Midlife hypertension is a risk factor for some, but not all, domains of cognitive decline in later life: a systematic review and meta-analysis.

INTRODUCTION: Management of midlife blood pressure and hypertension status may provide a window of intervention to mitigate cognitive decline with advancing age. The aim of this review was to investigate the relationship between midlife hypertension and cognition in midlife and later life. METHODS: Online electronic databases were searched from their inception to May 2022. Studies assessing midlife (40-65 years) hypertension and cognition at mid and/or later-life were included. A random effects meta-analysis was deemed appropriate. RESULTS: One hundred forty-nine studies across 26 countries were included. Qualitative synthesis found negative relationships between midlife hypertension and later life cognition in the domains of memory, executive function, and global cognition. Metanalytical evidence revealed midlife hypertension negatively impacts memory, executive function, and global cognition but had no observed effect on attention at midlife. DISCUSSION: Hypertension at midlife has a significant negative impact on cognition in mid-life and later life, namely memory, executive function, and global cognition.

Exercise-induced modulation of neuroinflammation in ageing.

Optimal performance of the central nervous system (CNS) depends on dynamic, multidirectional communication between different cell types both within and without the CNS to maintain the homeostatic environment. Ageing, in turn, is associated with CNS disequilibrium resulting in suboptimal functioning of its cells and potential cognitive impairment. Emerging evidence indicates that inter-organ communication influences the functioning of CNS cell types, which are subject to age- and environment-dependent alterations. Endurance exercise has specifically been demonstrated to have a marked impact on neuroimmune communications, particularly those involving microglia, the resident macrophages of the CNS parenchyma, as well as microglia-astrocyte interactions in rodents. Via its action on CNS glial cells, regular aerobic exercise has been shown to provide an adaptive advantage against perturbations to homeostasis, such as immunological challenge or ageing. In light of the accumulating evidence and evolutionary reasoning it may be argued that recurrent exercise-associated inter-organ signalling is necessary for the optimisation of glial function and hence CNS equilibrium. This, in turn, would imply that the absence of exercise-derived mediators and dysregulated inter-organ communication associated with a sedentary lifestyle may contribute to CNS dyshomeostasis, which is accelerated during ageing. As well as exploring the evidence of the impact of exercise on glial function, here we suggest potential next steps in identifying the mechanistic underpinnings of these effects and the potential importance of sex differences.

Exercise alters LPS-induced glial activation in the mouse brain.

Experimental and epidemiological evidence suggest that modifiable lifestyle factors, including physical exercise, can build structural and cognitive reserve in the brain, increasing resilience to injury and insult. Accordingly, exercise can reduce the increased expression of proinflammatory cytokines in the brain associated with ageing or experimentally induced neuroinflammation. However, the cellular mechanisms by which exercise exerts this effect are unknown, including the effects of exercise on classic or alternative activation of astrocytes and microglia. In the present study, we assess the effects of nine consecutive days of treadmill running on the glial cell response to a single systemic injection of lipopolysaccharide (LPS) and, in parallel, the effects on spatial learning and memory. We show that prior exercise protects against LPS-induced impairment of performance in the object displacement task concomitant with attenuation of IL-1ß, TNFα and IL-10 mRNA expression in the hippocampus. Assessment of isolated astrocytes and microglia revealed that LPS induced a proinflammatory response in these cells that was not observed in cells prepared from the brains of mice who had undergone prior exercise. The results suggest that exercise modulates neuroinflammation by reducing the proinflammatory microglial response, suggesting a mechanism by which exercise may be neuroprotective.

Exercise-induced re-programming of age-related metabolic changes in microglia is accompanied by a reduction in senescent cells.

Microglial activation and neuroinflammatory changes are characteristic of the aged brain and contribute to age-related cognitive impairment. Exercise improves cognitive function in aged animals, perhaps because of a modulatory effect on microglial activation. Recent evidence indicates that inflammatory microglia are glycolytic, driven by an increase in 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), an enzyme that is described as the master regulator of glycolysis. Here we investigated whether microglia from aged animals exhibited a glycolytic signature and whether exercise exerted a modulatory effect on this metabolic profile. Young (4 month-old) and aged (18 month-old) mice were trained for 10 days on a treadmill. One day before sacrifice, animals were assessed in the novel object recognition and the object displacement tests. Animals were sacrificed after the last bout of exercise, microglial cells were isolated, cultured for 5 days and assessed for metabolic profile. Performance in both behavioural tests was impaired in sedentary aged animals and exercise attenuated this age-related effect. A significant increase in glycolysis, glycolytic capacity and PFKFB3 was observed in microglia from aged animals and exercise ameliorated these effects, while it also increased the phagocytic capacity of cells. The senescent markers, ß-galactosidase and p16INK4A, were increased in microglia from sedentary aged mice, and expression of these markers was significantly decreased by exercise. The data demonstrate that the exercise-related improved cognition is orchestrated by a normalization of the metabolic profile and functionality of microglia.

Acute high-intensity aerobic exercise affects brain-derived neurotrophic factor in mild cognitive impairment: a randomised controlled study.

OBJECTIVE: To investigate the brain-derived neurotrophic factor (BDNF) and cognitive response to a short bout of high-intensity aerobic exercise in older adults with mild cognitive impairment (MCI). METHODS: Participants were randomised to one of two testing schedules, completing either a standardised exercise test (group A) or a resting control condition (group B). Blood sampling and cognitive measures (visuospatial learning and memory, sustained attention and executive function) were collected at baseline (T1) and postintervention (T2). An additional measurement of study outcomes was collected after exercise (T3) in group B only. RESULTS: 64 participants (female 53.2%, mean age 70.5±6.3 years) with MCI were recruited. From T1 to T2, serum BDNF (sBDNF) concentration increased in group A (n=35) (median (Md) 4564.61±IQR 5737.23 pg/mL to Md 5173.27±5997.54 pg/mL) and decreased in group B (Md 4593.74±9558.29 pg/mL to Md 3974.66±3668.22 pg/mL) (between-group difference p=0.024, effect size r=0.3). The control group made fewer errors on the sustained attention task compared with the exercise group (p=0.025). Measures of visuospatial learning and memory or executive function did not change significantly between groups. CONCLUSION: This study is the first to show that a short bout of high-intensity aerobic exercise increases peripheral sBDNF in a population with MCI. However, acute exercise did not improve cognitive performance.

An investigation into the relationship between cardiorespiratory fitness, cognition and BDNF in young healthy males.

BACKGROUND: Recent investigations demonstrate that cardiorespiratory fitness may benefit brain health and plasticity with concurrent enhancements in cognitive performance; possibly via a brain-derived neurotrophic factor (BDNF)-regulated mechanism. While a number of studies have demonstrated an increase in BDNF concentration post exercise the relationship between BDNF, cardiorespiratory fitness and cognitive function requires further investigation. OBJECTIVE: The present cross-sectional study assessed the association between cardiorespiratory fitness (VO2max), cognitive performance and circulating BDNF concentration. METHODS: Thirty-nine healthy male volunteers (mean age 21.7 ± 0.5 years) participated. Cognitive performance was measured by reaction time on a standard detection task and accuracy in a n-back and Continuous Paired Associative Learning (CPAL) task. Cardiorespiratory fitness was assessed using a standardised graded exercise test. Plasma and serum BDNF concentrations were assayed by ELISA. RESULTS: A significant negative correlation between VO2max and reaction time was demonstrated (p < 0.05). However VO2max was not associated with circulating BDNF concentration, or performance in the n-back and CPAL tasks (p > 0.05). CONCLUSIONS: Enhanced psychomotor speed was associated with higher cardiorespiratory fitness. In contrast to previous research no significant association between cardiorespiratory fitness and BDNF concentration was observed.

Lifelong environmental enrichment in the absence of exercise protects the brain from age-related cognitive decline.

Environmental manipulations enhance neuroplasticity, with enrichment-induced cognitive improvements linked to increased expression of growth factors and enhanced hippocampal neurogenesis. Environmental enrichment (EE) is defined as the addition of social, physical and somatosensory stimulation into an animal's environment via larger group housing, extra objects and, often, running wheels. Previous studies from our laboratory report that physical activity is a potent memory enhancer but that long-term environmental stimulation can be as effective as exercise at ameliorating age-related memory decline. To assess the effects of EE, in the absence of exercise, rats were housed in continuous enriched conditions for 20 months and memory assessed at young, middle aged and aged timepoints. MRI scans were also performed at these timepoints to assess regional changes in grey matter and blood flow with age, and effects of EE upon these measures. Results show an age-related decline in recognition, spatial and working memory that was prevented by EE. A parallel reduction in ßNGF in hippocampus, and cell proliferation in the dentate gyrus, was prevented by EE. Furthermore, EE attenuated an age-related increase in apoptosis and expression of pro-inflammatory markers IL-1ß and CD68. Long-term EE induced region-specific changes in grey matter intensity and partially rescued age-related reductions in cerebral blood flow. This study demonstrates that sensory enrichment alone can ameliorate many features typical of the ageing brain, such as increases in apoptosis and pro-inflammatory markers. Furthermore, we provide novel data on enrichment-induced regional grey matter alterations and age-related changes in blood flow in the rat. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".

Exercise-Induced Modulation of Neuroinflammation in Models of Alzheimer's Disease.

 Alzheimer's disease (AD), a progressive, neurodegenerative condition characterised by accumulation of toxic ßeta-amyloid (Aß) plaques, is one of the leading causes of dementia globally. The cognitive impairment that is a hallmark of AD may be caused by inflammation in the brain triggered and maintained by the presence of Aß protein, ultimately leading to neuronal dysfunction and loss. Since there is a significant inflammatory component to AD, it is postulated that anti-inflammatory strategies may be of prophylactic or therapeutic benefit in AD. One such strategy is that of regular physical activity, which has been shown in epidemiological studies to be protective against various forms of dementia including AD. Exercise induces an anti-inflammatory environment in peripheral organs and also increases expression of anti-inflammatory molecules within the brain. Here we review the evidence, mainly from animal models of AD, supporting the hypothesis that exercise can reduce or slow the cellular and cognitive impairments associated with AD by modulating neuroinflammation.

Effects of match play and training on circulating S100B concentration in professional rugby players.

OBJECTIVES: Examine the effects of match play and a season of training on serum S100B concentration in male professional rugby players. To assess the influence of contact play, values were compared with age- and fitness-matched athletes not involved in a contact sport. METHODS: Over a 2-year period, blood samples were collected from 38 players in pre-season, end of season, and post-matches (within 2 h). A control group of rowers (n = 15) was assessed pre- and post-training. RESULTS: S100B concentration changed significantly over a season (χ2(2) = 17.636, p < 0.0005); post-match values were significantly increased from baseline (early season: Z = -3.670, p < 0.0005; late season: Z = -3.408, p = 0.001). There were no significant differences in S100B concentrations between pre-seasons (Z = -1.601, p = 0.109), or between end of season and subsequent pre-season (Z = -0.330, p = 0.741). While comparable at baseline, samples taken from rugby players post-match were significantly increased compared with samples taken from rowers post-exercise (U = 47.0, p < 0.0005). CONCLUSION: Exercise has a significant effect on circulating S100B in elite male athletes, with levels following rugby matches significantly higher than following non-contact sport. This elevation in S100B is temporary, with a return to baseline values after periods without play.

Building Imaging Institutes of Patient Care Outcomes: Imaging as a Nidus for Innovation in Clinical Care, Research, and Education.

Traditionally, radiologists have been responsible for the protocol of imaging studies, imaging acquisition, supervision of imaging technologists, and interpretation and reporting of imaging findings. In this article, we outline how radiology needs to change and adapt to a role of providing value-based, integrated health-care delivery. We believe that the way to best serve our specialty and our patients is to undertake a fundamental paradigm shift in how we practice. We describe the need for imaging institutes centered on disease entities (eg, lung cancer, multiple sclerosis) to not only optimize clinical care and patient outcomes, but also spur the development of a new educational focus, which will increase opportunities for medical trainees and other health professionals. These institutes will also serve as unique environments for testing and implementing new technologies and for generating new ideas for research and health-care delivery. We propose that the imaging institutes focus on how imaging practices-including new innovations-improve patient care outcomes within a specific disease framework. These institutes will allow our specialty to lead patient care, provide the necessary infrastructure for state-of-the art-education of trainees, and stimulate innovative and clinically relevant research.

Interrater Agreement and Diagnostic Accuracy of a Novel Computer-Aided Detection Process for the Detection and Prevention of Retained Surgical Instruments.

OBJECTIVE: The purpose of this study is to evaluate the diagnostic accuracy of a process incorporating computer-aided detection (CAD) for the detection and prevention of retained surgical instruments using a novel nondeformable radiopaque µTag. MATERIALS AND METHODS: A high-specificity CAD system was developed iteratively from a training set (n = 540 radiographs) and a validation set (n = 560 radiographs). A novel test set composed of 700 thoracoabdominal radiographs (410 with a randomly placed µTag and 290 without a µTag) was obtained from 10 cadavers embedded with confounding iatrogenic objects. Data were analyzed first by the blinded CAD system; radiographs coded as negative (n = 373) were then independently reviewed by five blinded radiologists. The reference standard was the presence of a µTag. Sensitivity and specificity were calculated. Interrater agreement was assessed with Cohen kappa values. Mean (± SD) image analysis times were calculated. RESULTS: The high-specificity CAD system had one false-positive (sensitivity, 79.5% [326/410]; specificity, 99.7% [289/290]). A combination of the CAD system and one failsafe radiologist had superior sensitivity (98.5% [404/410] to 100% [410/410]) and specificity (99.0% [287/290] to 99.7% [289/290]), with 327 (47%) radiographs not requiring immediate radiologist review. Interrater agreement was almost perfect for all radiologist pairwise comparisons (κ = 0.921-0.992). Cumulative mean image analysis time was less than one minute (CAD, 29 ± 2 seconds; radiologists, 26 ± 16 seconds). CONCLUSION: The combination of a high-specificity CAD system with a failsafe radiologist had excellent diagnostic accuracy in the rapid detection of a nondeformable radiopaque µTag.

Use of Blood Biomarkers in the Assessment of Sports-Related Concussion-A Systematic Review in the Context of Their Biological Significance.

OBJECTIVES: To critically review current knowledge on the positive and negative predictive value of blood biomarkers for concussion; to illustrate the clinical and biological contexts that help evaluate the use of these markers in sport-related traumatic brain injuries (TBIs). METHODS: This systematic review was performed in accordance with PRISMA guidelines. We reviewed the measurement, clinical utility, endpoint, and biological significance of blood biomarkers in concussion. RESULTS: A total of 4352 publications were identified. Twenty-six articles relating to blood biomarkers were included in the review. Four common blood biomarkers, namely S100B, tau, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP), were examined. Overall, the studies showed S100B measurement and use, either acutely or at several time points, can distinguish injured from noninjured patients with an uncertain degree of utility in predicting mortality. At present, S100B has largely become an acceptable biomarker of TBI; however, studies have begun to highlight the need to incorporate clinical symptoms instead of S100B concentration in isolation on the basis of inconsistent results and lack of specificity across published studies. Further research is needed to evaluate and validate the use of tau, NSE, and GFAP as a diagnostic aid in the management of concussion and TBI. CONCLUSIONS: At present, blood biomarkers have only a limited role in the evaluation and management of concussion. Although several biomarkers of brain injury have been identified, continued research is required. S100B holds promise as the most clinically useful diagnostic biomarker. Blood biomarkers, in combination with other clinical data, such as head computed tomography, would maximize the diagnostic accuracy. The methodological limitations evident in blood biomarker research results in the need for the clinical utility of blood biomarker use in concussion to be further explored.

A Simplified Approach to Encephalitis and Its Mimics: Key Clinical Decision Points in the Setting of Specific Imaging Abnormalities.

RATIONALE AND OBJECTIVES: Infectious encephalitis is a relatively common cause of morbidity and mortality. Treatment of infectious encephalitis with antiviral medication can be highly effective when administered promptly. Clinical mimics of encephalitis arise from a broad range of pathologic processes, including toxic, metabolic, neoplastic, autoimmune, and cardiovascular etiologies. These mimics need to be rapidly differentiated from infectious encephalitis to appropriately manage the correct etiology; however, the many overlapping signs of these various entities present a challenge to accurate diagnosis. A systematic approach that considers both the clinical manifestations and the imaging findings of infectious encephalitis and its mimics can contribute to more accurate and timely diagnosis. MATERIALS AND METHODS: Following an institutional review board approval, a health insurance portability and accountability act (HIPAA)-compliant search of our institutional imaging database (teaching files) was conducted to generate a list of adult and pediatric patients who presented between January 1, 1995 and October 10, 2013 for imaging to evaluate possible cases of encephalitis. Pertinent medical records, including clinical notes as well as surgical and pathology reports, were reviewed and correlated with imaging findings. Clinical and imaging findings were combined to generate useful flowcharts designed to assist in distinguishing infectious encephalitis from its mimics. Key imaging features were reviewed and were placed in the context of the provided flowcharts. RESULTS: Four flowcharts were presented based on the primary anatomic site of imaging abnormality: group 1: temporal lobe; group 2: cerebral cortex; group 3: deep gray matter; and group 4: white matter. An approach that combines features on clinical presentation was then detailed. Imaging examples were used to demonstrate similarities and key differences. CONCLUSIONS: Early recognition of infectious encephalitis is critical, but can be quite complex due to diverse pathologies and overlapping features. Synthesis of both the clinical and imaging features of infectious encephalitis and its mimics is critical to a timely and accurate diagnosis. The use of the flowcharts presented in this article can further enable both clinicians and radiologists to more confidently differentiate encephalitis from its mimics and improve patient care.

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer's disease.

It is now well established, at least in animal models, that exercise elicits potent pro-cognitive and pro-neurogenic effects. Alzheimer's disease (AD) is one of the leading causes of dementia and represents one of the greatest burdens on healthcare systems worldwide, with no effective treatment for the disease to date. Exercise presents a promising non-pharmacological option to potentially delay the onset of or slow down the progression of AD. Exercise interventions in mouse models of AD have been explored and have been found to reduce amyloid pathology and improve cognitive function. More recent studies have expanded the research question by investigating potential pro-neurogenic and anti-inflammatory effects of exercise. In this review we summarise studies that have examined exercise-mediated effects on AD pathology, cognitive function, hippocampal neurogenesis and neuroinflammation in transgenic mouse models of AD. Furthermore, we attempt to identify the optimum exercise conditions required to elicit the greatest benefits, taking into account age and pathology of the model, as well as type and duration of exercise.

CT Pulmonary Angiography: Using Decision Rules in the Emergency Department.

PURPOSE: The aim of this study was to assess the appropriateness of utilization and diagnostic yields of CT pulmonary angiography (CTPA), comparing two commonly applied decision rules, the pulmonary embolism (PE) rule-out criteria (PERC) and the modified Wells criteria (mWells), in the emergency department (ED) setting. METHODS: Institutional review board approval was obtained for this HIPAA-compliant, prospective-cohort, academic single-center study. Six hundred two consecutive adult ED patients undergoing CTPA for suspected PE formed the study population. The outcome was positive or negative for PE by CTPA and at 6-month follow-up. PERC and mWells scores were calculated. A positive PERC score was defined as meeting one or more criteria and a positive mWells score as >4. The percentage of CT pulmonary angiographic examinations that could have been avoided and the diagnostic yield of CTPA using PERC, mWells, and PERC applied to a negative mWells score were calculated. RESULTS: The diagnostic yield of CTPA was 10% (61 of 602). By applying PERC, mWells, and PERC to negative mWells score, 17.6% (106 of 602), 45% (273 of 602), and 17.1% (103 of 602) of CT pulmonary angiographic examinations, respectively, could have been avoided. The diagnostic yield in PERC-positive patients was higher than in mWells-positive patients (10% [59 of 602] vs 8% [49 of 602], P < .0001). Among PERC-negative and mWells-negative patients, the diagnostic yields for PE were 1.9% (2 of 106) and 4% (12 of 273), respectively (P = .004). The diagnostic yield of a negative PERC score applied to a negative mWells score was 1.9% (2 of 103). CONCLUSIONS: The use of PERC in the ED has the potential to significantly reduce the utilization of CTPA and misses fewer cases of PE compared with mWells, and it is therefore a more efficient decision tool.

The role of cannabinoids in adult neurogenesis.

The processes underpinning post-developmental neurogenesis in the mammalian brain continue to be defined. Such processes involve the proliferation of neural stem cells and neural progenitor cells (NPCs), neuronal migration, differentiation and integration into a network of functional synapses within the brain. Both intrinsic (cell signalling cascades) and extrinsic (neurotrophins, neurotransmitters, cytokines, hormones) signalling molecules are intimately associated with adult neurogenesis and largely dictate the proliferative activity and differentiation capacity of neural cells. Cannabinoids are a unique class of chemical compounds incorporating plant-derived cannabinoids (the active components of Cannabis sativa), the endogenous cannabinoids and synthetic cannabinoid ligands, and these compounds are becoming increasingly recognized for their roles in neural developmental processes. Indeed, cannabinoids have clear modulatory roles in adult neurogenesis, probably through activation of both CB1 and CB2 receptors. In recent years, a large body of literature has deciphered the signalling networks involved in cannabinoid-mediated regulation of neurogenesis. This timely review summarizes the evidence that the cannabinoid system is intricately associated with neuronal differentiation and maturation of NPCs and highlights intrinsic/extrinsic signalling mechanisms that are cannabinoid targets. Overall, these findings identify the central role of the cannabinoid system in adult neurogenesis in the hippocampus and the lateral ventricles and hence provide insight into the processes underlying post-developmental neurogenesis in the mammalian brain.

Non-pharmacological Approaches to Cognitive Enhancement.

Pharmaceuticals and medical devices hold the promise of enhancing brain function, not only of those suffering from neurodevelopmental, neuropsychiatric or neurodegenerative illnesses, but also of healthy individuals. However, a number of lifestyle interventions are proven cognitive enhancers, improving attention, problem solving, reasoning, learning and memory or even mood. Several of these interventions, such as physical exercise, cognitive, mental and social stimulation, may be described as environmental enrichments of varying types. Use of these non-pharmacological cognitive enhancers circumvents some of the ethical considerations associated with pharmaceutical or technological cognitive enhancement, being low in cost, available to the general population and presenting low risk to health and well-being. In this chapter, there will be particular focus on the effects of exercise and enrichment on learning and memory and the evidence supporting their efficacy in humans and in animal models will be described.

How to report a research study.

Incomplete reporting hampers the evaluation of results and bias in clinical research studies. Guidelines for reporting study design and methods have been developed to encourage authors and journals to include the required elements. Recent efforts have been made to standardize the reporting of clinical health research including clinical guidelines. In this article, the reporting of diagnostic test accuracy studies, screening studies, therapeutic studies, systematic reviews and meta-analyses, cost-effectiveness assessments (CEA), recommendations and/or guidelines, and medical education studies is discussed. The available guidelines, many of which can be found at the Enhancing the QUAlity and Transparency Of health Research network, on how to report these different types of health research are also discussed. We also hope that this article can be used in academic programs to educate the faculty and trainees of the available resources to improve our health research.