions. Elevated Hcy level might be involved in sensory balance control systems impairment and dizziness occurrence. Dizziness, fitness Instrumental Activity of Daily Living scale (fitness IADL), systolic arterial pressure with ankle-brachial blood pressure index and homocysteinemia were studied in 61 noninstitutionized elderly women. Clinical balance tests (timed "Up and Go", 10-m walking and one-leg balance) and posturography (including sensory conflicting situations [SCS] and cognitive conflicting situations [CCS]) were performed. Clinical balance control was lower in dizzy women who presented particularly poor stability in SCS. Dizziness was related to low fitness IADL scores (odds ratio [OR] 0.452, 95% CI 0.216-0.946) and to elevated Hcy (OR 8.084, 95% CI 1.992-32.810). Elevated Hcy was correlated with balance disorders both in SCS and CCS. Dizziness is associated with a reduced ability in balance control management. Hcy is related both to dizziness and low postural performance. This relation between elevated Hcy levels and balance impairments, resulting in dizziness, may be explained by its angiotoxicity and neurotoxicity.

The CC genotype of transforming growth factor-ß1 increases the risk of late-onset Alzheimer's disease and is associated with AD-related depression.

Transforming growth factor-ß1 (TGF-ß1) is a neurotrophic factor that exerts neuroprotective effects against ß-amyloid-induced neurodegeneration. Recently, a specific impairment of the TGF-ß1 signaling pathway has been demonstrated in Alzheimer's disease (AD) brain. TGF-ß1 is also involved in the pathogenesis of depressive disorders, which may occur in 30-40% of AD patients. The TGF-ß1 gene contains single nucleotide polymorphisms (SNPs) at codon +10 (T/C) and +25 (G/C), which are known to influence the level of expression of TGF-ß1. We investigated TGF-ß1 +10 (T/C) and +25 (G/C) SNPs and allele frequencies in 131 sporadic AD patients and in 135 healthy age- and sex-matched controls. Genotypes of the TGF-ß1 SNPs at codon +10 (T/C) and +25 (G/C) did not differ between AD patients and controls, whereas the allele frequencies of codon +10 polymorphism showed a significant difference (P = 0.0306). We also found a different distribution of the +10 (C/C) phenotype (continuity-corrected χ(2) test with one degree of freedom = 4.460, P = 0.0347) between late onset AD (LOAD) patients and controls (P = 0.0126), but not between early onset AD (EOAD) patients and controls. In addition, the presence of the C/C genotype increased the risk of LOAD regardless of the status of apolipoprotein E4 (odds ratio [OR] = 2.34; 95% CI = 1.19-4.59). Compared to patients bearing the T/T and C/T polymorphisms, LOAD TGF-ß1 C/C carriers also showed > 5-fold risk to develop depressive symptoms independently of a history of depression (OR = 5.50; 95% CI = 1.33-22.69). An association was also found between the TGF-ß1 C/C genotype and the severity of depressive symptoms (HAM-D(17) ≥ 14) (P < 0.05). These results suggest that the CC genotype of the TGF-ß1 gene increases the risk to develop LOAD and is also associated with depressive symptoms in AD.

Prevalence of dementia in mountainous village of Sicily.

The progressive and rapid aging of population is the demographic characteristic in the Western countries. This rapid process of aging is causing an increasing burden on the social and health-care services. In this context, the precise knowledge of the environmental, socio-economical and clinical characteristics of the elderly population is mandatory to find the correct strategies to achieve the successful aging. Our study aimed to investigate the functional and clinical characteristics of the elderly (aged 60 to 85 years) of San Teodoro (1500 inhabitants), a rural village of Central Sicily, in particularly considering the dementia prevalence. In 2005, all the elderly between 60 and 85 years old were invited to participate to the study. The list of the potential participants was obtained from the Registry office of the municipality. The final number of the eligible subjects was 374. Rate of participation was 74.9% (280 subjects, 120 M and 160 F). The study was conducted door-to-door. Dementia prevalence was 7.1% (20 subjects, 8 M and 12 F), with 60% Alzheimer's disease and 15% vascular dementia, slightly higher than that of the European countries (6%). The high prevalence of hypertension (80.3%) and the low education level, two important risk factors for dementia, could explain in part the difference observed.

The APOE epsilon4 allele increases the risk of impaired spatial working memory in obstructive sleep apnea.

BACKGROUND: Contradictory data have been published on the influence of Apolipoprotein E (APOE) epsilon4 allele on obstructive sleep apnea (OSA). The aims of this study were to confirm the presence of specific neuropsychological changes in OSA patients carrying the APOE epsilon4 allele and to clarify if these changes are due to the sole presence of this allele or to its interactions with OSA pathology. METHODS: The APOE genotype was examined in 123 patients with OSA and in 121 controls, together with a series of neuropsychological tests. RESULTS: OSA and control subjects had similar APOE genotype and allele distribution, but when neuropsychological tests were considered, OSA patients showed significantly lower values for verbal long-term (delayed free recall at the Rey auditory-verbal learning test) and working memory (bisyllabic words). Moreover, spatial span was found to be lower in OSA epsilon4 allele carriers than in non-carriers; this difference was not observed in controls. CONCLUSIONS: This study confirms the presence of a verbal memory impairment in OSA patients and provides evidence for a significant interaction of APOE epsilon4 allele and OSA on frontal lobe function in adults, possibly mediated by the presence of specific frontal lobe neuroanatomical changes in these patients.

The CDC2 I-G-T haplotype associated with the APOE epsilon4 allele increases the risk of sporadic Alzheimer's disease in Sicily.

The cell division cycle 2 (CDC2) gene is a candidate susceptibility gene for Alzheimer's disease (AD). We investigated the CDC2 genotype, and allele and haplotype frequencies in AD patients and matched controls, distinguishing between apolipoprotein E (APOE) epsilon4 allele carriers and non-carriers. APOE epsilon4 is an established predictor of AD risk. APOE and CDC2 genotypes were examined in 109 sporadic AD patients and in 110 healthy age- and sex-matched controls from Sicily. The epsilon4 allele of APOE was predictive of AD risk in our study group (odds ratio: 5.37, 95% CI 2.77-10.41; P<0.0001). Genotype and allele frequencies of the three tested CDC2 polymorphisms (Ex6+7I/D, Ex7-15 G>A, Ex7-14 T>A) were not significantly different between AD patients and controls. However, a significant different distribution of a specific CDC2 haplotype (I-G-T) was found between AD patients and controls when analyzing APOE epsilon4-positive subjects (P=0.0288). Moreover, the combined presence of the I-G-T haplotype and the epsilon4 allele almost doubled the risk of AD (odds ratio: 10.09, 95% CI 3.88-26.25; P<0.0001) compared to carriers of epsilon4 alone. This study suggests that the I-G-T haplotype of the CDC2 gene increases the risk of AD in APOE epsilon4 carriers.

Plasma levels of neuropeptides in Alzheimer's disease.

BACKGROUND: In the central nervous system, several neuropeptides are believed to be involved in the pathophysiology of Alzheimer's disease (AD). Indeed, previous studies have documented that glucagon-like peptide 1 (GLP-1) possesses neurotropic properties and can reduce amyloid-beta peptide levels in the brain in vivo. Moreover, the concentrations of neuropeptide Y (NPY) seem to be altered in the cerebrospinal fluid of patients with AD and in subjects with major depression. Finally, among the modifications induced by aging, a dysregulation of the ghrelin-growth hormone (GH) system has been reported. METHODS: We investigated the plasma concentrations of these neuropeptides in 14 subjects with AD. Data obtained from these patients were compared with data from an age- and weight-matched healthy group. RESULTS: No significant differences were found between the two groups in relation to plasma levels of GLP-1, NPY, ghrelin and GH. Peripheral NPY concentrations were positively correlated with ghrelin levels in both groups, and with plasma GLP-1 concentration only in controls. CONCLUSION: On the basis of our results, peripheral levels of these neuropeptides seem not to serve as biochemical markers of AD.

Allele epsilon 4 of APOE is a stronger predictor of Alzheimer risk in Sicily than in continental South Italy.

The genotype of apolipoprotein E was examined in 173 sporadic Alzheimer's disease (AD) patients, 132 with late onset (LOAD) and 41 with early onset (EOAD), and in 174 healthy matched controls from Sicily. Despite a low frequency of the epsilon 4 allele (6.3%, 95% CI: 4.2--9.4) in controls, epsilon 4 allele was a stronger predictor of AD risk (odds ratio: 5.8, 95% CI: 3.5--9.4; p<0.0001) than in most of the studies performed in other regions of Italy, and it has no influence on age at onset. epsilon 4/epsilon 4 and epsilon 4/epsilon 3 genotypes were similar predictors of AD risk. Conversely, a decreased risk was found in epsilon 3 allele carriers (odds ratio: 0.3, 95% CI: 0.2--0.4; p<0.0001), which remained significant when considering EOAD cases only (odds ratio: 0.2, 95% CI: 0.1--0.4, p<0.0001). In conclusion, differences in association strength of epsilon 4 allele with AD between Sicily and other regions of Italy suggest an influence of complex gene-gene and gene-environment interactions.