No abstract

Accumulation of toxic protein aggregates—amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles—is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood–brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.

HE REFERENCE METHOD FOR blood pressure (BP) measurement during clinical consultations is the auscultatory method with a mercury sphygmomanometer. This method has been used to demonstrate the relationship between BP and cardiovascular risk. A meta-analysis of individual data from almost 1 million adults participating in 61 prospective studies precisely established the prognostic value of this method of measurement: for each increase of 10 mm Hg in systolic BP (SBP) or 5 mm Hg in diastolic BP (DBP), the average risk of cerebrovascular mortality increases by 40% and the risk of mortality from ischemic heart disease by 30%. 1 The mercury sphygmomanometer, used during clinical consultations, is also the tool that has demonstrated the benefit of antihypertensive treatment. In the first metaanalysis of randomized controlled trials using the sphygmomanometer, a decrease in DBP of 5 mm Hg to 6 mm Hg was associated with a 42% reduction in the risk of stroke syndrome and a 14% reduction in the risk of coronary events. 2

The purpose of this research was to review the literature on masked hypertension. Studies, reviews and editorials on masked hypertension were identified by PubMed, Pascal BioMed and Cochrane literature systematic searches. Then, we carried out a meta-analysis of the six cohort studies reporting quantitative data for masked hypertension prognosis. There is still no clear consensus definition of masked hypertension and the reproducibility of the phenomenon is unknown. Nevertheless, the prevalence of masked hypertension seems to lie between 8 and 20%, and can be up to 50% in treated hypertensive patients. Subjects with masked hypertension have a higher risk of cardiovascular accidents [hazard ratios: 1.92 (1.51-2.44)] than normotensive subjects. This is due to a possible failure to recognize and appropriately manage this particular form of hypertension, the frequent association with other risk factors and coexisting target organ damage. The remaining unresolved questions are as follows: is masked hypertension a clinical entity that requires identification and characterization or a statistical phenomenon linked to the variability of blood pressure measurements?; because screening of the entire population is not feasible, how to identify individuals with masked hypertension?; and, in the absence of randomized trial, how to treat masked hypertension?