Carolina Piccini

Brain-derived neurotrophic factor, apolipoprotein E genetic variants and cognitive performance in Alzheimer's disease.

Since greater attention has been paid to the direct link of genetic variation to cognition and memory performance, apolipoprotein E (ApoE) and brain-derived neurotrophic factor (BDNF) have been the two most frequently studied genes. To investigate the effect of BDNF and ApoE polymorphisms on the cognitive profile of mild-moderate Alzheimers disease (AD) cases, AD patients, genotyped for ApoE and BDNF polymorphisms, underwent extensive neuropsychological investigation. The effect of either ApoE epsilon4 allele and BDNF genetic variant on the neuropsychological pattern of mental impairment was examined both in terms of group differences in performance on the neuropsychological tests between carriers and non-carriers of each variant and by selecting the best predictor of cognitive performance among demographic and genetic factors by means of a multiple regression analysis. Our data confirm a specific effect caused by the presence and amount of ApoE epsilon4 allele, while they suggest that BDNF genetic variants are not a susceptibility factor to AD.

Alzheimer’s Disease: Role of Size and Location of White Matter Changes in Determining Cognitive Deficits

This study investigated the contribution that white matter changes (WMCs) make to clinical and cognitive features in Alzheimer’s disease (AD), independently ofpossible confounders such as cortical atrophy and the apolipoprotein E genotype as well as their relationship to vascular risk factors. We semiquantitatively assessed the degree and location of WMCs (global, periventricular and deep white matter), lacunes and global atrophy on brain MRI scans of 86 AD cases, extensively evaluated from a clinical and neuropsychological point of view. Multivariate logistic and linear regression analysis showed that age was the only significant predictor of all WMC measures and revealed a significant association of periventricular WMCs with performance on executive function tasks as well as of deep WMCs with history of mood depression. Our results underline the significance of WMC location over size in the occurrence of specific cognitive deficits in AD.

KIBRA gene variants are associated with episodic memory performance in subjective memory complaints.

The KIBRA gene encodes a cytoplasmatic protein, a member of the signal transduction protein family, expressed mainly in the brain. Recent studies have implicated the involvement of a genetic variation in the KIBRA gene (T allele) in human memory in normal subjects and in the risk of developing Alzheimers disease (AD). We report here the distribution of the KIBRA genetic variant and the Apolipoprotein E (ApoE) epsilon4 allele and their association with neuropsychological measures in older adults reporting problems with everyday memory (subjective memory complaints, SMC). We found that SMC subjects with the CT/TT genotype performed more poorly than those with the CC genotype on long-term memory tests. Thus, in our opinion, these data suggest that the KIBRA genotype could affect memory performance in a different way in those that complain of memory deficits compared to those that do not.

A presenilin-1 mutation (Leu392Pro) in a familial AD kindred with psychiatric symptoms at onset

Missense mutations in the presenilin genes are implicated in the majority of early-onset familial AD (EOFAD) cases. Presenilin 1 (PS-1) is a multispanning membrane protein composed of 467 amino acids, containing six to nine transmembrane helical domains and a large hydrophilic loop between domains six and seven. To date, more than 50 missense mutations1 and a splice site mutation in PS-1 have been found to cosegregate with EOFAD. Common phenotypic features of presenilin-1 linked families include onset of memory disturbances before age 50 years, shorter disease duration, and the presence of myoclonus and generalized seizures. We have performed a clinical and genetic screening in order to search for additional missense presenilin mutations in families with EOFAD, identifying a new family with a previously undescribed missense mutation in exon 11 leading to a Leu to Pro substitution at codon 392. This mutation was not detected in 50 unrelated subjects, indicating that this is not a common polymorphism. The members of this kindred belong to a three-generation family from central Italy ( figure). The proband, (III-1), a 38-year-old man, …

Treatable and reversible dementias: an update

The ever greater emphasis on the application of a standard work-up in the clinical diagnosis of dementia -- and Alzheimers Disease (AD) in particular -- has made it easier to identify potentially treatable and/or reversible cases. The aim of this paper is to update the issue of treatable and reversible dementias.

Metabolic correlates of executive dysfunction. Different patterns in mild and very mild Alzheimer's disease.

This study was designed to examine the correlations between resting-state brain glucose metabolism (CMRglc), as measured with Positron Emission Tomography and performance on executive function tasks in Alzheimers disease (AD), while taking into account the severity of cognitive deterioration. We addressed this issue in 50 AD patients, classified as very mild (n = 22) and mild (n = 28) AD on the basis of an extensive neuropsychological battery. Thirteen healthy subjects were selected as controls for the neuropsychological measures. Statistical Parametric Mapping (SPM) was used to examine voxel-wise correlations between CMRglc and scores on selected cognitive tests of executive functions: the Stroop Test, the Trail Making Test, the Dual Task and the Phonemic Fluency, while correcting for age and global CMRglc. All analyses were done separately for the two AD subgroups. The very mild AD patients showed significant associations between Stroop and Trail Making Test scores and prefrontal regions metabolism, whereas the mild AD patients exhibited more widely distributed cognitive–metabolic correlations extending to the posterior brain regions. These data suggest that a large cortical network is implicated in executive dysfunction in AD, and that the pattern of cognitive–metabolic correlations varies according to disease severity.

Neutrophils CD11b and fibroblasts PGE2 are elevated in Alzheimer’s disease

To evaluate whether inflammation-like mechanisms present in the brain of Alzheimers disease (AD) patients are reflected in the periphery, the expression of CD11b in peripheral blood neutrophils and the expression and activity of inflammatory markers in cultured skin fibroblasts were examined. We found significantly higher levels of CD11b in neutrophils from sporadic AD patients than in controls and this elevation was positively correlated with disease severity and progression rate of mental decline. Cultured skin fibroblasts from familial (FAD) and sporadic AD patients and from controls were immunopositive for both isoforms of cyclooxygenase with no differences between groups. In unstimulated culture, the production of prostaglandin-E2 in the medium was significantly higher in fibroblasts from sporadic AD and FAD patients than in controls, and this elevation was reverted by the addition of 25 microM of ibuprofen. Our findings provide further evidence of the presence of inflammatory and immuno-related markers in the periphery of AD patients and support those studies indicating the beneficial effects of anti-inflammatory therapy in AD.

Corpus callosum atrophy is associated with gait disorders in patients with leukoaraiosis

Cognitive impairment and gait disturbances are the most frequent clinical findings in patients with leukoaraiosis (LA). Corpus callosum (CC) atrophy has been associated with dementia in patients with LA, as well as with gait disturbances in patients with normal pressure hydrocephalus. We investigated, in patients with LA, the possible association between gait impairment and CC atrophy, taking into account cognitive deficits and the other brain lesions commonly present in these patients. Thirty patients (M:F=21:9; mean age 72.5±6.3 years) with gait disturbances and brain CT images consistent with LA underwent an assessment of gait and a cognitive assessment of global and selective functions. Magnetic resonance imaging (MRI) was used to measure thickness and area of the CC, total LA volume, lacunar infarcts and size of lateral ventricles. We examined the effect of every MRI change on each performance measure. Reduction of CC thickness, particularly that of the anterior segment, had a significant effect on severity of gait impairment, as measured using the gait scale’s score. It was independent of any other brain changes revealed by MRI, including LA. An independent, significant association was also found between CC area and the Left Hand Praxis test results. In patients with LA, CC atrophy is associated with gait impairment independently of LA and other brain abnormalities usually present in these patients.

Pattern and Progression of Cognitive Decline in Alzheimer’s Disease: Role of Premorbid Intelligence and ApoE Genotype

Background/Aims: Because of controversial results across studies, we evaluated the predictive value of premorbid intelligence and the apolipoprotein E (ApoE) genotype on baseline and progression of cognitive performance in Alzheimer’s disease (AD). Methods: Eighty-five mild AD cases, ApoE genotyped and included in a longitudinal cliniconeuropsychological-genetic study, underwent a premorbid intelligence test and up to 11 (average 5) neuropsychological assessments. We applied linear- and logistic-regression models for cross-sectional data and mixed models for longitudinal ones. Results: Higher premorbid intelligence was associated with higher global, executive and memory performance, while the ApoE Ε4 allele was specifically related to poorer memory performance. The premorbid intelligence-ApoE Ε4/Ε4 interaction was significant, with higher premorbid intelligence scores reducing the detrimental effect of ApoE Ε4 homozygosity on memory performance. Higher premorbid intelligence, but not the ApoE Ε4 allele, was related to faster memory deficit progression. Conclusion: The association of higher premorbid intelligence with better baseline cognitive performance and faster memory decline, as well as its interaction with the ApoE genotype, strengthens the role of cognitive reserve in shaping the disease’s clinical expression. Our findings confirm that the Ε4 allele affects memory deficit at baseline but does not exert any influence on the rate of cognitive decline.

Clinically relevant cognitive impairment after cardiac surgery: a 6-month follow-up study

BACKGROUND AND PURPOSE The majority of studies on neuropsychological complications after cardiac surgery used the raw variation of selective tests scores to define the occurrence of cognitive decline. We prospectively estimated the frequency of cognitive impairment after cardiac surgery, with a particular emphasis on persistent and clinically relevant cognitive decline. Possible baseline and operative predictors were also evaluated. METHODS An extensive neuropsychological battery was administered to 110 patients (mean age 64.1+/-9.4 years; 70.9% males) undergoing cardiac surgery before and 6 months after the operation. After evaluating the variations in the cognitive performances, two independent neuropsychologists ranked the patients as unchanged-improved, mildly-moderately deteriorated, or severely deteriorated, using a global and functionally oriented judgement. The degree of the impairment was determined in relation to its impact on everyday life activities. RESULTS Ten patients (9.1%) were ranked as severely deteriorated, 22 (20%) as mildly-moderately deteriorated, and 78 (70.9%) as unchanged-improved. Cognitively impaired patients were older (p=0.031), more often females (p=0.005), with a low education level (p=0.013). At multivariate analysis, female gender (odds ratio (OR) 6.14, 95% confidence interval (95% CI) 2.16-17.50), baseline use of beta-blockers (OR 4.55, 95% CI 1.30-15.92), and PaO2 at arrival in intensive care unit (OR for 1 mm Hg increment 1.012, 95% CI 1.004-1.020) were significant predictors of cognitive impairment of any degree. Positive predictors of severe cognitive impairment were history of hypertension (OR 5.33, 95% CI 1.03-27.64) and PaO2 at arrival intensive care unit (OR for 1 mm Hg increment 1.020, 95% CI 1.006-1.035), while education was protective (OR per year of increment 0.53, 95% CI 0.31-0.90). CONCLUSIONS A considerable proportion of cardiac surgery patients may undergo clinically relevant cognitive impairment. The knowledge of variables influencing cognitive outcome is essential for the adoption of preventive measures.