Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909 622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons. A polymorphism within SCN1A (encoding the alpha subunit of the type I voltage-gated sodium channel) was replicated in three independent populations of 1699 individuals. Functional magnetic resonance imaging during an n-back working memory task detected SCN1A allele-dependent activation differences in brain regions typically involved in working memory processes. These results suggest an important role for SCN1A in human short-term memory.Molecular Psychiatry advance online publication, 29 December 2009; doi:10.1038/mp.2009.133.

In younger patients with stroke, cerebral vasculitis and hereditary small vessel diseases should be considered as important differential diagnoses. Since the clinical course of cerebral vasculitis is highly variable, diagnostic workup, which includes laboratory tests, CSF analysis, cranial magnetic resonance imaging and biopsy, is often challenging. Therapy should be initiated on an interdisciplinary basis and includes immunosuppressive induction and maintenance regimes. Hereditary small vessel diseases, e.g. CADASIL or Fabry's disease, can mimic clinical features of cerebral vasculitis. Their diagnosis which is based on family history, typical clinical features and genetic analysis often has implications for treatment and genetic counselling.

We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5' to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).

We expanded our genome-wide association study on atrial fibrillation (AF) in Iceland, which previously identified risk variants on 4q25, and tested the most significant associations in samples from Iceland, Norway and the United States. A variant in the ZFHX3 gene on chromosome 16q22, rs7193343-T, associated significantly with AF (odds ratio OR = 1.21, P = 1.4 x 10(-10)). This variant also associated with ischemic stroke (OR = 1.11, P = 0.00054) and cardioembolic stroke (OR = 1.22, P = 0.00021) in a combined analysis of five stroke samples.

BACKGROUND AND PURPOSE: Suboccipital decompressive craniectomy (SDC) is a life-saving intervention for patients with malignant cerebellar infarction. However, long-term outcome has not been systematically analyzed. METHODS: In this monocentric retrospective study we analyzed mortality, long-term functional outcome, and quality of life of all consecutive patients that were treated by SDC for malignant cerebellar infarction in our institution between 1995 and 2006. RESULTS: A total of 57 patients were identified. All of them were treated by bilateral SDC. An external ventricular drainage was inserted in 82%, necrotic tissue was evacuated in 56% of patients. There were no fatal procedural complications. Five patients were lost for follow-up. In the remaining 52 patients, the mean follow-up interval was 4.7 years (1 to 11 years). Within the first 6 months after surgery 16 of 57 patients (28%) had died. At follow-up, 21 of 52 patients (40%) had died and 4 patients (8%) lived with major disability (mRS 4 or 5). Twenty-one patients (40%) lived functionally independent (mRS 0 to 2). The presence of additional brain stem infarction was associated with poor outcome (mRS >/=4; hazard ratio: 9.1; P=0.001). Quality of life in survivors was moderately lower than in healthy controls. CONCLUSIONS: SDC is a safe procedure in patients with malignant cerebellar infarction. Infarct- but not procedure-related early mortality is substantial. Long-term outcome in survivors is acceptable, particularly in the absence of brain stem infarction.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. Clinical and neuroimaging features resemble those of sporadic small-artery disease, although patients with CADASIL have an earlier age at onset of stroke events, an increased frequency of migraine with aura, and a slightly variable pattern of ischaemic white-matter lesions on brain MRI. NOTCH3 (Notch homolog 3), the gene involved in CADASIL, encodes a transmembrane receptor primarily expressed in systemic arterial smooth-muscle cells. Pathogenetic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, which accumulates in small arteries of affected individuals. Functional and imaging studies in cultured cells, genetically engineered mice, and patients with CADASIL have all provided insights into the molecular and vascular mechanisms underlying this disease. A recent multicentre trial in patients with cognitive impairment emphasises the feasibility of randomised trials in patients with CADASIL. In this Review, we summarise the current understanding of CADASIL, a devastating disorder that also serves as a model for the more common forms of subcortical ischaemic strokes and pure vascular dementia.

Deep cerebral venous system thrombosis (DCVST) is a rare variety of cerebral vein and sinus thrombosis (CVST), therefore clinical information regarding presentation, course and outcome are limited. In this two-center study including 32 patients, we tried to better define symptoms, neuroradiological findings, course, and outcome in DCVST. All consecutive patients with DCVST admitted to our two institutions over a period of more than 10 years were identified from prospective registries on CVST and stroke patients. Data from the registries were confirmed and complemented by retrospective analysis of patients' charts and neuroradiological imaging. Only patients with an unequivocal diagnosis of DCVST confirmed by MRI and MRA were included. Information on long-term functional outcome (modified Rankin Scale, mRS; ability to return to work) was obtained by telephone interviews performed between 2006 and 2008. The clinical presentation was highly variable with headache (81%) and reduced consciousness (72%) as the most frequent symptoms. In nine patients (28%) thrombosis was confined to the deep venous system (isolated DCVST). In the remaining patients other sinuses and/or cortical veins were additionally affected (non-isolated DCVST). Diagnosis was made within one to 76 days (mean = 10.0 +/- 14.1 days) but was significantly delayed in patients with isolated compared to non-isolated DCVST (19.1 +/- 23.0 vs. 6.3 +/- 6.5 days, P = 0.02). Thalamic edema was the most frequent parenchymal MRI finding present in 69% of patients, bilateral in 47%. D:-dimer levels were normal in 13% of patients. Most patients (75%) stabilized and later improved on intravenous heparin or subcutaneous low molecular weight heparin. Eight (25%) patients deteriorated with progressing coma; six of them received local endovascular therapy but two died. After a mean follow-up of 3.8 years (range 3 months-13 years), 26 patients (81%) were functionally independent (mRS </= 2) including 24 patients (75%) with a mRS </= 1 of whom 23 (96%) returned to their previous job, activity or education. No patients were severely disabled (mRS 4-5). Extension of thrombosis beyond the deep venous system had no effect on outcome. Due to its variable clinical presentation the diagnosis of DCVST is often difficult and heparin treatment therefore established with substantial delay. While most patients stabilize and have a good recovery, progressing coma associated with poor outcome is seen in a subset of patients who may thus require other treatment options, such as endovascular therapy.

OBJECTIVE: Recent studies have identified a major locus for risk for coronary artery disease and myocardial infarction on chromosome 9p21.3. Stroke, in particular, ischemic stroke caused by atherosclerotic disease, shares common mechanisms with myocardial infarction. We investigated whether the 9p21 region contributes to ischemic stroke risk. METHODS: In an initial screen, 15 single nucleotide polymorphisms (SNPs) covering the critical genetic interval on 9p21 were genotyped in samples from Southern Germany (1,090 cases, 1,244 control subjects) and the United Kingdom (758 cases, 872 control subjects, 3 SNPs). SNPs significantly associated with ischemic stroke or individual stroke subtypes in either of the screening samples were subsequently genotyped in 2,528 additional cases and 2,189 additional control subjects from Europe and North America. RESULTS: Genotyping of the screening samples demonstrated associations between seven SNPs and atherosclerotic stroke (all p < 0.05). Analysis of the full sample confirmed associations between six SNPs and atherosclerotic stroke in multivariate analyses controlling for demographic variables, coronary artery disease, myocardial infarction, and vascular risk factors (all p < 0.05). The odds ratios for the lead SNP (rs1537378-C) were similar in the various subsamples with a pooled odds ratio of 1.21 (95% confidence interval, 1.07-1.37) under both fixed- and random-effects models (p = 0.002). The point estimate for the population attributable risk is 20.1% for atherosclerotic stroke. INTERPRETATION: The chromosome 9p21.3 region represents a major risk locus for atherosclerotic stroke. The effect of this locus on stroke appears to be independent of its relation to coronary artery disease and other stroke risk factors. Our findings support a broad role of the 9p21 region in arterial disease. Ann Neurol 2009;65:531-539.

Cognitive functions show large variation in elderly people and are substantially heritable. Animal studies revealed that dynorphins influence cognition and memory, especially in aged animals. Thus, we tested the effect of four SNPs (rs7272891, rs1997794, rs2235751 and rs910080) and the VNTR promoter polymorphism in the prodynorphin gene (PDYN) on episodic memory and verbal fluency in a large (n = 1619) sample of elderly people (mean age: 80 +/- 3.39 years; range 75-90 years) recruited through the German study on ageing, cognition and dementia in primary care patients (AgeCoDe). We found that carriers of the minor alleles of rs1997794 (P < 0.002) and rs910080 (P < 0.005) presented with higher episodic memory scores than homozygote carriers of the major allele. Also, a three marker haplotype including these two SNPs and rs2235751 was associated with better episodic memory scores. Verbal fluency scores were non-significantly better in carriers of these respective alleles. Thus, our results suggest a role of PDYN gene variations in determining memory function also in elderly humans.