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Contains fulltext : 307382.pdf (Publisher’s version ) (Closed access), Alzheimer's disease (AD) is characterized by an initial decline in declarative memory, while nondeclarative memory processing remains relatively intact. Error-based motor adaptation is traditionally seen as a form of nondeclarative memory, but recent findings suggest that it involves both fast, declarative, and slow, nondeclarative adaptive processes. If the declarative memory system shares resources with the fast process in motor adaptation, it can be hypothesized that the fast, but not the slow, process is disturbed in AD patients. To test this, we studied 20 early-stage AD patients and 21 age-matched controls of both sexes using a reach adaptation paradigm that relies on spontaneous recovery after sequential exposure to opposing force fields. Adaptation was measured using error clamps and expressed as an adaptation index (AI). Although patients with AD showed slightly lower adaptation to the force field than the controls, both groups demonstrated effects of spontaneous recovery. The time course of the AI was fitted by a hierarchical Bayesian two-state model in which each dynamic state is characterized by a retention and learning rate. Compared to controls, the retention rate of the fast process was the only parameter that was significantly different (lower) in the AD patients, confirming that the memory of the declarative, fast process is disturbed by AD. The slow adaptive process was virtually unaffected. Since the slow process learns only weakly from an error, our results provide neurocomputational evidence for the clinical practice of errorless learning of everyday tasks in people with dementia., 13 p.

01 februari 2023, Item does not contain fulltext, The pathophysiology underlying cognitive decline is multifactorial, with increasing literature suggesting a role for cerebrovascular health. Cerebral blood flow (CBF) is an important element of cerebrovascular health, which raises questions regarding the relation between CBF and cognitive decline. Cross-sectional studies demonstrate lower CBF in patients with cognitive decline compared to healthy age-matched peers. Remarkably, longitudinal studies do not support a link between CBF reductions and cognitive decline. These studies, however, are often limited by small sample sizes and may therefore be underpowered to detect small effect sizes. Therefore, through a systematic review and meta-analysis of longitudinal studies, we examined whether longitudinal changes in global CBF are related to cognitive decline in subjects with Alzheimer's disease, and qualitatively described findings on regional CBF. Considering the growing impact of dementia and the lack of treatment options, it is important to understand the role of CBF as a prognostic biomarker and/or treatment target in dementia.

Item does not contain fulltext, Recent guidelines, including the ESC, have moved towards lower targets (<140 mmHg, 130 if tolerated systolic, < 80 mmHg diastolic) for antihypertensive treatment in older adults. The evidence for clinically relevant benefit against limited risk of side effects applies to relatively fit older adults, representing less than 30 % of older patients in clinical practice. We discuss that formal evidence of treatment benefit for frail older adults is absent, although there is limited evidence that this benefit is similar for frail and non-frail participants in clinical trials (e.g. SPRINT). On the other hand, we discuss that the evidence for harm associated with antihypertensive treatment in frail older adults is weak when critically appraised. This applies to the risk of cerebral hypoperfusion, orthostatic hypotension, coronary hypoperfusion, and renal hypoperfusion. The frequently cited J-curve reflects patient characteristics, but is not evidence of harm induced by treatment-induced blood pressure lowering. In this context of absent solid evidence for both benefit and harm, we provide practical treatment advice for hypertension in frail older adults.

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15 juni 2023, Item does not contain fulltext, Alzheimer's disease is characterized by a decline in episodic memory and executive functioning, hampering learning ability. Insight into outcome-based learning capacity may be relevant for optimizing the learning potential of these patients. To date, mixed results have been found in studies in which cognitively impaired participants have to learn based on positive and negative outcomes. In this study, we investigated the role of negative and positive feedback on memory performance and participants' ability to adjust their behaviour accordingly in a sample of 23 early-stage AD patients and 23 matched healthy controls. We administered a novel computerized object-location memory task, in which participants were instructed to learn and memorize the locations of different everyday objects following errorless learning (EL) and trial-and-error learning (TEL). A separate probabilistic TEL task was employed in which participants had to learn how to adjust their behaviour based on positive and negative feedback. EL had a beneficial general effect on memory performance for object locations. However, this effect was not larger in early-stage AD patients compared to controls and error frequency during acquisition of object locations was unrelated to later recall performance. No group differences were found on the probabilistic learning task with respect to learning performance over time and based on positive and negative feedback. Although the error monitoring system seems intact in patients with early-stage AD, errors during learning are likely acting as a source of interference causing difficulty in storage or retrieval of object locations.

Item does not contain fulltext, OBJECTIVES: The aim of this study was to examine whether perioperative changes in cerebral blood flow (CBF) relate to postoperative neurological deficits in patients undergoing aortic arch surgery involving antegrade selective cerebral perfusion (ASCP). METHODS: We retrospectively analysed data from patients who underwent aortic arch surgery involving ASCP and perioperative transcranial Doppler assessments. Linear mixed-model analyses were performed to examine perioperative changes in mean bilateral blood velocity in the middle cerebral arteries, reflecting changes in CBF, and their relation with neurological deficits, i.e. ischaemic stroke and/or delirium. Logistic regression analyses were performed to explore possible risk factors for postoperative neurological deficits. RESULTS: In our study population (N = 102), intraoperative blood velocities were lower compared to preoperative levels, and lowest during ASCP. Thirty-six (35%) patients with postoperative neurological deficits (ischaemic stroke, n = 9; delirium, n = 25; both, n = 2) had lower blood velocity during ASCP compared to patients without (25.4 vs 37.0 cm/s; P = 0.002). Logistic regression analyses revealed lower blood velocity during ASCP as an independent risk factor for postoperative neurological deficits (odds ratio = 0.959; 95% confidence interval: 0.923, 0.997; P = 0.037). CONCLUSIONS: Lower intraoperative CBF during ASCP seems independently related to postoperative neurological deficits in patients undergoing aortic arch surgery. Because CBF is a modifiable factor during ASCP, our observation has significant potential to improve clinical management and prevent neurological deficits.

Item does not contain fulltext, A large interventional trial, the Systolic Blood Pressure Intervention Trial sub-study termed Memory and Cognition in Decreased Hypertension (SPRINT-MIND), found reduced risk of cognitive impairment in older adults with intensive, relative to standard, blood-pressure-lowering targets (systolic BP < 120 vs. <140 mm Hg). In this perspective, we discuss key questions and make recommendations for clinical practice and for clinical trials, following SPRINT-MIND. Future trials should embody cognitive endpoints appropriate to the participant group, ideally with adaptive designs that ensure robust answers for cognitive and cardiovascular endpoints. Reliable data from diverse populations, including the oldest-old (age > 80 years), will maximize external validity and global implementation of trial findings. New biomarkers will improve phenotyping to stratify patients to optimal treatments. Currently no antihypertensive drug class stands out for dementia risk reduction. Multi-domain interventions, incorporating lifestyle change (exercise, diet) alongside medications, may maximize global impact. Given the low cost and wide availability of antihypertensive drugs, intensive BP reduction may be a cost-effective means to reduce dementia risk in diverse, aging populations worldwide.

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19 april 2023, Item does not contain fulltext, Objective: Cerebral small vessel disease (SVD) is considered the most important vascular contributor to cognitive decline and dementia, although a causal relation between its MRI markers and dementia still needs to be established. The authors investigated the relation between baseline SVD severity as well as SVD progression on MRI markers and incident dementia, by subtype, in individuals with sporadic SVD over a follow-up period of 14 years. Methods: The study included 503 participants with sporadic SVD, and without dementia, from the prospective Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study, with screening for baseline inclusion conducted in 2006. Follow-ups in 2011, 2015, and 2020 included cognitive assessments and MRI scans. Dementia was diagnosed according to DSM-5 criteria and stratified into Alzheimer's dementia and vascular dementia. Results: Dementia as an endpoint was available for 498 participants (99.0%) and occurred in 108 participants (21.5%) (Alzheimer's dementia, N=38; vascular dementia, N=34; mixed-etiology Alzheimer’s dementia/vascular dementia, N=26), with a median follow-up time of 13.2 years (interquartile range, 8.8-13.8). Higher baseline white matter hyperintensity (WMH) volume (hazard ratio=1.31 per 1-SD increase, 95% CI=1.02-1.67), presence of diffusion-weighted-imaging-positive lesions (hazard ratio=2.03, 95% CI=1.01-4.04), and higher peak width of skeletonized mean diffusivity (hazard ratio=1.24 per 1-SD increase, 95% CI=1.02-1.51) were independently associated with all-cause dementia and vascular dementia. WMH progression predicted incident all-cause dementia (hazard ratio=1.76 per 1-SD increase, 95% CI=1.18-2.63). Conclusions: Both baseline SVD severity and SVD progression were independently associated with an increase in risk of all-cause dementia over a follow-up of 14 years. The results suggest that SVD progression precedes dementia and may causally contribute to its development. Slowing SVD

01 augustus 2023, Item does not contain fulltext, Dynamic cerebral autoregulation (dCA) is a key mechanism that regulates cerebral blood flow (CBF) in response to transient changes in blood pressure (BP). Impairment of dCA could increase vulnerability to hypertensive vascular damage, but also to BP lowering effects of antihypertensive treatment. The literature remains conflicted on whether dCA is altered in Alzheimer's disease (AD) and mild cognitive impairment (MCI). We summarized available data on dCA in AD and MCI, by searching PubMed, Embase, PsycINFO and Web of Science databases (inception-January 2022). Eight studies (total n = 443) were included in the qualitative synthesis of which seven were eligible for meta-analysis. All studies used Transcranial Doppler (TCD) ultrasonography and transfer function analysis or the autoregulatory index to assess dCA during spontaneous or induced BP fluctuations. Meta-analysis indicated no significant difference between AD, MCI and healthy controls in dCA parameters for spontaneous fluctuations. For induced fluctuations, the available data were limited, but indicative of at least preserved and possibly better autoregulatory functioning in AD and MCI compared to controls. In summary, current evidence does not suggest poorer dCA efficiency in AD or MCI. Further work is needed to investigate dCA in dementia with induced fluctuations controlling for changes in end-tidal carbon dioxide.

Contains fulltext : 299851.pdf (Publisher’s version ) (Open Access), Orthostatic hypotension (OH) is an established and common cardiovascular risk factor for falls. An in-depth understanding of the various interacting pathophysiological pathways contributing to OH-related falls is essential to guide improvements in diagnostic and treatment opportunities. We applied systems thinking to multidisciplinary map out causal mechanisms and risk factors. For this, we used group model building (GMB) to develop a causal loop diagram (CLD). The GMB was based on the input of experts from multiple domains related to OH and falls and all proposed mechanisms were supported by scientific literature. Our CLD is a conceptual representation of factors involved in OH-related falls, and their interrelatedness. Network analysis and feedback loops were applied to analyze and interpret the CLD, and quantitatively summarize the function and relative importance of the variables. Our CLD contains 50 variables distributed over three intrinsic domains (cerebral, cardiovascular, and musculoskeletal), and an extrinsic domain (e.g., medications). Between the variables, 181 connections and 65 feedback loops were identified. Decreased cerebral blood flow, low blood pressure, impaired baroreflex activity, and physical inactivity were identified as key factors involved in OH-related falls, based on their high centralities. Our CLD reflects the multifactorial pathophysiology of OH-related falls. It enables us to identify key elements, suggesting their potential for new diagnostic and treatment approaches in fall prevention. The interactive online CLD renders it suitable for both research and educational purposes and this CLD is the first step in the development of a computational model for simulating the effects of risk factors on falls., 01 augustus 2023

Contains fulltext : 299852.pdf (Publisher’s version ) (Open Access), Orthostatic hypotension (OH) is highly prevalent in older adults and associated with dizziness, falls, lower physical and cognitive function, cardiovascular disease, and mortality. OH is currently diagnosed in a clinical setting with single-time point cuff measurements. Continuous blood pressure (BP) devices can measure OH dynamics but cannot be used for daily life monitoring. Near-infrared spectroscopy (NIRS) has potential diagnostic value in measuring cerebral oxygenation continuously over a longer time period, but this needs further validation. This study aimed to compare NIRS-measured (cerebral) oxygenation with continuous BP and transcranial Doppler-measured cerebral blood velocity (CBv) during postural changes. This cross-sectional study included 41 participants between 20 and 88 years old. BP, CBv, and cerebral (long channels) and superficial (short channels) oxygenated hemoglobin (O(2)Hb) were measured continuously during various postural changes. Pearson correlations between BP, CBv, and O(2)Hb were calculated over curves and specific characteristics (maximum drop amplitude and recovery). BP and O(2)Hb only showed good curve-based correlations (0.58-0.75) in the initial 30 s after standing up. Early (30-40 s) and 1-min BP recovery associated significantly with O(2)Hb, but no consistent associations were found for maximum drop amplitude and late (60-175 s) recovery values. Associations between CBv and O(2)Hb were poor, but stronger for long-channel than short-channel measurements. BP associated well with NIRS-measured O(2)Hb in the first 30 s after postural change. Stronger associations for CBv with long-channel O(2)Hb suggest that long-channel NIRS specifically reflects cerebral blood flow during postural transitions, necessary to better understand the consequences of OH such as intolerance symptoms., 01 augustus 2023

Contains fulltext : 299855.pdf (Publisher’s version ) (Open Access), We discuss the current evidence for both benefit and harm of antihypertensive treatment in people with dementia. We conclude that there is a lack of evidence to support the claim that there is an increased risk of cerebral hypoperfusion with antihypertensive treatment in dementia, and that there is growing evidence which refutes this claim., 4 p.

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Contains fulltext : 249322.pdf (Publisher’s version ) (Open Access)

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Item does not contain fulltext, WHAT IS KNOWN AND OBJECTIVE: Alpha-blockers have been associated with orthostatic hypotension (OH). We aimed to assess the prevalence of OH measured with beat-to-beat blood pressure monitoring in older male outpatients who used alpha-blockers for lower urinary tract symptoms (LUTS). In addition, we investigated associations of OH with duration of alpha-blocker use, concomitant medication use and comorbidity. METHODS: Cross-sectional explorative study in a urology outpatient clinic. Older white males ≥65 years using alpha-blockers for LUTS were included. Blood pressure responses to standing up from supine were recorded using a validated beat-to-beat blood pressure device (Finapres). Prevalence rates were derived from the beat-to-beat data to include OH measured between 60-110 s (OH), impaired recovery OH at 40 s (OH[40]), initial OH (IOH) and normal orthostatic response. Subgroups were defined based on duration of alpha-blocker use, polypharmacy, and Charlson comorbidity index (CCI), to obtain relative risks. RESULTS AND DISCUSSION: Sixty-five patients were included. Median age was 75 years (range 65-92). The prevalence of OH was 7.7% (n = 5). The prevalence of OH(40) was 16.9% (n = 11) and of IOH 38.5% (n = 25). Thirty-six patients (55.4%) had a normal orthostatic response. The relative risk of OH for the subgroup using ≥ 10 medications (n = 13) was 6.0 (95%CI 1.1-32.3). For the subgroup with multimorbidity (CCI ≥3, n = 11) this was 7.4 (95%CI 1.4-39.0). Recent initiation of alpha-blocker use (<3 months) did not increase OH risk (RR 0.6 [95%CI 0.1-5.1]). WHAT IS NEW AND CONCLUSION: The overall prevalence of OH was low and comparable to age-matched population prevalence, suggesting that the relative contribution of alpha-blockers to OH was small. However, OH risk significantly increased in patients with multimorbidity or polypharmacy. For these patients, the benefits of starting alpha-blockers for LUTS should be weighed against the increased risk of OH.

Contains fulltext : 282878.pdf (Publisher’s version ) (Open Access), Sedentary behaviour may increase the risk of dementia. Studying physiological effects of sedentary behaviour on cerebral health may provide new insights into the nature of this association. Accordingly, we reviewed if and how acute and habitual sedentary behaviour relate to brain health factors in middle-aged and older adults (≥45 years). Four databases were searched. Twenty-nine studies were included, with mainly cross-sectional designs. Nine studies examined neurotrophic factors and six studied functional brain measures, with the majority of these studies finding no associations with sedentary behaviour. The results from studies on sedentary behaviour and cerebrovascular measures were inconclusive. There was a tentative association between habitual sedentary behaviour and structural white matter health. An explanatory pathway for this effect might relate to the immediate vascular effects of sitting, such as elevation of blood pressure. Nevertheless, due to the foremost cross-sectional nature of the available evidence, reverse causality could also be a possible explanation. More prospective studies are needed to understand the potential of sedentary behaviour as a target for brain health.

Contains fulltext : 251796.pdf (Publisher’s version ) (Open Access), Background: In older age, the benefits of antihypertensive treatment (AHT) become less evident, with greater associated risk. Of particular concern is compromising cerebral blood flow (CBF), especially in those with cognitive impairment. Methods: We created a synthesis of the published evidence by searching multiple electronic databases from 1970 to May 2021. Included studies had participants with mean age ≥50 years, hypertension or cognitive impairment, and assessed CBF before and after initiating AHT. Two authors independently determined eligibility and extracted data. Study quality was assessed using The Risk of Bias in Nonrandomized Studies of Interventions tool. We summarized study characteristics (qualitative synthesis) and performed random-effects meta-analyses (quantitative synthesis). Results: Thirty-two studies (total n=1306) were included, of which 23 were eligible for meta-analysis. In line with the qualitative synthesis, the meta-analysis indicated no effect of AHT initiation on CBF (standardized mean difference, 0.08 [95% CI, -0.07 to 0.22]; P=0.31, I2=42%). This was consistent across subgroups of acute versus chronic AHT, drug class, study design, and CBF measurement. Subgroups by age demonstrated an increase in CBF after AHT in those aged >70 years (standardized mean difference, 4.15 [95% CI, 0.16-8.15]; P=0.04, I2=42%), but not in those aged 50 to 65 and 65 to 70 years (standardized mean difference, 0.18 [95% CI,-2.02 to 2.38]; P=0.87, I2=49%; standardized mean difference, 1.22 [95% CI, -0.45 to 2.88]; P=0.15, I2=68%). Overall, risk of bias was moderate-to-high and quality of evidence (Grading of Recommendations Assessment, Development and Evaluation) was very low, reflecting the observational nature of the data. Conclusions: Accepting the observed limitations, current evidence does not suggest a harmful effect of AHT on CBF. Concerns over CBF should not preclude treatment of hypertension.

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Contains fulltext : 231413.pdf (Publisher’s version ) (Closed access), PURPOSE: Sedentary behavior increases the risk for cardiovascular and cerebrovascular disease. To understand potential benefits and underlying mechanisms, we examined the acute and long-term impact of reduced sitting-intervention on vascular and cerebrovascular function. METHODS: This prospective study included 24 individuals with increased cardiovascular risk (65±5 years, 29.8±3.9 kg/m). Before and after 16-week reduced sitting, using a mobile-Health device with vibrotactile feedback, we examined: i. vascular function (flow-mediated dilation (FMD)), ii. cerebral blood flow (CBFv, transcranial Doppler), and iii. cerebrovascular function (cerebral autoregulation (CA) and cerebral vasomotor reactivity (CVMR)). To better understand potential underlying mechanisms, before and after intervention, we evaluated the effects of 3-hour sitting with and without light-intensity physical activity breaks (every 30-minutes). RESULTS: The first wave of participants showed no change in sedentary time (n=9, 10.3±0.5 to 10.2±0.5 hours/day, P=0.87). Upon intervention optimization by participants' feedback, the subsequent participants (n=15) decreased sedentary time (10.2±0.4 to 9.2±0.3 hours/day, P<0.01). This resulted in significant increases in FMD (3.1±0.3 to 3.8±0.4%, P=0.02) and CBFv (48.4±2.6 to 51.4.±2.6 cm/s, P=0.02), without altering CA or CVMR. Before and after the 16-week intervention, 3-hour exposure to uninterrupted sitting decreased FMD and CBFv, whereas physical activity breaks prevented a decrease (both P<0.05). CA and CVMR did not change (P>0.20). CONCLUSION: Long-term reduction in sedentary behavior improves peripheral vascular function and cerebral blood flow, and acutely prevents impaired vascular function and decreased cerebral blood flow. These results highlight the potential benefits of reducing sedentary behavior to acutely and chronically improve cardio-/cerebrovascular risk.

Contains fulltext : 219405.pdf (Publisher’s version ) (Open Access), Acute total sleep deprivation and partial sleep deprivation have negative impacts on cognitive performance. Studies in subjects who regularly experience sleep loss, however, are rare and often restricted to examination of internal sleeping disorders. To address this issue, we set up a pilot study to explore the effects of a week characterized by sleep disruption on cognitive functioning, using a case–control setting in a maritime pilot group with chronic exposure to intermittent extrinsic, work-related sleep disruption. Twenty maritime pilots (aged 30–50 years) were compared to sex- and education-matched controls with normal sleep behaviour, from the same age range. We assessed subjective and objective cognitive function, including attention, psychomotor speed, memory and executive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Although we were able to confirm poorer sleep in maritime pilots and subjective complaints in some cognitive domains, we did not find objective cognitive deficits in the maritime pilot group compared to controls without sleep disruption. This could suggest that in this group of healthy, young maritime pilots, exposure to sleep disruption resulted in some subjective cognitive complaints, but objective deficits of cognitive function were not detected in comparison with a non-pilot control group. However, given the small sample size, the absence of an effect does not exclude the possibility that sleep disruption could result in cognitive deficits in general. Therefore, our findings have to be confirmed in future prospective studies with a larger sample size and matched controls, regarding age, education and work history.

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Contains fulltext : 232926.pdf (Publisher’s version ) (Open Access), KEY POINTS: The post-exercise recovery of phosphocreatine, a measure of the oxidative capacity of muscles, as assessed by (31) P MR spectroscopy, shows a striking increase from distal to proximal along the human tibialis anterior muscle. To investigate why this muscle exhibits a greater oxidative capacity proximally, we tested whether the spatial variation in phosphocreatine recovery rate is related to oxygen supply, muscle fibre type or type of exercise. We revealed that oxygen supply also increases from distal to proximal along the tibialis anterior, and that it strongly correlated with phosphocreatine recovery. Carnosine level, a surrogate measure for muscle fibre type was not different between proximal and distal, and type of exercise did not affect the gradient in phosphocreatine recovery rate. Taken together, the findings of this study suggest that the post-exercise spatial gradients in oxygen supply and phosphocreatine recovery are driven by a higher intrinsic mitochondrial oxidative capacity proximally. ABSTRACT: Phosphorus magnetic resonance spectroscopy ((31) P MRS) of human tibialis anterior (TA) revealed a strong proximo-distal gradient in the post-exercise phosphocreatine (PCr) recovery rate constant (kPCr ), a measure of muscle oxidative capacity. The aim of this study was to investigate whether this kPCr gradient is related to O2 supply, resting phosphorylation potential, muscle fibre type, or type of exercise. Fifteen male volunteers performed continuous isometric ankle dorsiflexion at 30% maximum force until exhaustion. At multiple locations along the TA, we measured the oxidative PCr resynthesis rate (VPCr = kPCr x PCr depletion) by (31) P MRS, the oxyhaemoglobin recovery rate constant (kO2Hb ) by near infrared spectroscopy, and muscle perfusion with MR intravoxel incoherent motion imaging. The kO2Hb , kPCr , VPCr and muscle perfusion depended on measurement location (P < 0.001, P < 0.001, P = 0.032 and P = 0.003, respectively), all being greater p

Contains fulltext : 238387.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, Due to its cardiovascular effects sedentary behaviour might impact cerebrovascular function in the long term, affecting cerebrovascular regulatory mechanisms and perfusion levels. Consequently this could underly potential structural brain abnormalities associated with cognitive decline. We therefore assessed the association between sedentary behaviour and brain measures of cerebrovascular perfusion and structural abnormalities in community-dwelling older adults. Using accelerometery (GENEActiv) data from The Irish Longitudinal Study on Ageing (TILDA) we categorised individuals by low- and high-sedentary behaviour (≤8 vs >8 hours/day). We examined prefrontal haemoglobin oxygenation levels using Near-Infrared Spectroscopy during rest and after an orthostatic challenge in 718 individuals (66 ± 8 years, 52% female). Global grey matter cerebral blood flow, total grey and white matter volume, total and subfield hippocampal volumes, cortical thickness, and white matter hyperintensities were measured using arterial spin labelling, T1, and FLAIR MRI in 86 individuals (72 ± 6 years, 55% female). While no differences in prefrontal or global cerebral hemodynamics were found between groups, high-sedentary individuals showed lower hippocampal volumes and increased white matter hyperintensities compared to their low-sedentary counterparts. Since these structural cerebral abnormalities are associated with cognitive decline and Alzheimer's disease, future work exploring the causal pathways underlying these differences is needed.

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Item does not contain fulltext, Brain function critically depends on a close matching between metabolic demands, appropriate delivery of oxygen and nutrients, and removal of cellular waste. This matching requires continuous regulation of cerebral blood flow (CBF), which can be categorized into four broad topics: 1) autoregulation, which describes the response of the cerebrovasculature to changes in perfusion pressure; 2) vascular reactivity to vasoactive stimuli [including carbon dioxide (CO(2))]; 3) neurovascular coupling (NVC), i.e., the CBF response to local changes in neural activity (often standardized cognitive stimuli in humans); and 4) endothelium-dependent responses. This review focuses primarily on autoregulation and its clinical implications. To place autoregulation in a more precise context, and to better understand integrated approaches in the cerebral circulation, we also briefly address reactivity to CO(2) and NVC. In addition to our focus on effects of perfusion pressure (or blood pressure), we describe the impact of select stimuli on regulation of CBF (i.e., arterial blood gases, cerebral metabolism, neural mechanisms, and specific vascular cells), the interrelationships between these stimuli, and implications for regulation of CBF at the level of large arteries and the microcirculation. We review clinical implications of autoregulation in aging, hypertension, stroke, mild cognitive impairment, anesthesia, and dementias. Finally, we discuss autoregulation in the context of common daily physiological challenges, including changes in posture (e.g., orthostatic hypotension, syncope) and physical activity.

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