The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe):design and baseline characteristics

Growing evidence suggests that elevated cholesterol levels in mid-life are associated with increased risk of developing Alzheimer's disease (AD), and that statins might have a protective effect against AD and dementia. The Lipitor's Effect in Alzheimer's Dementia (LEADe) study tests the hypothesis that a statin (atorvastatin 80 mg daily) will provide a benefit on the course of mild to moderate AD in patients receiving background therapy of a cholinesterase inhibitor (donepezil 10 mg daily).

Analysis of alteration of p75NTR processing and signalling by PS2 mutation and gamma-secretase inhibition

The presenilins (PSs) were identified as causative genes in cases of early-onset familial Alzheimer's disease (AD) and current evidence indicates that PSs are part of the gamma-secretase complex responsible for proteolytic processing of type I membrane proteins. p75NTR, a common neurotrophin receptor, was shown to be subject to gamma-secretase processing. However, it is not clear if the p75NTR downstream signal is altered in response to gamma-secretase cleavage, and further there is a possibility that AD-related PS mutations may affect this cleavage, resulting in pathogenic alterations in signal transduction. In this study, we confirmed that p75NTR downstream signalling is altered by PS2 mutation or gamma-secretase inhibition in SHSY-5Y cells. The activity of the small GTPase RhoA is strongly affected by these treatments. This study demonstrates that gamma-secretase and PS2 play an important role in regulating neurotrophin signal transduction and either mutation of PS2 or inhibition of gamma-secretase disturbs this function.

Cognitive, global, and functional benefits of donepezil in Alzheimer's disease and vascular dementia:results from large-scale clinical trials

Alzheimer's disease (AD) and vascular dementia (VaD) are both associated with deficits in cholinergic neurotransmission that are amenable to therapeutic intervention. The cholinesterase inhibitor, donepezil, is clinically effective in both AD and VaD. Results from a 10-study metaanalysis of donepezil (5 or 10 mg/day) in AD and a two-study combined analysis of donepezil (5 or 10 mg/day) in VaD are presented to compare patient characteristics and donepezil treatment outcomes. The analyzed studies were randomized, placebo-controlled, and of up to 24 weeks duration. In both AD and VaD, donepezil provided significant benefits compared with placebo on measures of cognition and global function. Placebo-treated AD patients showed a decline in cognition and global function, whereas placebo-treated VaD patients remained stable, suggesting treatment effects of donepezil in VaD were driven by improvement rather than stabilization or reduced decline. More VaD patients than AD patients received concomitant medications. Cardiovascular adverse events were more common in VaD than AD patients but were not increased by donepezil. In conclusion, although there are differences between AD and VaD patients in comorbid conditions and concomitant medications, donepezil is effective and well tolerated in both types of dementia.

Alzheimer's disease and age-related macular degeneration have different genetic models for complement gene variation

Alzheimer's disease (AD) and age-related macular degeneration (AMD) are both neurodegenerative disorders which share common pathological and biochemical features of the complement pathway. The aim of this study was to investigate whether there is an association between well replicated AMD genetic risk factors and AD. A large cohort of AD (n = 3898) patients and controls were genotyped for single nucleotide polymorphisms (SNPs) in the complement factor H (CFH), the Age-related maculopathy susceptibility protein 2 (ARMS2) the complement component 2 (C2), the complement factor B (CFB), and the complement component 3 (C3) genes. While significant but modest associations were identified between the complement factor H, the age-related maculopathy susceptibility protein 2, and the complement component 3 single nucleotide polymorphisms and AD, these were different in direction or genetic model to that observed in AMD. In addition the multilocus genetic model that predicts around a half of the sibling risk for AMD does not predict risk for AD. Our study provides further support to the hypothesis that while activation of the alternative complement pathway is central to AMD pathogenesis, it is less involved in AD.

Genetic variants influencing human aging from late-onset Alzheimer's disease (LOAD) genome-wide association studies (GWAS)

Genetics plays a crucial role in human aging with up to 30% of those living to the mid-80s being determined by genetic variation. Survival to older ages likely entails an even greater genetic contribution. There is increasing evidence that genes implicated in age-related diseases, such as cancer and neuronal disease, play a role in affecting human life span. We have selected the 10 most promising late-onset Alzheimer's disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1) have been tested for association with human aging in our dataset (1385 samples with documented age at death [AAD], age range: 58-108 years; mean age at death: 80.2) using the most significant single nucleotide polymorphisms (SNPs) found in the previous studies. Apart from the APOE locus (rs2075650) which showed compelling evidence of association with risk on human life span (p = 5.27 × 10(-4)), none of the other LOAD gene loci demonstrated significant evidence of association. In addition to examining the known LOAD genes, we carried out analyses using age at death as a quantitative trait. No genome-wide significant SNPs were discovered. Increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in the future. In this report, we also discuss issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome-wide significant signals from real SNP associations.

No consistent evidence for association between mtDNA variants and Alzheimer disease

Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain.

Functional and genetic analysis of haplotypic sequence variation at the nicastrin genomic locus

Nicastrin (NCSTN) is a component of the ?-secretase complex and therefore potentially a candidate risk gene for Alzheimer's disease. Here, we have developed a novel functional genomics methodology to express common locus haplotypes to assess functional differences. DNA recombination was used to engineer 5 bacterial artificial chromosomes (BACs) to each express a different haplotype of the NCSTN locus. Each NCSTN-BAC was delivered to knockout nicastrin (Ncstn(-/-)) cells and clonal NCSTN-BAC(+)/Ncstn(-/-) cell lines were created for functional analyses. We showed that all NCSTN-BAC haplotypes expressed nicastrin protein and rescued ?-secretase activity and amyloid beta (Aß) production in NCSTN-BAC(+)/Ncstn(-/-) lines. We then showed that genetic variation at the NCSTN locus affected alternative splicing in human postmortem brain tissue. However, there was no robust functional difference between clonal cell lines rescued by each of the 5 different haplotypes. Finally, there was no statistically significant association of NCSTN with disease risk in the 4 cohorts. We therefore conclude that it is unlikely that common variation at the NCSTN locus is a risk factor for Alzheimer's disease.

Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial:a double-blind, active and placebo-controlled study

The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial.

Aneurysms increase the risk of rebleeding after stereotactic radiosurgery for hemorrhagic arteriovenous malformations

BACKGROUND AND PURPOSE:
The purpose of this study was to define the risk of rebleeding after stereotactic radiosurgery (SRS) for hemorrhagic arteriovenous malformations with or without associated intracranial aneurysms.

METHODS:
Between 1987 and 2006, we performed Gamma Knife SRS on 996 patients with brain arteriovenous malformations; 407 patients had sustained an arteriovenous malformation hemorrhage. Sixty-four patients (16%) underwent prior embolization and 84 (21%) underwent prior surgical resection. The median target volume was 2.3 mL (range, 0.1-20.7 mL). The median margin dose was 20 Gy (range, 13.5-27 Gy).

RESULTS:
The overall rate of total obliteration defined by angiography or MRI was 56%, 77%, 80%, and 82% at 3, 4, 5, and 10 years, respectively. Before obliteration, 33 patients (8%) sustained an additional hemorrhage after SRS. The overall annual hemorrhage rate until obliteration after SRS was 1.3%. The presence of a patent aneurysm was significantly associated with an increased rehemorrhage risk after SRS (annual hemorrhage rate, 6.4%) compared with patients with a clipped or embolized aneurysm (annual hemorrhage rate, 0.8%; P=0.033).

CONCLUSIONS:
When an aneurysm is identified in patients with arteriovenous malformations selected for SRS, additional endovascular or surgical strategies should be considered to reduce the risk of bleeding during the latency interval.

Cognitive maturation in preterm and term born adolescents

Background: Adolescence is a critical period of brain structural reorganisation and maturation of cognitive abilities. This relatively late developmental reorganisation may be altered in individuals who were born preterm.

Methods: We carried out longitudinal neuropsychological testing in 94 very preterm individuals (VPT; before 33 weeks' gestation) and 44 term born individuals at mean ages of 15.3 years ( adolescence) and 19.5 years (young adulthood).

Results: Full scale, verbal and performance IQ and phonological verbal fluency were significantly lower in the VPT group than the term group at both ages. Repeated measures ANOVA showed only one group by time point interaction for semantic verbal fluency (F= 10.25; df = 107; p = 0.002). Paired- sample t tests showed that semantic verbal fluency increased significantly in the term group over adolescence (t = -5.10; df = 42; p < 0.001), but did not increase in the VPT group (t = 0.141; df = 69; p = 0.889). For verbal IQ, there was a significant interaction between time point and sex (F = 4.48; df = 1; p = 0.036) with paired- sample t tests showing that verbal IQ decreased in males between adolescence and adulthood (t = 3.35; df = 71; p = 0.001), but did not change significantly in females (t = 0.20; df = 52; p = 0.845).

Conclusion: Decrements of intellectual functioning in VPT individuals persist into adulthood. Additionally, there is a deficit in the adolescent maturation of semantic verbal fluency in individuals born VPT.

Cognitive deficits in first-episode psychosis: A population-based study in Sao Paulo, Brazil

Background: Studies conducted in high-income countries have reported significant cognitive deficits in first on set schizophrenia subjects relative to asymptotic controls, and it has been suggested that the severity of such deficits could be directly related to the duration of untreated psychosis (DUP). It is relevant to conduct similar studies in developing countries, given the supposedly better outcome for schizophrenia patients living in the latter environments.

Methods: We applied verbal fluency and digit span tests to an epidemiological-based series of patients with first-onset psychoses (n = 179) recruited in the city of Sao Paulo, and compared the findings with those from non-psychotic control subjects randomly selected from the same geographical areas (n=383).

Results: Psychosis subjects showed lower scores on the three tests relative to controls, with greatest between-group differences for the backward digit span task (p < 0.0001). There were no significant differences between subjects with affective and schizophreniform psychosis. Cognitive performance indices were negatively correlated with the severity of negative symptoms, but showed no relation to DUP.

Conclusion: We found significant cognitive deficits in patients investigated early during the course of psychotic disorders in an environment that is distinct from those where the subjects investigated in previous studies have been drawn from. We found no support to the hypothesis of an association between greater cognitive deficits and a longer DUP. (c) 2006 Published by Elsevier B.V.

Effects of very low birthweight on brain structure in adulthood

Very-low-birthweight (VLBW) individuals are at high risk of brain injury in the perinatal period. We wished to determine how such early brain lesions affect brain structure in adulthood. Thirty-two VLBW adults (20 female, 12 male) and, 18 term, normal birthweight sibling control individuals (nine female, nine male) underwent structural MRI at a mean age of 23 years 4 months (range 17 to 33 years; SD 3.4). Images were analyzed using an automated tissue segmentation algorithm in order to estimate whole brain tissue class volumes in native space. Images were then warped to a template image in standard space. There was no significant between-group difference in whole brain, greymatter, white matter, or total cerebral spinal fluid (CSF) volumes. However, lateral ventricular volume was significantly increased by 41% in those with VLBW. The ratio of grey to white matter was also significantly increased (by 10%) in those with VLBW. Group comparison maps showed widespread changes in the distribution of grey and white matter, and relative excess of ventricular CSF, in the brains of VLBW individuals. Increased ventricular volume predicted decreased grey matter in subcortical nuclei and limbic cortical structures, and decreased periventricular white matter. We conclude that these diffuse abnormalities of grey and white matter are a consequence,of the interaction of perinatal brain injury and ongoing neurodevelopmental processes.

Premorbid IQ in patients with functional psychosis and their first-degree relatives

Numerous studies have found deficits in premorbid IQ in schizophrenic patients, but it is not clear whether this deficit is shared by (a) patients with other functional psychoses, and (b) relatives of these patients. Ninety-one schizophrenic patients, 66 affective psychotic patients (29 schizoaffective and 37 manic or depressed), and 50 normal control subjects were administered the National Adult Reading Test (NART) which provides an estimate of premorbid IQ. The NART was also completed by 85 first-degree relatives of schizophrenic patients and by 65 first-degree relatives of affective psychotic patients. After adjustments were made for sex, social class, ethnicity and years of education, schizophrenic patients had significantly lower premorbid IQ than their relatives, the affective psychotic patients and controls. Manic and depressed patients had significantly lower NART scores than their first-degree relatives, but schizoaffective patients did not, and neither group differed significantly from controls. There was no significant difference in premorbid IQ between patients who had experienced obstetric complications (OC +) and those who had not (OC -). Both OC + and OC - schizophrenic patients differed significantly from their relatives, but the disparity was greatest between OC + patients and their relatives. Relatives of OC + schizophrenic patients had significantly higher IQ than relatives of OC - schizophrenic patients. (C) 2000 Elsevier Science B.V. All rights reserved.

Language and crossed finger localization in patients with schizophrenia

Language deficits are frequently reported in studies of patients with schizophrenia. The present study sought to test the hypothesis that such deficits are related to callosal function in this group. The FAS test of verbal fluency and Perin's Spoonerisms test of phonological processing were the tests of language. Callosal function was assessed using a Crossed Finger Localisation Test (CFLT), which is a measure of the interhemispheric transfer of somatosensory information. Patients with schizophrenia performed less well than controls on measures of language function. as well as on the CFLT. Significant positive correlations between CFLT performance and language function were present in the patient group, but not the control group. These findings extend on previous studies that report functional abnormalities of the corpus callosum in schizophrenia and are consistent with the hypothesis that language deficits in schizophrenia are related to impaired callosal functioning in this group. However, other explanations cannot be ruled Out.

Neuropsychological outcome at adolescence of very preterm birth and its relation to brain structure

Neuropsychological outcome at 14 to 15 years of age of a cohort of 75 participants (39 male, 36 female) born at <33 weeks' gestation was investigated. Research was conducted parallel to a recent MRI study by Stewart and colleagues which reported that 55% of this cohort had evidence of brain abnormality. One aim of the studs was to compare neuropsychological function in those very preterm children with and without MRI abnormality. Compared to a control sample of term adolescents, very preterm participants had impairment only on a measure of word production. On measures of attention, memory, perceptual skill, and visuomotor and executive function, the adolescents born very preterm performed in the normal range, whether or not they had evidence of MRI abnormality. Our findings are encouraging as the neuropsychological consequences of damage to the very preterm brain, still evident on MRI at 14 to 15 years of age, appear to be minor.