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Brain reserve definitions foster debate and disagreements. A consensus definition of brain reserve would fill gaps in converging ongoing research and action plans to promote brain health. Different terms are used for the capacity to adapt to life hardships and cognitive and social compliance and to neutralize or compensate for age-related neurological degeneration to prevent impaired cognition. Brain reserve, resilience, cognitive reserve, and brain maintenance have been used usually in isolation, but at times interchangeably. However, the need remains for a simplified overarching definition of brain reserve. Brain health is a continuous development and exercise of the brain, and thus the brain reserve requires a definition encompassing this continuum. We propose for discussion a new definition of brain reserve that incorporates available definitions and emphasizes the dynamic and interactive nature of a healthy brain. Brain reserve is the lifelong, dynamic, interactive, accumulating capacity to resist physical, emotional, and/or social harms.

Introduction The relative contributions of vascular and degenerative pathology to dementia are unknown. We aim to quantify the proportion of dementia explained by potentially preventable vascular lesions. Methods We systematically searched for population-based cohorts before February 2017 reporting clinicopathological data for individuals with and without dementia. We calculated the summary proportion and absolute risk of dementia comparing subjects with and without the pathology. Results We identified 10 studies comprising 2856 subjects. Vascular-type pathology and mixed pathology are respectively two and three times more likely in demented patients. The summary proportion of dementia is 77%–86% in subjects with mixed degenerative and vascular pathology and 45% in subjects with pure Alzheimer-type pathology. Discussion Patients with mixed pathologies have nearly twice the incremental risk of dementia compared with patients with only Alzheimer-type lesions. Consequently, many cases of dementia could be prevented or delayed by targeting the vascular component.

Background Stroke, dementia, and cognitive impairment no dementia (CIND) pose major threats to the elderly but have rarely been studied together in the same population. We aimed to compare the relative frequencies of stroke, CIND, and dementia in an elderly population and to examine whether cognitive impairment poses a risk for stroke. Methods Prevalences of stroke, CIND, and dementia were estimated among participants in the first clinical examination of the Canadian Study of Health and Aging (CSHA-1, n=2,914). Incidence rates were determined at the 5-year follow-up (CSHA-2) among those cognitively normal and stroke free at CSHA-1 (n = 828). The associations between cognitive impairment and stroke were assessed by Cox regression analyses. Results Among elderly Canadians, the age-standardized prevalence of stroke, CIND, and dementia were 8%, 17%, and 8%, respectively. Alone or combined, they affected one fourth of the elderly. Among stroke survivors, 64% had cognitive impairment compared with 21% among stroke-free persons. Among the cognitively impaired, 25% had a stroke compared with 4% among the cognitively normal. The incidence rates of stroke, CIND, and dementia were 3, 6, and 3 per 100 person-years, respectively. Compared with cognitively normal subjects, the adjusted risk for incident stroke was 1.3 (95% confidence interval [CI], 0.9 to1.9) in patients with CIND and 2.3 (95% CI, 1.7 to 3.2) in patients with dementia regardless of whether "questionable stroke" was included. Conclusions Stroke and cognitive impairment pose risk for each other. CIND is highly prevalent, and some of its subtypes may represent treatable preludes to stroke and/or dementia.

The ‘‘Decade of the Brain’’ (1990–2000) witnessed remarkable advances in neuroscience, but also some not-sobrainy attempts at finding a neuroprotective drug for acute stroke. The reasons for failure were many [1], and they included a failure to assess whether a promising drug crossed the blood-brain barrier (BBB). Based on Pardridge’s review, it seems we may have not learned much from history, and may be in danger of repeating it with therapies targeting Alzheimer’s disease (AD). The BBB represents not only a physical but a conceptual challenge. The vast majority of researchers in AD do not work on the BBB, and may not perceive it as a problem at all. The BBB represents a major challenge, but a small field: a boutique enterprise compared with the Wal-Mart dimensions of the amyloid emporium. Ironically, we need to co-opt the type of research that Pardridge advocates if we are to succeed with the long list of potential anti-amyloid therapies [2]. One indispensable research tool is the quantitative assessment of BBB permeability of therapeutic drugs using noninvasive imaging methods, such that the influx of putative drugs from the blood into the brain can be serially monitored. The physiological parameter that measures BBB permeability is the product of permeability and the total surface area of the capillary endothelium in a unit mass of tissue (PS). It gives the unidirectional flux of blood-borne solutes across all capillaries into the brain under the generally valid condition that brain-blood flow is much greater than the PS [3]. Positron emission tomography [4], computed tomography [5], and magnetic resonance [6] methods for measuring PS in patients were developed for inert contrast agents that permeate the BBB via passive diffusion. In principle, these same imaging methods can be applied to agents that are transported through the BBB via carrier-mediated and receptor-mediated mechanisms. For these imaging methods to work, the newer molecularly targeted agents must be appropriately labeled for them to be detected by positron emission tomography, computed tomography, and magnetic resonance imaging [7]. Alternatively, an analogue that is transported by a specific carrier-mediated transport or receptor-mediated transport mechanism has to be identified. For example, the overexpression of multidrug-resistant P-glycoprotein can be imaged with the ligand [8–10] Ga-[3-ethoxy-ENBDMPI] and positron emission tomography [8]. Although an intact BBB impedes the delivery of bloodborne therapeutic drugs, a compromised BBB has been implicated in the pathogenesis of a number of central nervous system diseases, including AD, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and others [9,10]. The presence of amyloid-b plaques in the vicinity of the cerebral microvasculature and the association of cerebral amyloid angiopathy with AD [11] suggest that vascular disease is a significant component of AD pathology. In accordance with this concept, there is increasing evidence for BBB disruption in AD [12–14]. Barriers such as the BBB can be breached through potential openings, if we can find the keys and the means of transportation. Pardridge is showing the way, and we need to join him.

Most discoveries are reinterpreted rediscoveries. A few decades ago the view prevailed that most cognitive impairment resulted from a slow strangulation of the brain’s blood supply. Alzheimer’s disease gradually supplanted vascular disease as the favored explanation. Now we are rediscovering the importance of vascular causes of cognitive impairment but no longer think that it simply reflects chronic ischemia. The mechanisms of damage, however, remain unclear and controversial. Helena Chiu asks, “Are we really that confused?” Those not confused have not been paying close attention to the literature. However, insight is a good prognostic sign in a confusional state, and Chiu’s review goes a long way in laying out the issues, the unknowns, and the steps to address them. Chiu postulates a sequence of vascular risk factors i