Association study between the DNMT3A -448A>G polymorphism and risk of Alzheimer's disease in Caucasians of Italian origin

Increasing evidence points to an epigenetic contribution in Alzheimer's disease (AD) pathogenesis. In this regard, variants and polymorphisms of DNA methyltransferase genes (DNMTs) are being investigated for their contribution to cognitive decline and dementia, but results are still scarce or controversial. In the present study we genotyped 710 Caucasian subjects of Italian descent, including 320 late-onset AD (LOAD) patients, 70 individuals with amnestic Mild Cognitive Impairment (MCI), and 320 matched healthy controls, for the presence of a functional DNMT3A -448A>G (rs1550117) polymorphism, searching for association with disease risk. In addition, we searched for correlation between the studied polymorphism and circulating levels of folate, homocysteine (hcy) and vitamin B12, all involved in DNA methylation reactions and available from 189 LOAD patients and 186 matched controls. Both allele and genotype frequencies of rs1550117 were closely similar between MCI, LOAD and control subjects, and no association with dementia or pre-dementia conditions was observed. Plasma hcy levels were significantly higher (p = 0.04) and serum folate levels significantly lower (p = 0.01) in LOAD than in controls, but no difference in circulating folate, hcy or vitamin B12 levels was seen between carriers and non-carriers of the minor DNMT3A -448A allele. Collectively, present results confirmed previous associations of increased hcy and decreased folate with LOAD risk, but do not support an association between the DNMT3A -448A>G polymorphism and AD in our population

Increase in Mitochondrial D-Loop Region Methylation Levels in Mild Cognitive Impairment Individuals

Methylation levels of the mitochondrial displacement loop (D-loop) region have been reported to be altered in the brain and blood of Alzheimer's disease (AD) patients. Moreover, a dynamic D-loop methylation pattern was observed in the brain of transgenic AD mice along with disease progression. However, investigations on the blood cells of AD patients in the prodromal phases of the disease have not been performed so far. The aim of this study was to analyze D-loop methylation levels by means of the MS-HRM technique in the peripheral blood cells of 14 mild cognitive impairment (MCI) patients, 18 early stage AD patients, 70 advanced stage AD patients, and 105 healthy control subjects. We found higher D-loop methylation levels in MCI patients than in control subjects and AD patients. Moreover, higher D-loop methylation levels were observed in control subjects than in AD patients in advanced stages of the disease, but not in those at early stages. The present pilot study shows that peripheral D-loop methylation levels differ in patients at different stages of AD pathology, suggesting that further studies deserve to be performed in order to validate the usefulness of D-loop methylation analysis as a peripheral biomarker for the early detection of AD

Long-term beneficial impact of the randomised trial 'Train the Brain', a motor/cognitive intervention in mild cognitive impairment people: effects at the 14-month follow-up

: No treatment options are currently available to counteract cognitive deficits and/or delay progression towards dementia in older people with mild cognitive impairment (MCI). The 'Train the Brain' programme is a combined motor and cognitive intervention previously shown to markedly improve cognitive functions in MCI individuals compared to non-trained MCI controls, as assessed at the end of the 7-month intervention. Here, we extended the previous analyses to include the long-term effects of the intervention and performed a data disaggregation by gender, education and age of the enrolled participants. We report that the beneficial impact on cognitive functions was preserved at the 14-month follow-up, with greater effects in low-educated compared to high-educated individuals, and in women than in men

Alexithymia may modulate decision making in patients with de novo Parkinson’s disease

The aim of this study was to investigate whether and how alexithymia may influence decision making under conditions of uncertainty, assessed using the Iowa Gambling Task, in patients with newly diagnosed, untreated (de novo) Parkinson’s disease, as previously reported for healthy subjects. Twenty-four patients with de novo Parkinson’s disease underwent a neuropsychological and neuropsychiatric assessment, including the Toronto Alexithymia Scale, the Geriatric Depression Scale Short Form, and the Iowa Gambling Task (IGT). The assessment showed that 12 patients were alexithymic and 12 were non-alexithymic; seven patients were found to be mildly depressed and 17 non-depressed. Alexithymic and non-alexithymic patients did not differ in the IGT total score; however, significant differences emerged across the third block of the IGT, in which the alexithymic patients outperformed the nonalexithymic patients. Depression did not influence IGT performance. Alexithymia may modulate decision making, as assessed with the IGT; alexithymia could be associated with faster learning to avoid risky choices and negative feedback, as previously reported in some studies conducted in anxious or depressed patients

P2‐239: POTENTIAL DIAGNOSTIC VALUE OF RED BLOOD CELLS α‐SYNUCLEIN HETEROAGGREGATES IN ALZHEIMER'S DISEASE

n/

Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations

Recent genome-wide association studies have identified five loci (BIN1, CLU, CR1, EXOC3L2 and PICALM) as genetic determinants of Alzheimer’s disease (AD). We attempted to confirm the association between these genes and the AD risk in three contrasting European populations (from Finland, Italy and Spain). Since CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3 and PICALM. In a total of 2,816 AD cases and 2,706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (OR=1.26, 95% CI [1.15-1.38], p=2.9x10-7, and OR=0.80, 95% CI [0.74-0.88], p=4.6x10-7, respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR=1.19, 95% CI [1.06-1.32], p=2.0x10-3). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation

Operationalizing mild cognitive impairment criteria in small vessel disease: The VMCI-Tuscany Study

Introduction Mild cognitive impairment (MCI) prodromic of vascular dementia is expected to have a multidomain profile. Methods In a sample of cerebral small vessel disease (SVD) patients, we assessed MCI subtypes distributions according to different operationalization of Winblad criteria and compared the neuroimaging features of single versus multidomain MCI. We applied three MCI diagnostic scenarios in which the cutoffs for objective impairment and the number of considered neuropsychological tests varied. Results Passing from a liberal to more conservative diagnostic scenarios, of 153 patients, 5% were no longer classified as MCI, amnestic multidomain frequency decreased, and nonamnestic single domain increased. Considering neuroimaging features, severe medial temporal lobe atrophy was more frequent in multidomain compared with single domain. Discussion Operationalizing MCI criteria changes the relative frequency of MCI subtypes. Nonamnestic single domain MCI may be a previously nonrecognized type of MCI associated with SVD

The epidemiology and clinical manifestations of dysexecutive syndrome in Parkinson's disease

This mini-review summarizes the evidence of the cognitive and behavioral features of dysexecutive syndrome in Parkinson's disease (PD). Deficits in response inhibition, setshifting, mental flexibility, and strategy have been frequently described from the earliest stages of PD, although there are inconsistencies in study findings due to the complexity of the executive function (EF) construct and methodological limitations. Behavioral disorders of PD, e.g., apathy, distractibility, perseverative behavior, and impulse-control disorders, may be viewed as the other side of dysexecutive syndrome. Despite the interrelationship between the cognitive and behavioral domains, some reports reveal that the two syndromes may be dissociated, suggesting that both aspects must be clinically assessed. EFs are widely associated with the prefrontal areas, although dysexecutive syndrome may be observed in patients with damage to other brain regions. EFs drive numerous abilities essential to daily life, such as prospective remembering and language comprehension, which may be impaired in PD subjects. Considering the impact of dysexecutive syndrome on independence and quality of life, early detection of executive impairment is crucial in the management of PD. © 2012 Ceravolo, Pagni, Tognoni and Bonuccelli