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Apolipoprotein E (APOE) epsilon4 allele is the strongest hitherto known risk factor for sporadic Alzheimer's disease (AD). Liver X receptor-beta (LXRbeta) is a transcription factor that controls expression of genes involved in brain cholesterol metabolism, and one of the main LXRbeta targets is APOE. To evaluate the relationship between LXRbeta genetic variants and AD, independently or in concert with the APOE epsilon4 allele, we examined three LXRbeta polymorphisms located in introns 2 (rs 2695121), 5 (rs 1052533), and 7 (rs 1405655), in 414 Spanish AD patients and 447 controls. The current study does not demonstrate an association between LXRbeta genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE epsilon4 allele.

Pleomorphic xanthoastrocytoma (PXA) is a brain neoplasm included in the astrocytic group, exceptionally manifesting with meningeal dissemination. We described a 27-year-old patient presented with acute bilateral visual loss and papilledema with normal brain computed tomography scan, initially mimicking idiopathic intracranial hypertension (IIH). Brain and spinal cord magnetic resonance imaging (MRI) study revealed a subtle area of hyperintensity of the gyri surrounding the left central sulcus, and contrast enhancement of the thoracic leptomeninges. Brain biopsy of the parietal lesion revealed nonanaplastic PXA. Treatment with temozolomide was given. Yearly control MRI demonstrated new brain lesions and marked progression of leptomeningeal spinal enhancement. In spite of this, the patient has remained stable with no new symptoms. Nonanaplastic PXA may present with widespread meningeal dissemination with acute visual loss and papilledema mimicking IIH, and no clinical progression at 3 years.

Background: Oxidative stress is a central factor in the pathogenesis of Parkinson’s disease (PD). Heme oxygenase-1 (HO-1) is an antioxidant protein expressed in response to oxidative challenge, and its expression levels are inversely correlated with glycogen synthase kinase-3β (GSK3β) activity. Underexpression of HO-1 in concert with an upregulation of GSK3β would result in a less effective antioxidant response and might increase the risk of PD. Methods: We examined two functional polymorphism in the promoter regions of HO-1 (−413, rs2071746) and GSK3β (−157, rs6438552) in a group of 251 Spanish patients with PD and 234 controls. Results: Subjects carrying both the HO-1 (−413, rs2071746) TT genotype and the GSK3β (−157, rs6438552) TT genotype had a four times higher risk of developing PD than subjects without these genotypes (adjusted by age and sex OR = 4.12; 95% CI = 1.45–11.71; Bonferroni corrected P = 0.024). Conclusions: Considering synergistic effects between polymorphisms in oxidative stress-related genes may help in determining the risk profile for PD.

For the first time, the multilocus approach by the set-association method has been applied for the analysis of a cluster of five genes [tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-8, IL-1alpha and IL-10] involved in the brain neuroinflammatory pathway in Parkinson's disease (PD), in a well-defined group of 197 PD patients and 173 control subjects from Spain. Set-association analysis did not reveal an independent or an interactive effect of these inflammatory genes on the PD risk.

Elevated cerebral levels of amyloid beta-protein (Aβ) occur in Alzheimer's disease (AD), yet only a few patients show evidence of increased Aβ production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of Aβ. Megalin, which plays an important role in mediating Aβ clearance, is an attractive candidate gene for genetic association with AD. To investigate this hypothesis, we analyzed the megalin gene in a population of 2,183 subjects. Genetic analysis indicated that the rs3755166 (G/A) polymorphism located in the megalin promoter associated with risk for AD, dependently of apolipoprotein E genotype. The rs3755166 AA genotype frequency was significantly greater in AD patients than in control subjects. Furthermore, the luciferase reporter assay indicated that the rs3755166 A variant has 20% less transcriptional activity than the rs3755166 G variant. This study provides strong evidence that this megalin polymorphism confers a greater risk for AD, and supports a biological role for megalin in the neurodegenerative processes involved in AD, This work was supported by grants from Fondo de Investigación Sanitaria (FIS) (CP04/00179, PI060155), Fundación Investigación Médica Mutua Madrileña (2006.125), CIBERNED, Obra Social Caja Madrid, Comunidad Autónoma de Madrid (GR/SAL/0783/2004). We thank Drs. P. Gil, P. Coria, and A. Labad-Alquézar for their cooperation in the generation of the case–control samples