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Cognitive aging trajectories differ widely across individuals, and genetic factors such as APOE and BDNF polymorphisms may contribute to this variability. While APOE ε4 has been widely studied, the influence of APOE ε2, particularly in interaction with sex, remains underexplored. This study aims to examine the longitudinal trajectory of APOE ε2 individuals on cognitive performance, and their interactions with sex, age, and BDNF Val66Met polymorphism, in a population-based cohort of older adults with vascular risk. We analyzed data from 386 participants (mean age: 71.8) from the Barcelona-AsIA Neuropsychology Study, followed over a 7-year period. Verbal memory, verbal fluency, and visuospatial domains were assessed. Linear regression models tested associations between cognitive change and genotypes, controlling for age, sex, education, depression, and vascular risk. Interaction terms and permutation testing were applied. Regression to the mean (RTM) effects were assessed. BDNF showed no significant associations with cognitive performance. RTM effects were evident across subgroups, particularly among ε2 carriers, suggesting this phenomenon partly explains the divergent results over time. APOE ε2 does not confer a consistent protective effect on cognition over time. Our results highlight that APOE ε2 may be detrimental to verbal memory in aging males.

A previously well 63-year-old male presented with acute encephalopathy and fevers after being seen well one week earlier. Cerebrospinal fluid (CSF) analysis demonstrated markedly elevated protein concentration and mononuclear pleocytosis. Other than a newly identified active hepatitis C infection, comprehensive infective screening was negative. Magnetic resonance imaging (MRI) demonstrated diffuse leptomeningeal enhancement, several punctate foci of restricted diffusion and microhaemorrhages in both cerebral hemispheres. Further extensive investigations did not identify an inflammatory, malignant or paraneoplastic aetiology. The patient subsequently underwent a brain biopsy. Histopathology demonstrated transmural granulomatous vasculitis predominantly involving the leptomeningeal vessels. Immunohistochemistry confirmed the presence of amyloid-beta, consistent with a diagnosis of amyloid-beta related angiitis (ABRA). The patient had significant neurological improvement after treatment with corticosteroids and was able to be discharged home. Repeat MRI demonstrated resolution of the leptomeningeal enhancement.DiscussionThis case highlights the need for a broad differential diagnosis when approaching a patient with acute encephalopathy. ABRA more commonly presents with subacute cognitive dysfunction,1 whereas this patient presented with acute symptoms over days. The confounding bystanders of fevers and active hepatitis C infection led to infective causes being prioritised in the initial work-up. The MRI findings were difficult to interpret given it is uncharacteristic for ABRA to lack the T2/FLAIR subcortical white matter changes. While clinical-radiologic criteria have been suggested,2 this case demonstrates the importance of proceeding with brain biopsy for pathological diagnosis. While rare, ABRA should be considered as a differential diagnosis as it is a treatable cause of progressive cognitive dysfunction.ReferencesDanve A, Grafe M, Deodhar A. Amyloid beta-related angiitis—a case report and comprehensive review of literature of 94 cases. InSeminars in arthritis and rheumatism 2014 Aug 1 (Vol. 44, No. 1, pp. 86–92). WB Saunders.Auriel E, Charidimou A, Gurol ME, Ni J, Van Etten ES, Martinez-Ramirez S, Boulouis G, Piazza F, DiFrancesco JC, Frosch MP, Pontes-Neto OM. Validation of clinicoradiological criteria for the diagnosis of cerebral amyloid angiopathy-related inflammation. JAMA Neurology 2016 Feb 1;73(2):197–202.

A risk for developing progressive multifocal leukoencephalopathy is a major barrier to natalizumab use. Extended dosing intervals have been proposed as a way to maintain therapeutic efficacy and reduce progressive multifocal leukoencephalopathy incidence. This is the first reported case of progressive multifocal leukoencephalopathy in a patient using an extended dosing regimen (300 mg/6 weeks). A close clinical and imaging monitoring allowed early detection, which is a major prognostic factor. A favorable outcome was seen with a therapy comprising plasma exchange therapy, mirtazapine, mefloquine and cidofovir. Further studies will be needed to assess the potential role of extended dosing intervals to improve prognosis in patients receiving natalizumab and also to measure its impact clinically and/or radiologically.