From dark horse to front-runner: vascular contributions to brain health

Abstract

It is becoming increasingly clear that the cerebral microcirculation plays a central role in the development and progression of Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD). Despite recent advances in understanding the vascular contributions to cognitive impairment and decline, many gaps exist in our collective knowledge. The 2022 Annual Workshop of the Albert Research Institute for White Matter and Cognition brought together investigators in the fields of neurovascular function and health, blood–brain barrier integrity, neurodegeneration, cerebral microvascular function, brain imaging, integrative systems neuroscience, and clinicians to discuss exciting and novel findings on how the vasculature contributes to progression of dementia. During the Workshop, the participants shared their most novel findings on the subject and discussed the implications of their data in reference to advancement of our knowledge in the basic mechanisms underlying microvascular pathology in the brain, as well as possible areas for clinical intervention. Overall, this meeting successfully highlighted some of the excellent progress in elucidating vascular contributions to dementia, and identified areas where rigorous scientific investigation is needed.

Introduction

Vascular contributions to cognitive impairment and dementia (VCID)

Vascular contributions to cognitive impairment and dementia (VCID) are characterized by progressive decline in brain function related—at least in part—to cerebrovascular pathologies, particularly in the brain microcirculation. Sequelae of these vascular pathologies can be identified via neuroimaging, such as infarcts, hemorrhages, and white matter disease and degeneration [1]. Other neuroimaging measures such as changed size of radiographically visible perivascular spaces, blood–brain barrier dysfunction as measured by dynamic contrast-enhanced magnetic resonance imaging (MRI), reduced brain perfusion, and changes to cerebrovascular reactivity are more direct measures of early cerebrovascular dysfunction. However, these abnormalities still represent multi-cellular read-outs of cerebrovascular function that can be affected by a plethora of molecular abnormalities, involving multiple cell types in the neurovascular unit and beyond. Molecular markers of cerebrovascular disease remain elusive and currently none are measured as part of clinical work-up and differential diagnosis for an individual suspected to have VCID based on imaging and clinical phenotyping. From a therapeutic perspective, exactly what molecules and cellular mechanisms link vascular pathologies to dysfunction and degeneration of glia and neurons is not understood. These challenges have impeded progress in drug development and clinical applications and contributed to the relatively low estimated 7% of dementia research examining vascular pathological contributions to neurodegeneration. Notwithstanding, autopsy studies suggest that 80–90% of brains affected with Alzheimer’s disease have concomitant evidence of cerebrovascular disease pathologies and sequalae [2–4]. In fact, cerebral amyloid angiopathy (CAA), an AD-related subtype of cerebral small vessel disease, is present in a majority of aging brains, thus it can be argued that cerebrovascular disease is the most common umbrella category of pathologies or tissue abnormalities in the degenerating, aging brain. Nonetheless, there are currently no FDA-approved therapies for VCID and recently approved anti-amyloid therapies present concerning vascular side-effects, such as ARIA (amyloid related imaging abnormalities) [5]. The 2022 Albert Institute for White Matter and Cognition Workshop convened investigators across disciplines and modalities of research to share work relevant to mechanistic understanding and/or therapeutic developments in VCID, as well as some mechanisms underlying microvascular dysfunction in the aging brain.

Overview of 2022 Albert institute for white matter and cognition workshop

The workshop scientific program was organized by Dr. Sandra Billinger, Dr. Fanny Elahi and Dr. Kristen Zuloaga and centered around 6 topics: 1) a problem of barriers: brain-body crosstalk in VCID (Elahi, Daneman, Kaufer), 2) honing in on cellular pathologies of VCID (Carmichael, Blanchard), 3) VCID risk factors (Zuloaga, Pires, Gupta, Williamson), 4) resiliency to vascular-metabolic injury (Cortes, Billinger, Stillman Coyle), 5) imaging of vascular disease of the human brain (Hu, Yabluchanskiy, Levendovsky, Tarantini), and 6) future directions for VCID (Wilcock, Sorond). The meeting was held in West Palm Beach FL on March 27-29th, 2022. Individual summaries of the talks are provided below.

A problem of barriers and brain-body cross-talk

Blood–brain barrier dysfunction is associated with A/T/N biomarkers and cognition in the aging brain

Fanny Elahi, M.D., Ph.D.

Departments of Neurology and Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Age-associated dysfunction of brain barriers results in increased non-specific permeability of barriers, including blood–brain and CSF-brain barriers (BBB and CBB respectively), referred to as “leakage.” Blood proteins pass through dysfunctional barriers into the central nervous system (CNS) parenchyma, with potential effects on glia and neurons. Measuring blood proteins in cerebrospinal fluid (CSF) serves as a surrogate measure of barrier (especially BBB) dysfunction in humans. By using measures such as CSF/serum albumin quotient or CSF fibrinogen concentrations, barrier function has been associated with brain-centric outcomes, such as mood and cognition. It remains unclear, however, whether BBB and CBB dysfunctions can be early pathological features of the aging brain, instigating the development of neurodegenerative disease pathologies. We used colorimetric enzyme-linked immunosorbent and chemiluminescence immunoassays to quantify CSF concentrations of fibrinogen and A/T/N AD biomarkers in a cohort of 84 deeply phenotyped functionally normal older adults and built linear models to test the associations of fibrinogen (barrier leakage) with A/T/N biomarkers and cognition (processing speed). The “N” biomarkers included three synaptic proteins (neurogranin, SNAP25, and GAP43). We set significance at α = 0.05. We found strong, significant associations of BBB leakage (CSF fibrinogen levels) with all three synaptic proteins, as well as tau and p-tau. With respect to Aβ, we found a significant association of BBB leakage with Aβ 1–40, which is the peptide most strongly associated with cerebral amyloid angiopathy, an aging and AD-related microangiopathy of the CNS. Importantly, we also found a significant association with processing speed–a highly relevant cognitive measure for the aging brain. In this work, we demonstrate associations between BBB leakage and levels of AD A/T/N biomarkers in the aging brain. Although correlation is not causation, prior mechanistic studies in mice have demonstrated that fibrinogen leakage into the CNS triggers and propagates degenerative brain pathologies, relevant to AD. This is the first in vivo translation and extension of these pathways to the aging brain. Our reported findings have implications for therapeutics, given great interest in development of therapies for brain barrier dysfunction and leakage in neurodegenerative disorders. This process may start early in the aging brain and therefore trials may consider the inclusion of preclinical disease stages.

The response of the central nervous system vasculature to neuroinflammation

Richard Daneman, Ph.D.

University of California, San Diego.

The blood vessels in the brain form a highly restrictive barrier, termed the blood–brain barrier, that controls the extracellular environment of the central nervous system. This barrier is critical for proper neuronal function as well as protecting the brain from injury and disease. Many of the symptoms of stroke, traumatic brain injury, epilepsy, multiple sclerosis and many other neurological and neurodegenerative diseases are due to a breakdown of the blood–brain barrier that accompanies the primary insult. Therefore, it is critical to understand how different vascular cells respond to injury and inflammation, in order to develop methods to limit the severity of many different neurological disorders. We use a combination of cellular, molecular and genetic approaches to identify how vascular cells change in disease, and how these changes play a role in the damage and repair of the neural tissue. In particular, we have found an important role for perivascular fibroblasts in modulating the response to neuroinflammation.

From football players to aging brains—trajectories of vulnerability and resilience to cognitive decline

Daniela Kaufer, Ph.D.

Dept of Integrative Biology and Helen Wills Neuroscience Institute, UC Berkeley.

Under healthy conditions, the brain is protected by the blood–brain barrier (BBB), which regulates the communication between blood-borne factors and brain cells. We studied the consequences of BBB impairments in aging and in disease and found that in patients with epilepsy or Alzheimer’s disease, as well as in aging mice, BBB impairments were spatially associated with transient electroencephalographic abnormalities (Milikovsky et al., Sci Trans Med, 2019). Our studies revealed a role for leaky BBB in pathological plasticity, ictogenesis and cognitive decline (Senatorov et al., Sci Trans Med, 2019). Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of the inflammatory transforming growth factor–β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology in rodents. Specifically, infusion of the serum protein albumin into the young rodent brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors or pharmacological inhibition of TGFβ signaling reversed these symptomatic outcomes in aged mice. Last, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging and demonstrates that the aging brain may retain considerable latent capacity, which can be revitalized by therapeutic inhibition of TGFβ signaling.

Honing in on cellular pathologies in VCID

Single-nucleus transcriptome analysis reveals disease- and regeneration-associated endothelial cells and candidate mechanistic molecular systems in white matter vascular dementia

S. Thomas Carmichael, M.D., Ph.D.

Departments of Neurology and of Molecular, Cell and Developmental Biology, UCLA.

Vascular dementia (VaD) is the accumulation of vascular lesions in the subcortical white matter of the brain. These lesions progress and there is no direct medical therapy. In particular, VaD lesions progress locally, and do so in a region of brain that has evidence of white matter repair in other diseases, such as multiple sclerosis. A determination of specific cellular responses in VaD will provide molecular targets for therapeutic development. In the presented studies, single-nucleus transcriptome analysis was performed in human periventricular white matter (PVWM) samples of VaD and normal control (NC) subjects. Samples were taken from the most common site for VaD lesions, the periventricular white matter near the frontal horn. Only samples with RIN > 5.9 were taken, necessitating the intake of a large number of potential samples and screening for those with an acceptable RNA integrity. We compared this human snRNAseq to RNAseq of white matter cells in a mouse model of vascular dementia. Differential analysis shows that cell type-specific transcriptomic changes in VaD are associated with the disruption of specific biological processes, including angiogenesis, immune activation, axonal injury and myelination. Each cell type in the neurovascular unit within white matter has a specific alteration in gene expression in VaD. In a central cell type for this disease, subcluster analysis of endothelial cells (EC) indicates that VaD contains a disease-associated EC subcluster that expresses genes associated with programmed cell death and a response to protein folding. Two other subpopulations of EC in VaD express molecular systems associated with regenerative processes in angiogenesis, and in axonal sprouting and oligodendrocyte progenitor cell maturation. Overlap analysis of human and mouse VaD-regulated genes identifies molecular signaling systems that may lead to candidate therapies. Mechanistic studies are ongoing. This comprehensive molecular profiling of brain samples from patients and a laboratory model of VaD reveals previously unknown molecular changes in cells of the neurovascular niche, and an attempt at regeneration in injured white matter.

Risk factors of VCID

Influence of endocrine aging on metabolic and vascular contributions to dementia

Kristen L. Zuloaga, Ph.D.

Department of Neuroscience & Experimental Therapeutics, Albany Medical College.

Around mid-life, endocrine aging (menopause in women, andropause in men) begins to impact physiology and brain health. Mid-life is also a key time period the pathogenesis of dementia, as neuropathology begins to accumulate in the brain decades before a dementia diagnosis. Major mid-life risk factors for dementia include metabolic diseases, such as obesity, prediabetes, and diabetes. How endocrine aging impacts brain health in the context of other co-morbidities is not well understood. Using mouse models of aging, Alzheimer’s disease, vascular contributions to cognitive impairment and dementia (VCID), and multi-etiology dementia (MED; vascular + AD pathology), we examined effects of endocrine aging (gonadectomy or an accelerated ovarian failure models) with or without co-morbid metabolic disease (modeled by chronic high fat diet) in female mice. We found that menopause caused metabolic impairment and cognitive deficits across all three dementia models. Further, a brain-specific estrogen pro-drug reversed cognitive impairment in post-menopausal females. Ongoing work in our lab is now assesses the impact of endocrine aging and brain-specific estrogen therapy on underlying neuropathology.

Cerebral microvascular alterations induced by menopause: implications for cognitive impairment

Paulo W. Pires, Ph.D.

Department of Physiology, University of Arizona.

Cognitive decline is linked to decreased cerebral blood flow, particularly in post-menopausal women. Impaired cerebral microvascular function precedes the onset of cognitive decline, possibly due to imbalances in regulation of parenchymal arteriolar function; the bottlenecks of the cerebral microcirculation. Menopause was shown to reduce the function of large-conductance Ca²⁺-activated K⁺ (BKCa) channels, which are important regulators of vascular smooth muscle cells contractility. However, little is known about the effects of menopause on the cerebral microcirculation, and its possible effects on cognition. Thus, the goal of this study was to determine whether menopause impairs function of parenchymal arterioles of menopausal C57bl/6 J mice in mechanistic detail. Menopause was induced by the 4-vinylcyclohexene diepoxide (Meno) model, which induces gradual ovarian failure (Vehicle: sesame oil). Cerebral parenchymal arterioles were isolated and studied by pressure myography. Parenchymal arterioles from Meno showed significantly higher basal myogenic tone and lower resting lumen diameter, despite maintaining intact endothelial function. However, Meno did impair the function of smooth muscle K⁺ channels, observed as a trend towards a reduction in Kv function in parenchymal arterioles from Meno (p = 0.086), as well as and a significant reduction in BKCa activity (p = 0.04). Interestingly, cognitive capabilities were unaffected by Meno. Together, our data suggest that Meno induces cerebral microvascular dysfunction in healthy mice, which, at the time-points studied, has not yet progressed to cognitive decline.

The brain-kidney axis

Aditi Gupta, M.D., M.S., FASN, FNKF.

Division of Nephrology and Hypertension, Department of Internal Medicine and Department of Neurology, The Jared Grantham Kidney Institute and the KU Alzheimer's Disease Research Center, University of Kansas Medical Center.

Approximately 40% of persons aged > 60 years have chronic kidney disease (CKD). CKD is associated with cognitive impairment and dementia; 87% of patients on chronic dialysis have some degree of cognitive impairment. With increasing life expectancy, prevalence of both CKD and dementia are expected to increase. Patients with CKD are older, and with multiple comorbidities such as hypertension, diabetes mellitus, dyslipidemia, metabolic syndrome, obesity, history of smoking; making CKD is a model for accelerated aging and vascular dysregulation. Vascular dysregulation influences amyloid clearance, one of the earliest biomarkers for Alzheimer’s disease (AD) and related disorders, and a predictor of disease progression. Structural brain alterations in CKD including changes in cerebral blood flow, brain white matter integrity, and brain neurochemicals are similar to those seen in AD. We investigated whether brain alterations seen in end stage kidney disease (ESKD) are reversible after a successful kidney transplant. We found that 1) cerebral blood flow was elevated in ESKD, decreased post-transplant to levels seen in controls, both globally and in most anatomic regions of gray matter analyzed, 2) Certain brain neurochemicals (Cho/Cr and ml/Cr ratios) were elevated in ESKD and normalized post-transplant, and 3) Fractional anisotropy increased and mean diffusivity decreased post-transplant. Age-related changes in brain measurements seen in the general population were present in ESKD. These changes, especially alterations in neurochemicals that normalize after transplantation also support increased permeability of the blood brain barrier (BBB) in ESKD that improves after a successful transplantation. Inspired by these data, we for the first time assessed BBB permeability in ESKD patients and found it to be higher than that of normal controls without CKD. Understanding mechanisms underlying cognitive impairment in CKD and the potential for reversibility of cognitive impairment and brain alterations seen in CKD is important. The potential reversibility in brain alterations seen in kidney disease indicate an opportunity to develop strategies (other than kidney transplant) for management of cognitive impairment in kidney disease.

A review and new insights from the sprint mind trial data

Jeff D. Williamson, M.D., MHS,

Geriatric Medicine and Gerontology, Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest School of Medicine and the Atrium Health System.

Proven treatments for reducing the risk of mild cognitive impairment (MCI) and dementia have been lacking. The impact of intensive treatment of hypertension on the incidence of Mild Cognitive Impairment (MCI) and dementia was tested in the Systolic Blood Pressure Intervention Trial (SPRINT-MIND) by prospectively assessing the effect of intensive blood pressure control to a target systolic blood pressure of < 120 mmHg versus a standard target (< 140 mmHg). This presentation reviews the SPRINT results demonstrating a reduction in risk of developing dementia and MCI and presents additional data on the reliability of the MCI and dementia diagnosis. We will also provide preliminary evidence for differential cognitive benefit from specific antihypertensive medicines. At 1 year, mean systolic blood pressure was 121.4 mmHg in the intensive-treatment group and 136.2 mmHg in the standard-treatment group. Treatment was stopped on 8/20/2015 due to CVD benefit after a median follow-up of 3.26 years, but cognitive assessment continued. Participant mean age was 67.9 years (35.6% women) and 8,626 (92.1%) completed at least one follow-up cognitive assessment. There was a significantly lower rate of adjudicated incident MCI (HR 0.81, CI 0.67–0.97) and a non-significant reduction in probable dementia (HR 0.83, CI 0.69–1.04). The combined outcome of MCI plus probable all cause dementia was significantly lower (HR 0.85, CI 0.74–0.97) in the intensive versus standard treatment group. Most cases occurred in persons over age 70. At 2 years, MCI classification was 10 × more likely to transition to dementia than normal cognition and 30% of classified as MCI reverted to normal, consistent with other large epidemiologic studies of MCI trajectory. Among ambulatory adults at increased risk for CVD but without diabetes, treating to a SBP target < 120 mmHg compared to a target of < 140 mmHg reduces the risk of incident MCI and combined MCI/probable dementia. Reduction of dementia risk by cardiovascular interventions is feasible in the Medicare population.

Resilience to vascular-metabolic injury

Geroprotection on the treadmill: exercise and the aging brain

Constanza J. Cortes, Ph.D.

Leonard Davis School of Gerontology, University of Southern California.

Skeletal muscle has recently arisen as a novel regulators of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions in targeted tissues, including the CNS. Myokine secretion is heavily modified by exercise, suggesting that myokine signaling in the periphery may underlie the well document geroprotective benefits of exercise on the brain. The following studies address muscle proteostasis, a pathway highly activated during exercise, as a potential new regulator of the neurocognitive benefits of exercise. We have recently generated a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E-B (TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity and reduce neuroinflammation in the aging CNS. To directly test the potential neuroprotective effectsof enhancing skeletal muscle proteostasisin AD-associated pathologies, we derived cTFEB;HSA-Cre transgenic mice in the P301S MAPT background. This is a well-characterized model of fronto-temporal dementia and neurofibrillary tangle toxicity and has been previously shown to benefit from exercise interventions. We detected a significant reduction in the accumulation of hyperphosphorylated tau [AT8 phospho-tau antibody] in whole hippocampal lysates and in the dentate gyrus of cTFEB;HSACre;P301S mice compared to their single transgenic P301S littermate controls. Nanostring nCounter®AD panel analysis reveals displayed reductions in microglia activation modules in P301S MAPT/cTFEB:HSACre hippocampi, suggesting reduced neuroinflammation. We also determined that these CNS benefits in P301S MAPT/cTFEB:HSACre mice were accompanied by activation of exercise-associated neurotrophic signaling and reduced markers of advancing tau-associated pathologies in the hippocampus. These provocative results suggest that enhanced skeletal muscle proteostasis modifies the accumulation of pathogenic tau isoforms and reduces neuroinflammation in the CNS of P301S MAPT mice via activation of exercise-associated signaling in the CNS.

Cerebrovascular hemodynamic response during acute exercise: the role of aging and chronic disease

Sandra A. Billinger, Ph.D., PT, FAHA.

Department of Neurology, Department of Cell Biology and Physiology and the University of Kansas Alzheimer’s Disease Research Center, University of Kansas Medical Center.

Cerebral blood flow declines as humans age even in the absence of disease. Age-related cerebrovascular decline may be mitigated through chronic exercise. To best understand the cerebrovascular hemodynamic response during an acute bout of exercise, we developed a novel method for measuring the cerebrovascular response during moderate, continuous exercise in the middle cerebral artery (MCA) using transcranial Doppler ultrasound. The resolution of the MCA velocity (MCAv) response has provided unique information for age- and sex-differences with a blunted response in older adults when compared to their younger counterparts. For those with elevated beta amyloid, MCAv response to moderate intensity exercise was attenuated and we reported a significant negative relationship to amyloid burden, processing speed and response inhibition. For individuals with stroke, we found an attenuated MCAv response to acute exercise compared to age-and sex-matched sedentary individuals. However, for those people post stroke who engaged in greater amounts of physical activity, the MCAv response was significantly higher than those who were sedentary. We are currently exploring the MCAv response during a single bout of high intensity interval exercise and preliminary data will be presented in older adults and those with stroke. The cerebrovascular hemodynamic response during an acute exercise bout may have a role as an emerging cerebrovascular biomarker for brain health.

The effects of physical activity on white matter integrity in healthy aging

Chelsea M. Stillman, Ph.D.

Department of Psychology, University of Pittsburgh and Murdoch University.

There is a wealth of evidence linking physical activity (PA) engagement to preserved cognitive and brain health in late life. The hippocampus has emerged in this work as a brain region that is especially sensitive to PA. In fact, to date most research on the effects of PA in humans has focused on the hippocampus. More specifically, there is evidence that hippocampal volume and connectivity are mechanisms for PA-induced cognitive changes. However, emerging evidence suggests there are also other important brain mechanisms of PA. In this talk, I will present results from studies in our lab examining the effects of cardiorespiratory fitness and PA on white matter integrity in healthy older adults. I will also highlight many important questions remaining in this field: How long do the effects of physical activity training on brain health last? What is the timescale for white matter as compared to gray matter changes? What dosage of PA is necessary to maximize salutary effects? Why do some people benefit more from PA than others? I will conclude by discussing several ongoing projects in our research group that may provide insight on some of these questions.

Imaging vascular disease of the human brain

Algorithms to assess neurovascular coupling characteristics

Xiao Hu, Ph.D.

Nell Hodgson Woodruff School of Nursing, Department of Biomedical Informatics, School of Medicine and Department of Computer Science, College of Arts and Sciences’ Emory University.

There is increase amount of evidence showing that dementia is associated with cerebrovascular diseases. Pathological changes in cerebral vasculature may alter cerebral hemodynamics and lead to inadequate cerebral perfusion. In addition to understanding changes in the ability of the cerebral vasculature to regulate blood flow, it is particularly important to understand and assess how cerebral perfusion is regulated to accommodate changes in neuronal activities. Neurovascular coupling (NVC) is a vital function of the neurovascular unit to maintain balance between demand and supply regarding blood flow. It can be hypothesized that cerebrovascular diseases may cause weakening of NVC, either acutely or gradually, so that brain perfusion is suboptimal given specific neuronal activities. Characterizing NVC at an individual patient level may offer a more personalized assessment of risk factors for dementia because it factors in the neuronal activities specific to individual subject. However, algorithms to characterize NVC using readily available signal modalities are lacking but this presents a unique opportunity for innovations. The ongoing work of the presenter has been mostly in developing algorithms to monitor patients with acute brain injuries under neurocritical care, some of which has the potential applications for characterizing NVC in primary care and ambulatory care settings for a larger population including patients at risk developing dementia. In this talk, we will review some relevant aspects of these algorithms and others from the literature with a goal towards developing collaborative projects with colleagues in dementia research field.

Age-related changes of neurovascular coupling and global brain network function and its association to cognitive performance in human subjects

Andriy Yabluchanskiy, M.D., Ph.D.

Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center.

Aging is a major risk factor of vascular cognitive impairment, a common cause of disability in older adults. Cognitive processes require coordinated operations between brain regions featuring simultaneous hemodynamic responses evoked by neural activity. Either attenuated neurovascular coupling (NVC) responses or the inability of the brain to reorganize its functional connections between task-associated regions can impair cognitive function. To investigate the impact of aging on NVC and brain networks, we assessed cerebromicrovascular and cognitive function of healthy young (n = 21, 33.2 ± 7.0 years) and aged (n = 30, 75.9 ± 6.9 years) participants. We recorded hemoglobin concentration changes with near-infrared spectroscopy from 48 regions of the frontal cortex during n-back task. Using these hemoglobin signals we characterized NVC responses with the aid of a general linear model and brain networks by computing the functional connectivity (FC). The impact of age and task condition was evaluated on NVC responses and on network connection density (D), a global measure of FC. Compared to young group, NVC responses during 2-back task showed a marked reduction among aged participants (p < 0.05, false discovery rate corrected). In these participants, D was found higher in the frontal network that was however not affected by mental workload. Increased D significantly correlated with accuracy during 2-back—that was significantly lower among the aged—and NVC impairment. These observations suggest an age-related impairment of NVC responses and accompanying increase in functional connectivity in the aged group. Our data indicate that brain states require stronger functional relationship and thus higher wiring cost of the frontal networks.

Understanding degenerative disease mechanisms in the white matter using advanced MRI

Swati R. Levendovszky, Ph.D.

Department of Radiology, University of Washington School of Medicine.

White matter hyperintensities (WMH) on a T2-MRI represent white matter damage associated with vascular risk factors and are predictive of worse cognitive outcomes. The in vivo pathophysiology of WMH is complicated and there is a critical need to understand it. Upon fulfilling this need, we will be able to target specific biological mechanisms and improve treatment beyond the current simplistic approaches of lifestyle management. We propose novel, non-invasive MRI markers of cerebral blood flow, vascular reactivity, blood–brain-barrier function, glymphatic function, demyelination, and neuronal injury. In a group of 54 older adults from a community-based cohort, we showed that cerebral blood flow is reduced by 42% and vascular reactivity is completely exhausted in WMH, and that these reductions are related to cognitive impairment. Further, WMH disrupt fiber tracts connecting cortical regions and the degree of disruption is associated with severity of cognitive impairment. In an independent histological evaluation, we confirmed vascular and degenerative pathology in WMH by assessing perivascular spaces and myelin pallor. Lastly, the recent discovery of the glymphatic waste clearance system has shown that interstitial fluid movement in the white matter is integral to the removal of abnormal protein aggregates from the brain. WMH and diffuse white matter injury could precede a disrupted clearance process. Therefore, we have established a minimally invasive MRI to assess contrast clearance in the white matter as a marker of glymphatic function. In summary, our approaches can help understand white matter changes in the aging brain and their role in cognitive impairment and dementia.

Microhemorrhages in the aging white matter

Stefano Tarantini, Ph.D.

Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center.

Clinical and experimental studies show that aging exacerbates hypertension-induced cerebral microhemorrhages (CMHs), which progressively impair neuronal function. In the clinical setting CMHs are increasingly recognized as an important contributor to white matter damage. CMHs and white matter disease are both manifestations of brain aging, with recent evidence suggesting mechanistic commonality. There is growing evidence that aging promotes insulin-like growth factor 1 (IGF-1) deficiency, which compromises multiple aspects of cerebromicrovascular and brain health. To determine the role of IGF-1 deficiency in the pathogenesis of CMHs, we induced hypertension in mice with circulating IGF-1 defiicency (liver-specific knockdown of IGF-1; Igf1^f/f + TBG-Cre-AAV8) and control mice by angiotensin II plus l-NAME treatment. In IGF-1-deficient mice, the same level of hypertension led to significantly earlier onset and increased incidence and neurological consequences of CMHs, as compared to control mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. 13% of CMHs were localized to the white matter. Previous studies showed that in aging, increased oxidative stress-mediated matrix metalloprotease (MMP) activation importantly contributes to the pathogenesis of CMHs. Thus, it is significant that hypertension-induced cerebrovascular oxidative stress and MMP activation were increased in IGF-1-deficient mice. We found that IGF-1 deficiency impaired hypertension-induced adaptive media hypertrophy and extracellular matrix remodeling, which together with the increased MMP activation likely also contributes to increased fragility of intracerebral arterioles. Collectively, IGF-1 deficiency promotes the pathogenesis of CMHs, mimicking the aging phenotype.

Going forward

Why should the VCID field care about what’s happening with amyloid therapeutics?

Donna M. Wilcock, Ph.D.

Sanders-Brown Center on Aging, University of Kentucky.

Anti-Ab immunotherapy has been a focus of the Alzheimer’s disease (AD) field for over twenty years. Several high-profile clinical trials have been performed, and most failed to achieve a clinically meaningful outcome. However, with the advent of PET ligands to assess brain amyloid, anti-Ab immunotherapy is now known to be highly efficacious in the lowering of brain amyloid load. In 2021, the FDA gave accelerated approval to aducanamab, and two additional antibodies are expected to be considered in the coming year; donanemab, and lecanemab. While these antibodies hold great promise for the future of dementia treatment, their broad acceptance and use has been hindered by significant concerns regarding safety. It is almost two decades ago when microhemorrhages in the brains of transgenic mice resulting from anti-Ab immunotherapy were first described. Later, clinical trials found vasogenic edema with and without microhemorrhages. Re-defined as amyloid-related imaging abnormalities (ARIA) of the edema- (ARIA-E) or hemorrhagic- (ARIA-H) types, vascular adverse events remain the number one concern surrounding the use of anti-Ab immunotherapy, occurring in up to 35% of trial participants for aducanamab. Underlying mechanisms of ARIA remain poorly understood, with ApoE4 genotype being the main risk factor, along with pre-existing cerebrovascular disease. Given our current appreciation that many sporadic AD patients also have co-morbid small vessel disease, it is vital the field understand mechanisms of ARIA so that these therapies are used in the appropriate patient. Also, it may be possible to prevent ARIA, opening up this therapy to a broader population.

Conclusions

The 2022 Annual Workshop of the Albert Research Institute for White Matter and Cognition discussed the importance of cerebral vascular dysfunction as a risk factor for AD/ADRD. A wide range of basic science, translational and clinical studies were discussed with focus on the efforts and strategies to evaluate the brain microvasculature as a putative therapeutic target to mitigate cognitive decline in AD/ADRD. Below is a summary of the groundbreaking research discussed in this year’s Workshop. It should be noted, however, that in-person discussions extended beyond the highlights described here and paved the way to exciting avenues for future collaboration and investigation.

• There is a renewed focus on vascular contributions to dementia in AD/ADRD, particularly on the detrimental effects of amyloid-β (Aβ) on the neurovascular unit, and the sensitivity of the white matter to microvascular disease.

• There is evidence of associations between blood brain barrier leakage and markers of AD/ADRD and synapse degradation in the CNS of aging humans. The associations are stronger between barrier leakage and CSF levels of Aβ_1-40 (in comparison with Aβ_1-42) the main culprit in cerebral amyloid angiopathy.

• Blood–brain barrier leakage has been mechanistically associated with microglial and astrocytic activations. In astrocytes it induces astrocyte TGFβ signaling, leading to an “aging brain” phenotype. This is prevented by TGFβ knockdown or pharmacological inhibition, identifying a putative therapeutic for cognitive maintenance during aging.

• Single-nucleus transcriptomic analysis of human and mouse white matter samples identified target genes altered in VCID, including genes associated with angiogenesis, cell death, protein folding and immune responses. Ongoing mechanistic studies will further validate possible targets for intervention against white matter degeneration.

• IGF-1 is protective against hypertension-induced cerebral microhemorrhages in mice, as genetic ablation of IGF-1 leads to higher incidence of brain microbleeds, remodeling of perivascular extracellular matrix and cognitive/motor deficits.

• Using functional near-infrared spectroscopy to assess increases in regional brain hemoglobin coupled to network modeling of functional connectivity in the brain, Csiszar et al. observed that neurovascular coupling responses in the aged brain require a stronger functional connectivity than in the young brain, suggesting that metabolic demands to maintain such structures may also be higher.

• Enhancing muscle proteostasis without exercise reduces neuroinflammation in a mouse model of frontotemporal dementia. It also reduced accumulation of pTau and activated-exercise-induced neurotrophic signaling in the hippocampus. Together, these findings show that muscle proteostasis can be neuroprotective even without active exercise.

• Hemodynamic responses in the MCA in response to moderate exercise are blunted in older adults when compared to young adults, as well as in individuals with elevated cerebral Aβ. A similar hemodynamic pattern is observed in individuals with stroke, where older adults show little to no increase in MCAv in response to exercise. As such, MCAv may be a non-invasive vascular biomarker of brain health.

• Growing evidence shows that exercise is paramount for brain health, particularly for hippocampal health and white matter integrity in aged patients.

• Kidney disease is associated with a higher prevalence of cognitive impairment, stroke, and brain alterations such as altered cerebral blood flow, brain neurochemicals, and while matter integrity. These abnormalities can be explained by BBB disruption. CKD animal models could help understand target lesions disrupting the BBB.

• The SPRINT-MIND trial showed that intensive lowering of SBP (target SBP < 120 mmHg) is more effective than standard lowering of SBP (target SBP < 140 mmHg) in slowing cognitive decline. These data provide valuable insight into a modifiable risk factor for prevention of dementia. Further, the trial provides valuable data for the safety of lowering BP even in the older population where may hesitate to aggressively lower BP.

• Menopause, in particular the loss of estrogen, has a synergistic effect on cognitive decline in mouse models of AD, VCID, and mixed-etiology dementia. Treatment of mice with a brain-specific estrogen pro-drug reversed the cognitive deficit observed in menopausal females, highlighting a cerebral-specific role for estrogen in cognitive health.

• Mechanistic studies showed that menopause impairs microvascular responses in the cerebral circulation, which ultimately lead to a reduction in hemodynamic responses needed to maintain neurovascular coupling in wild-type mice.

Together, these studies and the discussions that followed highlighted the need for more thorough characterization and assessment of vascular contributions to cognitive decline and dementia. The cerebral microcirculation is central to the pathogenesis of dementia and white matter damage, either by changes in the BBB and/or by failure to elicit appropriate hemodynamic responses when faced with metabolic challenges. The role of the systemic factors such as BP regulation can also affect brain function despite the cerebral autoregulation. An important point of discussion throughout the meeting was the need to develop more suitable models of mixed dementia that better represent the human population, as well as a better integration between –omics findings and physiological outcomes.

Funding

This Workshop was supported by funds from the Albert White Matter Research Institute.

Declarations

Conflict of interest

The authors declare no competing interests.