Neurodegenerative and cerebrovascular diseases cause considerable human suffering, and therapy options for these two disease categories are limited or non‐existing. It is an emerging notion that ...neurodegenerative and cerebrovascular diseases are linked in several ways, and in this review, we discuss the current status regarding vascular dysregulation in neurodegenerative disease, and conversely, how cerebrovascular diseases are associated with central nervous system (CNS) degeneration and dysfunction. The emerging links between neurodegenerative and cerebrovascular diseases are reviewed with a particular focus on pericytes—important cells that ensheath the endothelium in the microvasculature and which are pivotal for blood–brain barrier function and cerebral blood flow. Finally, we address how novel molecular and cellular insights into pericytes and other vascular cell types may open new avenues for diagnosis and therapy development for these important diseases.
This review focuses on how pericytes link cerebrovascular and neurodegenerative diseases, and how recent insight into pericyte function might potentially be used for therapy.
Arterial stiffness has been associated with evidence of cerebral small vessel disease (cSVD) and fibrillar β-amyloid (Aβ) deposition in the brain. These complex relationships have not been examined ...in racially and cognitively diverse cohorts.
The Atherosclerosis Risk in Communities (ARIC)-Neurocognitive Study collected detailed cognitive testing for adjudication of dementia and mild cognitive impairment (MCI), brain MRI, and arterial stiffness by pulse wave velocity (PWV, carotid-femoral cfPWV and heart-carotid hcPWV). The ARIC-PET ancillary study added Aβ imaging using florbetapir (
F-AV-45) to obtain standardized uptake volume ratios and defined global Aβ-positivity as standardized uptake volume ratio >1.2. One-SD increase in PWV was related to brain volume, MRI-defined cSVD (e.g., cerebral microbleeds and white matter hyperintensity), and cortical Aβ deposition adjusted for age, body mass index, sex, race, and
ε4 status. We examined the cross-sectional relationships including interactions by race,
ε4 status, and cognition.
Among the 320 ARIC-PET participants (76 5 years, 45% black, 27% MCI), greater central stiffness (hcPWV) was associated with greater Aβ deposition (odds ratio OR = 1.31, 95% confidence interval CI 1.01-1.71). Greater central stiffness (cfPWV) was significantly associated with having lower brain volumes in Alzheimer disease-susceptible regions (in mm
, β = -1.5 0.7 SD,
= 0.03) and high white matter hyperintensity burden (OR = 1.6, 95% CI 1.2-2.1). Furthermore, cfPWV was associated with a higher odds of concomitant high white matter hyperintensity and Aβ-positive scans (OR = 1.4, 95% CI 1.1-2.1). These associations were strongest among individuals with MCI and did not differ by race or
ε4 status.
Arterial stiffness, measured by PWV, is an emerging risk factor for dementia through its repeated relationships with cognition, cSVD, and Aβ deposition.
Neurovascular coupling reflects the close temporal and regional linkage between neural activity and cerebral blood flow. Although providing mechanistic insight, our understanding of neurovascular ...coupling is largely limited to non-physiological ex vivo preparations and non-human models using sedatives/anesthetics with confounding cerebrovascular implications. Herein, with particular focus on humans, we review the present mechanistic understanding of neurovascular coupling and highlight current approaches to assess these responses and the application in health and disease. Moreover, we present new guidelines for standardizing the assessment of neurovascular coupling in humans. To improve the reliability of measurement and related interpretation, the utility of new automated software for neurovascular coupling is demonstrated, which provides the capacity for coalescing repetitive trials and time intervals into single contours and extracting numerous metrics (e.g., conductance and pulsatility, critical closing pressure, etc.) according to patterns of interest (e.g., peak/minimum response, time of response, etc.). This versatile software also permits the normalization of neurovascular coupling metrics to dynamic changes in arterial blood gases, potentially influencing the hyperemic response. It is hoped that these guidelines, combined with the newly developed and openly available software, will help to propel the understanding of neurovascular coupling in humans and also lead to improved clinical management of this critical physiological function.
Remote ischemic preconditioning (RIPC) is an intrinsic protective phenomenon in which 3 to 4 interspersed cycles of non-fatal regional ischemia followed by reperfusion to the remote tissues protect ...the vital organs including brain, heart and kidney against sustained ischemia-reperfusion-induced injury. There is growing preclinical evidence supporting the usefulness of RIPC in eliciting neuroprotection against focal and global cerebral ischemia-reperfusion injury. Scientists have explored the involvement of HIF-1α, oxidative stress, apoptotic pathway, Lcn-2, platelets-derived microparticles, splenic response, adenosine A1 receptors, adenosine monophosphate activated protein kinase and neurogenic pathway in mediating RIPC-induced neuroprotection. The present review discusses the early and late phases of neuroprotection induced by RIPC against cerebral ischemic injury in animals along with the various possible mechanisms.
Atrial fibrillation (AF) and dementia are both frequent diseases with substantial socioeconomic impact. While AF has been associated with cognitive dysfunction and dementia, we currently lack an ...exact understanding of the complex association between AF and cognitive decline. Based on an extended literature search we summarize key publications focusing on AF-related cognitive decline and dementia. Moreover, ongoing trials and potential therapeutic implications are discussed. While further prospective studies using a standardized definition of AF and cognitive decline are urgently needed, growing evidence supports the hypothesis that AF is an independent risk factor for cognitive decline and dementia in general and for Alzheimer's disease in particular. In addition to AF-related ischaemic stroke, white matter damage and systemic inflammation are candidate pathomechanisms and therefore a potential target for prevention of cognitive decline. Whether individualized best-medical therapy of AF holds the promise of preventing cognitive decline should be tested in randomized trials.
Abstract
Both type 1 and type 2 diabetes adversely affect the microvasculature in multiple organs. Our understanding of the genesis of this injury and of potential interventions to prevent, limit, or ...reverse injury/dysfunction is continuously evolving. This statement reviews biochemical/cellular pathways involved in facilitating and abrogating microvascular injury. The statement summarizes the types of injury/dysfunction that occur in the three classical diabetes microvascular target tissues, the eye, the kidney, and the peripheral nervous system; the statement also reviews information on the effects of diabetes and insulin resistance on the microvasculature of skin, brain, adipose tissue, and cardiac and skeletal muscle. Despite extensive and intensive research, it is disappointing that microvascular complications of diabetes continue to compromise the quantity and quality of life for patients with diabetes. Hopefully, by understanding and building on current research findings, we will discover new approaches for prevention and treatment that will be effective for future generations.
This scientific statement reviews and discusses the microvascular complications of diabetes on an organ-by-organ basis.
The goal of this work was to investigate trends (2001-2019) for cardiovascular events and cardiometabolic risk factor levels in individuals with type 2 diabetes (T2D) and matched control subjects.
...This study included 679 072 individuals with T2D from the Swedish National Diabetes Register and 2 643 800 matched control subjects. Incident outcomes comprised coronary artery disease, acute myocardial infarction, cerebrovascular disease, and heart failure (HF). Trends in time to first event for each outcome were analyzed with Cox regression and standardized incidence rates. In the group with T2D, Cox regression was also used to assess risk factor levels beyond target and outcomes, as well as the relative importance of each risk factor to each model.
Among individuals with T2D, incidence rates per 10 000 person-years in 2001 and 2019 were as follows: acute myocardial infarction, 73.9 (95% CI, 65.4-86.8) and 41.0 (95% CI, 39.5-42.6); coronary artery disease, 205.1 (95% CI, 186.8-227.5) and 80.2 (95% CI, 78.2-82.3); cerebrovascular disease, 83.9 (95% CI, 73.6-98.5) and 46.2 (95% CI, 44.9-47.6); and HF, 98.3 (95% CI, 89.4-112.0) and 75.9 (95% CI, 74.4-77.5). The incidence for HF plateaued around 2013, a trend that then persisted. In individuals with T2D, glycated hemoglobin, systolic blood pressure, estimated glomerular filtration rate, and lipids were independently associated with outcomes. Body mass index alone potentially explained >30% of HF risk in T2D. For those with T2D with no risk factor beyond target, there was no excess cardiovascular risk compared with control subjects except for HF, with increased hazard with T2D even when no risk factor was above target (hazard ratio, 1.50 95% CI, 1.35-1.67). Risk for coronary artery disease and cerebrovascular disease increased in a stepwise fashion for each risk factor not within target. Glycated hemoglobin was most prognostically important for incident atherosclerotic events, as was body mass index for incident of HF.
Risk and rates for atherosclerotic complications and HF are generally decreasing among individuals with T2D, although HF incidence has notably plateaued in recent years. Modifiable risk factors within target levels were associated with lower risks for outcomes. This was particularly notable for systolic blood pressure and glycated hemoglobin for atherosclerotic outcomes and body mass index for heart failure.
Longitudinal clinical–pathological studies have increasingly recognized the importance of mixed pathologies (the coexistence of one or more neurodegenerative and cerebrovascular disease pathologies) ...as important factors in the development of Alzheimer’s disease (AD) and other forms of dementia. Older persons with AD pathology, often have concomitant cerebrovascular disease pathologies (macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy) as well as other concomitant neurodegenerative disease pathologies (Lewy bodies, TDP-43, hippocampal sclerosis). These additional pathologies lower the threshold for clinical diagnosis of AD. Many of these findings from pathologic studies, especially for CVD, have been confirmed using sophisticated neuroimaging technologies. In vivo biomarker studies are necessary to provide an understanding of specific pathologic contributions and time course relationships along the spectrum of accumulating pathologies. In this review, we provide a clinical–pathological perspective on the role of multiple brain pathologies in dementia followed by a review of the available clinical and biomarker data on some of the mixed pathologies.
There are no generally accepted protocols for post-mortem assessment in cases of suspected vascular cognitive impairment. Neuropathologists from seven UK centres have collaborated in the development ...of a set of vascular cognitive impairment neuropathology guidelines (VCING), representing a validated consensus approach to the post-mortem assessment and scoring of cerebrovascular disease in relation to vascular cognitive impairment. The development had three stages: (i) agreement on a sampling protocol and scoring criteria, through a series of Delphi method surveys; (ii) determination of inter-rater reliability for each type of pathology in each region sampled (Gwet's AC2 coefficient); and (iii) empirical testing and validation of the criteria, by blinded post-mortem assessment of brain tissue from 113 individuals (55 to 100 years) without significant neurodegenerative disease who had had formal cognitive assessments within 12 months of death. Fourteen different vessel and parenchymal pathologies were assessed in 13 brain regions. Almost perfect agreement (AC2 > 0.8) was found when the agreed criteria were used for assessment of leptomeningeal, cortical and capillary cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microhaemorrhage, larger haemorrhage, fibrinoid necrosis, microaneurysms, perivascular space dilation, perivascular haemosiderin leakage, and myelin loss. There was more variability (but still reasonably good agreement) in assessment of the severity of arteriolosclerosis (0.45-0.91) and microinfarcts (0.52-0.84). Regression analyses were undertaken to identify the best predictors of cognitive impairment. Seven pathologies-leptomeningeal cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microinfarcts, arteriolosclerosis, perivascular space dilation and myelin loss-predicted cognitive impairment. Multivariable logistic regression determined the best predictive models of cognitive impairment. The preferred model included moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, moderate/severe arteriolosclerosis in occipital white matter, and at least one large infarct (area under the receiver operating characteristic curve 77%). The presence of 0, 1, 2 or 3 of these features resulted in predicted probabilities of vascular cognitive impairment of 16%, 43%, 73% or 95%, respectively. We have developed VCING criteria that are reproducible and clinically predictive. Assuming our model can be validated in an independent dataset, we believe that this will be helpful for neuropathologists in reporting a low, intermediate or high likelihood that cerebrovascular disease contributed to cognitive impairment.10.1093/brain/aww214_video_abstractaww214_video_abstract.
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