We identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed. We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells. (Funded by the Swiss Cancer League and others.).

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By considering an HR response throughout an exercise test, we found that a blunted HR increase at 40-100% of maximal workload was associated with increased CVD mortality.

There is no consensus on the pathologic conditions or severity implied by the term "hippocampal sclerosis" (HS). In this study, a panel of experienced neuropathologists evaluated inter-rater agreement for pathologic diagnoses in the hippocampus and proposes consensus recommendations on the use of the term "HS." In a group of 251 cases of HS selected from a large autopsy cohort (1,388; 18%), a coordinating group identified 5 patterns of degenerative or vascular pathology. Four independent neuropathologists assessed a single set of hematoxylin and eosin-stained sections following descriptive definitions to classify the appearances and assign the diagnosis of HS, if appropriate. Diagnostic agreement (range, 36%-70%) was highest for vascular lesions. Subsequent joint review of all cases highlighted the need to identify neurodegenerative lesions using immunohistochemistry. Initial agreement in assigning the diagnosis of HS varied from 0% to 86%. After a joint review, the group recommended that the term "HS" should be applied to all cases with complete/near-complete neuronal loss and gliosis in the subfields of the cornu Ammonis but not to hippocampal microinfarction. Therefore, the etiology of HS must be defined in association with a neurodegenerative process or as "lacking neurodegenerative markers," a pathologic condition presumed to arise from hypoxic/ischemic mechanisms.

ObjectiveTo examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer’s disease-related amyloid β (Aβ) production and aggregation, cortical neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders.MethodsThe study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson’s disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer’s disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ species (Aβ38, Aβ40 and Aβ42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1).ResultsPatients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aβ40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aβ40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers.ConclusionsThe combination of the CSF biomarkers T-tau, Aβ40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH.

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