Gerwin Roks

Genomewide Association Studies of Stroke

BACKGROUND The genes underlying the risk of stroke in the general population remain undetermined. METHODS We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

Octapeptide repeat insertions in the prion protein gene and early onset dementia

Objectives: The most common familial early onset dementia mutations are found in the genes involved in Alzheimer’s disease; the amyloid precursor protein (APP) and the presenilin 1 and 2 (PSEN1 and 2) genes; the prion protein gene (PRNP) may be involved. Methods: Following identification of a two-octapeptide repeat insertion in PRNP, we conducted a meta-analysis to investigate the relation of number of PRNP octapeptide repeats with age at disease onset and duration of illness; identifying 55 patients with PRNP octapeptide repeat insertions. We used a linear mixed effects model to assess the relation of number of repeats with age at disease onset, and studied the effect of the number of inserted octapeptide repeats on disease duration with a Cox proportional hazards regression analysis. Results: We found an increasing number of repeats associated with younger age at onset (p<0.001). Duration of the disease decreased significantly with the length of the octapeptide repeat (p<0.001) when adjusting for age at onset. Conclusions: Our findings show significant inverse associations of the length of the PRNP octapeptide repeat with age at disease onset and disease duration in the spongiform encephalopathies.

The α2-macroglobulin gene in AD A population-based study and meta-analysis

Background: Whereas several authors recently reported a positive association between the α2-macroglobulin gene (A2M) and late-onset AD (LOAD), others were unable to replicate these findings. Early-onset AD (EOAD) is defined as onset age <65 years. Virtually all patients with LOAD are >65 years of age. Objective: To evaluate the role of A2M in AD, the authors conducted a population-based study of EOAD and LOAD as well as a meta-analysis of all studies conducted to date. Methods: Patients with EOAD (n = 100) were derived from a population-based study in four northern provinces of the Netherlands and the area of metropolitan Rotterdam. Patients with LOAD (n = 344) were drawn from the Rotterdam Study, a population-based prospective study on residents aged 55 years and over of a Rotterdam suburb in the Netherlands. Two polymorphisms were studied, A2M-I/D and A2M-Ile1000Val, in relation to the APOE ε4 allele (APOE*4). Results: No genotypic or allelic association was found for either polymorphism in the population-based series of patients with LOAD. In patients with EOAD without APOE*4, a significant increase of carriers of A2M-1000Val was found. The meta-analysis of available published case–control data on these polymorphisms in white and mixed ethnic populations yielded no significant differences between cases and controls. Pooling the Asian studies conducted to date showed a significant decrease in the frequency of A2M-D among patients. Conclusions: These results suggest that A2M is not genetically associated with LOAD in white patients or mixed populations as found in the United States. In these populations A2M does not have clinical relevance. From a scientific perspective, the findings on EOAD and Asian patients require replication and further research in the A2M region.

Delirium in the acute phase after stroke: Incidence, risk factors, and outcome

Objectives: This prospective cohort study assesses incidence of delirium after stroke. In addition, risk factors during the first week were assessed. Finally, outcome in relation to development of delirium was studied. Methods: A total of 527 consecutive patients with stroke (median age, 72 years; range, 29–96 years) were screened for delirium during the first week after admission. We diagnosed delirium with the Confusion Assessment Method. Cognitive functioning prior to the stroke was assessed with the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Neurologic deficits were assessed with the NIH Stroke Scale. Results: A total of 62 patients with stroke (11.8%) developed delirium during the first week of admission. Independent risk factors were preexisting cognitive decline (odds ratio [OR] for IQCODE above 50: 2.6, 95% confidence interval [CI] 1.2–5.7) and infection (OR 3.4, 95% CI 1.7–6.8). Furthermore, right-sided hemispheric stroke (OR 2.0, 95% CI 1.0–3.0), anterior circulation large-vessel stroke (OR 3.4, 95% CI 1.1–10.2), the highest tertile of the NIH Stroke Scale (OR for highest vs lowest tertile 15.1, 95% CI 3.3–69.0), and brain atrophy (OR for highest versus lowest tertile 2.7, 95% CI 1.1–6.8) increased the risk for delirium. Delirium was associated with a worse outcome in terms of duration of hospitalization, mortality, and functional outcome. Conclusions: Delirium occurs in almost 1 out of every 8 patients with stroke on a stroke unit and is associated with cognitive decline, infection, right-sided hemispheric stroke, anterior circulation large-vessel stroke, stroke severity, and brain atrophy. Delirium after stroke is associated with a worse outcome.

The microtubule associated protein Tau gene and Alzheimer's disease--an association study and meta-analysis.

Several studies have suggested an association between polymorphisms and an extended haplotype of the microtubule associated protein tau gene and Alzheimers disease (AD) in synergy with apolipoprotein E (APOE) epsilon 4 status. However these findings have not been consistently replicated. We investigated the role of the tau haplotype in AD by conducting an association study as well as a meta-analysis of all the studies conducted to date. We examined six polymorphisms known to be in the extended tau haplotypes, one in exon 7 and five in and around exon 9 in 200 late onset AD and 189 control samples. All the polymorphisms examined fell into the recognised tau haplotypes. There was no statistical significant association with any of the polymorphisms and late onset AD. Stratification of data by APOE epsilon 4 status also produced no strongly significant association. The meta-analysis showed no significant differences between AD cases and controls, however stratification of data by APOE epsilon 4 status showed a small significant decrease in the H1 haplotype in AD before correction for multiple testing.

A pilot study of rivastigmine in the treatment of delirium after stroke: a safe alternative.

BackgroundDelirium is a common disorder in the early phase of stroke. Given the presumed cholinergic deficiency in delirium, we tested treatment with the acetylcholinesterase inhibitor rivastigmine.MethodsThis pilot study was performed within an epidemiological study. In 527 consecutive stroke patients presence of delirium was assessed during the first week with the confusion assessment method. Severity was scored with the delirium rating scale (DRS). Sixty-two patients developed a delirium in the acute phase of stroke. Only patients with a severe and persistent delirium (defined as a DRS of 12 or more for more than 24 hours) were enrolled in the present study. In total 26 fulfilled these criteria of whom 17 were treated with orally administered rivastigmine with a total dose between 3 and 12 mg a day. Eight patients could not be treated because of dysphagia and one because of early discharge.ResultsNo major side effects were recorded. In 16 patients there was a considerable decrease in severity of delirium. The mean DRS declined from 14.8 on day one to 8.5 after therapy and 5.6 after tapering. The mean duration of delirium was 6.7 days (range; 2–17).ConclusionRivastigmine is safe in stroke patients with delirium even after rapid titration. In the majority of patients the delirium improved after treatment. A randomized controlled trial is needed to establish the usefulness of rivastigmine in delirium after stroke.Trial registrationNederlands Trial Register NTR1395

Complex compulsive behaviour in the temporal variant of frontotemporal dementia

Objective As metabolic and structural changes in frontotemporal-subcortical pathways have been reported in patients with obsessive-compulsive disorders, we investigated the correlation between complex compulsive behaviour (CCB) and the distribution of atrophy in a group of 90 patients with frontotemporal dementia (FTD). Methods CCB was defined as complex, intentional, and time consuming repetitive behaviour, which was distinguished from simple compulsive behaviour (SCB), such as verbal and motor repetitions and utilisation behaviour. Cortical atrophy on CT and/or MRI was semi-quantitatively assessed in frontal, temporal, parietal and occipital regions, and the pattern of atrophy was compared between patients with and without CCB or SCB. Linear measures were used to establish the presence of caudate atrophy (bicaudate ratio) and ventricular enlargement (bifrontal ratio). Results CCB was reported in 18 (21 %) and SCB in 53 (61 %) FTD patients. Frontotemporal atrophy was present in 64 patients (74 %), and predominant temporal atrophy in 23 (26 %). The pattern of atrophy was asymmetric in 25 patients (29 %). Logistic regression analysis showed that temporal lobe atrophy (p < 0.005), as well as asymmetry of atrophy (p < 0.05) were independently associated with CCB, after adjusting for age at onset, gender, duration of symptoms at the time of imaging, severity of atrophy, and bicaudate and bifrontal ratio. No relationship was found between the presence of SCB and the distribution of atrophy, although patients with SCB tended to have more caudate atrophy (p < 0.1). Conclusion Temporal lobe atrophy appears to mediate CCB in patients with FTD, especially if asymmetry of atrophy is present. Future studies with quantitative and volumetric measurements of the cortical and subcortical structures may further clarify the aetiology of CCB in FTD.

Amyloid β secretase gene (BACE) is neither mutated in nor associated with early-onset Alzheimer's disease

The beta-site of β-amyloid precursor protein cleaving enzyme (BACE) cleaves the β-amyloid (Aβ) precursor protein at the N-terminal end of Aβ, allowing for the production of Aβ by C-terminal γ-secretase cleavage. We hypothesized that over-activity of BACE might lead to the overproduction of Aβ, hence causing Alzheimers disease (AD). Molecular genetic analyses of BACE in 9 autosomal dominant AD families and a population-based sample of 101 presenile AD cases did not identify genetic linkage, pathogenic mutations or genetic association with BACE, suggesting that BACE is not genetically involved in the etiology of AD.

Mutation screening of the tau gene in patients with early-onset Alzheimer's disease

Hyperphosphorylated microtubule associated protein tau, present in neurofibrillary tangles, is a prominent pathological feature of Alzheimers disease (AD). The gene encoding tau (MAPT) was recently found mutated in frontotemporal dementia (FTD) and other tauopathies. We studied MAPT as a candidate gene in the etiology of AD. The study population consisted of 101 early-onset AD patients and 117 controls. Mutation analysis did not detect causal mutations in exons 9 to 13 encoding the microtubule-binding domains involved in FTD, however, two novel polymorphisms were detected in exon 9. Using the Ala169 polymorphism in exon 9 and a previously reported (CA)n-repeat polymorphism in intron 9, an association study was performed. No association with early-onset AD was detected. Together, our data indicate that MAPT does not play a role in early-onset AD.

The -491 A/T polymorphism in the regulatory region of the apolipoprotein E gene and early-onset Alzheimer's disease

The -491 polymorphism in the promoter region of the apolipoprotein E gene (APOE) has been suggested to be associated with increased risk for Alzheimers disease (AD) independent of APOE status. We studied the association between the -491 polymorphism and risk for early-onset Alzheimers disease in 99 Dutch and 78 Spanish patients. In patients with early-onset AD, we found no consistent relationship with a single allele of the -491 polymorphism. Linkage disequilibrium between the polymorphism and the APOE gene was found which most likely might explain the inconsistent findings.