Rosario S. Spada

Homocysteine and methylenetetrahydrofolate reductase polymorphism in Alzheimer's disease.

Homocysteine metabolism is influenced by genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR 677 C→T and 1298 A→C) and transcobalamin genes (TCN1 776 C→G ). We evaluated the association of homocysteine with Alzheimers disease (AD) and the influence of related polymorphisms and APOE, in 180 cases and 181 controls from southern Italy. Homocysteine (upper tercile) was associated with AD risk, with an odds ratio of 2.8 (95% confidence interval (CI) 1.54–5.22, p=0.0008), which was increased 2.2- and 2.0-fold by MTHFR 677 T (odds ratio 6.28, 95% CI 2.88–16.20, p < 0.0001) and APOE &egr;4 (odds ratio: 5.60, 95% CI 1.12–28.05, p=0.0361), respectively. In conclusion, association of homocysteine with AD was aggravated by MTHFR 677 T and APOE &egr;4 alleles.

A single question for the rapid screening of restless legs syndrome in the neurological clinical practice

The purposes of this study were to validate the use of a single standard question for the rapid screening of restless legs syndrome (RLS) and to analyze the eventual effects of the presence of RLS on self‐assessed daytime sleepiness, global clinical severity and cognitive functioning. We evaluated a group of 521 consecutive patients who accessed our neurology clinic for different reasons. Beside the answer to the single question and age, sex, and clinical diagnosis, the following items were collected from all patients and normal controls: the four criteria for RLS, the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Severity (CGI‐S), and the Mini‐Mental State evaluation. RLS was found in 112 patients (70 idiopathic). The single question had 100% sensitivity and 96.8% specificity for the diagnosis of RLS. ESS and CGI‐S were significantly higher in both RLS patient groups than in normal controls. RLS severity was significantly higher in idiopathic than in associated/symptomatic RLS patients. RLS can be screened with high sensitivity and good reliability in large patient groups by means of the single question; however, the final diagnosis should always be confirmed by the diagnostic features of RLS and accompanied by a careful search for comorbid conditions.

Association of IL-1 RN*2 allele and methionine synthase 2756 AA genotype with dementia severity of sporadic Alzheimer’s disease

Background: Genetic polymorphisms of APO-E, homocysteine, and the IL-1 gene cluster (IL-1A, IL-1B, receptor antagonist IL-1RN) are associated with sporadic Alzheimer’s disease and may involve interdependent pathways of neuronal toxicity. Objective: To determine whether these polymorphisms and the genetic determinants of homocysteine (methylenetetrahydrofolate reductase, MTHFR; methionine synthase, MTR; transcobalamin, TC) are associated with an increased risk of severe dementia in Alzheimer’s disease. Methods: 152 patients with Alzheimer’s disease and 136 controls were studied. The association of occurrence and dementia severity (Reisberg score <6 and ⩾6) of Alzheimer’s disease with APO-E, IL-1A, IL-1B, IL-1RN, MTHFR677 C→T and 1298A→C, MTR 2756 A→G, and TC 776 C→G polymorphisms was evaluated by multivariate logistic regression analysis after adjustment for age, sex, and age of onset of Alzheimer’s disease. Results:IL-1A TT and IL-1B CT/TT associated genotypes were at risk of Alzheimer’s disease (odds ratio 4.80 (95% confidence interval, 1.32 to 17.40), p = 0.017); the MTR 2756 AA genotype was at risk of severe dementia (OR 2.97 (1.23 to 7.21), p = 0.016); IL-1 RN*2 was protective (OR 0.28, (0.11 to 0.69), p = 0.006). Allele ϵ4 of the APO-E and IL-1B CC genotypes increased the risk of severe Alzheimer’s disease associated with the MTR 2756 AA genotype by 3.3-fold and 1.5-fold, respectively. Conclusions: Distinct determinants of the IL-1 gene cluster are related to the generation and progression of Alzheimer’s disease. MTR only influences progression of the disease, which may be enhanced by carriage of allele ϵ4 of APO-E.

Leptin Levels in Menopause: Effect of Estrogen Replacement Therapy

To evaluate the effect of menopause and estrogen replacement therapy on leptin levels, 17 white postmenopausal women were recruited for the study. After an overnight fasting, blood samples were collected for LH, FSH, estradiol, testosterone, androstenedione, DHEA sulfate, insulin and leptin assays. Body mass index (BMI) and the waist-to-hip ratio were also evaluated. Patients were reanalyzed after a 12-week administration of transdermal estrogen patches delivering 50 μg 17β-estradiol. The results were compared to those obtained from a group of 11 female volunteers in reproductive age, in whom basal blood was sampled during the early follicular phase of their cycle. Patients were divided into lean and obese according to their BMI. Obese postmenopausal women showed lower leptin levels when compared to premenopausal counterparts (25.1 ± 5.9 vs. 37 ± 11.3; p < 0.05), whereas no significant differences were found between the lean groups (14.5 ± 3.8 vs. 14.4 ± 4.9). Estrogen administration did not significantly change serum leptin concentrations in hypoestrogenized women (obese: 25.1 ± 5.9 vs. 28.6 ± 9.2; lean: 14.4 ± 4.9 vs. 17.6 ± 7.2). A positive linear correlation was found between leptin plasma levels and BMI only in obese patients (r = 0.58; p < 0.01) both before and after estrogen treatment. Menopause is characterized by a decreased expression of the obese gene, even if estrogens do not seem to represent a main causal factor.

The CC genotype of transforming growth factor-β1 increases the risk of late-onset Alzheimer's disease and is associated with AD-related depression

Transforming growth factor-β1 (TGF-β1) is a neurotrophic factor that exerts neuroprotective effects against β-amyloid-induced neurodegeneration. Recently, a specific impairment of the TGF-β1 signaling pathway has been demonstrated in Alzheimers disease (AD) brain. TGF-β1 is also involved in the pathogenesis of depressive disorders, which may occur in 30-40% of AD patients. The TGF-β1 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-β1. We investigated TGF-β1 +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-β1 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-β1 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-β1 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-β1 gene increases the risk to develop LOAD and is also associated with depressive symptoms in AD.

Scalp topographic mapping of middle-latency somatosensory evoked potentials in normal aging and dementia

Middle-latency somatosensory evoked potentials (MLSEPs) were recorded in four groups of subjects: 13 normal young controls (mean age, 17.9 years). 11 normal elderly (mean age, 66.9 years), 11 patients with dementia of Alzheimers type (DAT: mean age, 70.5), and four with vascular dementia (mean age, 79.3). MLSEPs in normal elderly showed an increase in the latency of P22, N30, P45, N60, and P100, and in the amplitude of N60. DAT patients also presented such changes; however, the increase in the amplitude of N60 was much more evident than that found in normal aging and was accompanied by a significant increase in amplitude of P45. Patients with vascular dementia tended to show longer latencies and larger amplitudes than the other groups. The increase in amplitude of P45 and N60 in MLSEPs seems to be characteristically associated with normal aging and the development of dementia. It is suggested that the mechanism of such functional changes might be correlated with the structural and neurochemical changes accompanying neuronal loss in these conditions.

Skin pathology findings in a cohort of 1500 adult and elderly subjects

Background No extensive studies are available in the literature on the eventual skin pathology induced by neurologic or systemic diseases in elderly individuals. Other factors, such as health and hygiene, socioeconomic status, and climate can also play an important role.

Homocysteine is a determinant of ApoA-I and both are associated with ankle brachial index, in an Ambulatory Elderly Population

OBJECTIVE The ankle brachial index (ABI) is an indicator of lower extremity peripheral arterial disease (PAD) and a predictor of atherothrombosis. ApoA-I and HDL are associated with PAD, in humans. Homocysteine influences the liver expression of ApoA-I and decreases its blood level and HDL in genetic mice models. We aimed therefore to evaluate whether homocysteine and its nutritional determinants, folate and vitamin B12 are associated with ABI by influencing HDL metabolism, in an ambulatory elderly population. METHODS 667 elderly volunteers from rural Sicily were assessed for ABI, homocysteine and its determinants, lipid markers and other predictors of PAD. HDL size was assessed in 15 sera in upper and lower quartiles of Hcy distribution. RESULTS In multivariate analysis, ApoA-I and homocysteine were two predictors of ABI (β-coefficient = 2.86, P<0.004 and β-coefficient = -3.41, P<0.001, respectively). Homocysteine correlated negatively with ApoA-I (R = -0.147, P<0.001) and with HDL-Cholesterol (R = -0.113, P = 0.003). The associations of homocysteine, vitamin B12 and methylmalonic acid with ApoA-I and HDL2a particles and that of homocysteine with increased small size HDL3c suggested mechanisms related with impaired synthesis of ApoA-I and HDL and abnormal maturation of HDL particles. CONCLUSION The influence of homocysteine on ApoA-I and HDL metabolism provides new insights on its role on vascular diseases, at a cross-point between atherosclerosis and atherothrombosis.

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 Alzheimers disease (AD). Indeed, previous studies have documented that glucagon-like peptide 1 (GLP-1) possesses neurotropic properties and can reduce amyloid-β 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.

Homocysteine predicts increased NT-pro-BNP through impaired fatty acid oxidation☆

BACKGROUND The deficiency in methyl donors, folate and vitamin B12, increases homocysteine and produces myocardium hypertrophy with impaired mitochondrial fatty acid oxidation and increased BNP, through hypomethylation of peroxisome-proliferator-activated-receptor gamma co-activator-1α, in rat. This may help to understand better the elusive link previously reported between hyperhomocysteinemia and BNP, in human. We investigated therefore the influence of methyl donors on heart mitochondrial fatty acid oxidation and brain natriuretic peptide, in two contrasted populations. METHODS Biomarkers of heart disease, of one carbon metabolism and of mitochondrial fatty acid oxidation were assessed in 1020 subjects, including patients undergoing coronarography and ambulatory elderly subjects from OASI cohort. RESULTS Folate deficit was more frequent in the coronarography population than in the elderly ambulatory volunteers and produced a higher concentration of homocysteine (19.3 ± 6.8 vs. 15.3 ± 5.6, P<0.001). Subjects with homocysteine in the upper quartile (≥ 18 μmol/L) had higher concentrations of NT-pro-BNP (or BNP in ambulatory subjects) and of short chain-, medium chain-, and long chain-acylcarnitines, compared to those in the lower quartile (≤ 12 μmol/L), in both populations (P<0.001). Homocysteine and NT-pro-BNP were positively correlated with short chain-, medium chain-, long chain-acylcarnitines and with acylcarnitine ratios indicative of decreased mitochondrial acyldehydrogenase activities (P<0.001). In multivariate analysis, homocysteine and long chain acylcarnitines were two interacting determinants of NT-pro-BNP, in addition to left ventricular ejection fraction, body mass index, creatinine and folate. CONCLUSIONS This study showed that homocysteine predicts increased NT-pro-BNP (or BNP) through a link with impaired mitochondrial fatty oxidation, in two contrasted populations.