Targeting the Vasculature in Alzheimer's Disease and Vascular Cognitive Impairment

Abstracts

Vascular Contributions to Cognitive Impairment and Dementia
Philip B. Gorelick, MD, MPH, Hauenstein Neuroscience Institute

We carried out a systematic literature review to develop a guide for practitioners to gain a better understanding of vascular cognitive impairment (VCI), vascular contributions to cognitive impairment and dementia, and the potential for prevention and treatment of VCI or related cognitively impairing disorders of later life [1]. In this presentation we will primarily review cardiovascular risk markers for VCI and the prospects for prevention or slowing of cognitively impairing conditions of later life based on treatment or prevention of these factors. The discovery that certain cardiovascular factors are now considered risk markers for Alzheimer's disease (AD) has provided a new potential avenue for the prevention or treatment of AD. Thus, in addition to vascular amyloid, a focus of AD prevention and treatment may be the interface between traditional cardiovascular risk factors and the neurovascular unit. The complex interplay between vascular and AD pathologies in the evolution of clinically manifest VCI and AD must be kept in mind, and long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone these disorders.
 
1. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42: 2672–2713.
 

The Overlap between Neurodegenerative and Vascular Factors in Dementia
Costantino Iadecola, MD, Weill Cornell Medical College

The brain is uniquely dependent on a well-regulated delivery of oxygen and glucose through the blood supply. If the delivery of cerebral blood flow is not adequate to match the dynamic energetic requirements imposed by neural activity, brain dysfunction and damage ensues. There is increasing evidence that alterations in cerebral blood flow play a role not only in vascular causes of cognitive impairment, but also in Alzheimer's disease (AD). Vascular risk factors and AD impair the structure and function of cerebral blood vessels and associated cells (neurovascular unit), effects mediated by vascular oxidative stress and inflammation. Thus suppression of the major source of radicals in mice overexpressing the amyloid precursor protein (APP) ameliorates the cerebrovascular dysfunction and the attendant cognitive deficits. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood-brain barrier and reduces the brain's repair potential, effects that amplify the brain dysfunction and damage exerted by incident ischemia and coexisting neurodegeneration. In support of this hypothesis occlusion of the middle cerebral artery in mice overexpressing APP leads to larger ischemic lesions, highlighting the reduced vascular reserves associated with cerebrovascular dysfunction. Clinical-pathological studies support the notion that vascular lesions aggravate the deleterious effects of AD pathology by reducing the threshold for cognitive impairment and accelerating the pace of the dementia. In addition, disturbances of cerebral perfusion and/or energy metabolism have also been observed early in the course of AD or even in non-demented subjects at genetic risk for AD. These observations, collectively, indicate that vascular alterations may be a contributing factor in the pathogenesis of AD. In the absence of mechanism-based approaches to counteract cognitive dysfunction in AD, targeting vascular risk factors and improving cerebrovascular health offers the opportunity to mitigate the impact of one of the most disabling human afflictions.
 

Gain-of-Function Somatic Mutations Initiate the Vascular Damage that Leads to Alzheimer's Dementia: A Hypothesis
Vincent Marchesi, MD, PhD, Yale School of Medicine

Alzheimer's dementia is the result of brain injury caused by oxidative damage, inflammatory reactions, and amyloid/abeta dysregulation. The late stages of this disease are well known, but the mechanisms that trigger this potentially lethal cascade are unknown and will have to be identified before rational approaches to prevention and treatment can be devised. The idea proposed here is that the human body, including the brain, is constantly exposed to reactive oxygens that have the potential to generate mutant proteins that provoke local inflammatory reactions and the accumulation of amyloid abeta peptides, creating conditions for localized ischemia, neuronal dysfunction, and eventually cell death. These non-germ line mutations result from ROS-induced miscoding of DNA and RNA that occur during one's lifetime and are distributed in mosaic patches throughout the body. It is proposed that these postulated proteins are products of genes and m-RNAs that code for activated forms of inflammasomes, such as NALP3 and cryopyrin, and mutant forms of the amyloid precursor protein (APP). Their identification could lead to novel diagnostic procedures and the development of new interventional therapies.
 

Understanding Cerebral Amyloid Angiopathy
Steven M. Greenberg, MD, PhD, Harvard Medical School

Cerebrovascular deposition of β-amyloid (cerebral amyloid angiopathy, CAA) is both a major cause of spontaneous hemorrhagic stroke in the elderly and an increasingly recognized contributor to vascular cognitive impairment (VCI). Although traditionally diagnosed post-mortem, CAA can now be identified during life by the neuroimaging presence of cortical microbleeds. The current presentation will focus on three rapidly developing features of CAA relevant to Alzheimer's disease and VCI: 1) detection of CAA via amyloid imaging, 2) CAA's effects on vascular function, and 3) the contribution of CAA to cerebral microinfarction. CAA's effects on vascular structure and physiology give it an important role in ongoing treatment approaches for both vascular and neurodegenerative forms of age-related cognitive impairment.
 

MRI Markers of Vascular Cognitive Impairment
Bruce R. Reed, PhD, UC Davis Alzheimer's Disease Research Center

It is well established that the major risk factors for cardiovascular disease are also risk factors for dementia in general and Alzheimer's disease (AD) specifically, as is the fact that the most common neuropathological substrate for dementia is a combination of ischemic vascular lesions and AD pathology. Our understanding of the exact role of vascular factors in the many intervening steps between risk, pathology and dementia is, however, quite incomplete. MRI is a method sensitive to the presence of vascular brain injury that can be used as an in vivo measure to help elucidate these relationships. This is especially so when MRI is combined with PIB PET to define the presence of AD pathology.
 
The traditional MRI markers of vascular brain injury identify infarcts and areas of altered white matter. Most models of vascular cognitive impairment emphasize a predilection of these lesions to occur in fronto-subcortical circuits with consequent cognitive executive deficits. In this talk I will present work from our laboratory that support the following points: 1) the concept of VBI should be extended to include cortical atrophy, which is a major driver of cognitive impairment in general. 2) the view that VBI causes executive dysfunction is overly simple, 3) the direct effects of VBI are most prominent and can be best differentiated from those of AD in non-demented persons, 4) VBI likely plays a very important role in MCI (and "normal" cognitive aging), independent of those of AD. These findings support an integrated model of vascular contributions to cognitive impairment that identifies VBI as having both focal and diffuse effects on brain and with cognitive consequences that change with the progression of the disorder and with comorbid AD.
 

The Effects of Abeta Immunotherapy on the Vasculature
Kejal Kantarci, MD, Mayo Clinic

Lowering Amyloid-β load with immunotherapy is the goal of many of the current clinical trials in Alzheimer's disease. The effects of active and passive immunization on the cerebral vasculature specifically in cases with cerebral amyloid angiopathy is an area of active research. MRI abnormalities associated with immunotherapy are recently classified into two subgroups: Amyloid-Related Imaging Abnormalities with vasogenic edema and sulcal effusions (ARIA-E) and microhemorrhages and hemosiderosis (ARIA-H). This presentation will focus on the possible pathophysiological mechanisms underlying ARIA-E and ARIA-H and the association between these imaging abnormalities and amyloid-β pathology in patients with Alzheimer's disease.
 

Hypertension, Cognitive Decline and Dementia: The Hidden Role of Obstructive Sleep Apnea
Gustavo C. Román, MD, Methodist Neurological Institute

Background: Hypertension has a deleterious effect on cognitive function particularly when midlife hypertension remains undiagnosed and untreated. The injury to the vascular system is manifested by ventricular enlargement, hypertensive retinopathy, renal damage, and brain injury from hemorrhagic and ischemic stroke. The primary alterations resulting from the physical effects of the increased intravascular pressure include endothelial damage, arteriolosclerosis, and atherosclerosis. Strokes, large and small, are the main cause of vascular cognitive impairment in hypertensive subjects. Onset of hypertension late in life causes added damage to a microvascular bed that has decreased in density and capacity for angiogenesis. Also, important is the decreased autoregulation of the elderly. These mechanisms increase the likelihood of cerebral hypoperfusion and hypoxemia leading to damage of distal and watershed territories manifested by ischemic demyelination of the white matter and lacunar strokes. Patients: We have recently observed in a group of consecutive elderly patients evaluated for cognitive decline at the Alzheimer and Dementia Clinic of the Methodist Neurological Institute (Houston, Texas). Polysomnography was performed in 106 patients for suspected obstructive sleep apnea (OSA) syndrome (history of snoring, nocturnal awakenings, and excessive daytime sleepiness).
 
Results: The mean age was 72.9 years; 51.5% men and 48.5% women. Mean Body Mass Index was 27.5 kg/m² [range=19 – 41]. Most patients were Caucasian (59%), followed by Hispanics (25%), African Americans (12%) and Asian (4%). The main vascular risk factors were hypertension (77%), hypercholesterolemia (45%), cardiovascular disease (33%), diabetes (28%), and prior history of stroke (22%). A third of the cases had a family history of dementia. Clinical diagnoses of the cognitive problems included Mild Cognitive Impairment (MCI) Dysexecutive type (24%), Mixed Alzheimer's disease + Vascular Dementia (20%), MCI Amnestic type (17%), Vascular Dementia (12%), Alzheimer's disease (9%) and Normal Pressure Hydrocephalus (7%). MRI revealed extensive small vessel disease in 86% of the cases including lacunar strokes in the corona radiata and basal ganglia, as well as isolated white matter hyperintensities (34%). Large-vessel strokes were found in 17% of the cases. Severe OSA was found in 31% of the patients, moderate OSA in 47%, mild OSA in 19% and 4% had normal sleep.
 
Conclusion: OSA appears to be a significant factor in cognitive decline in the elderly, enhancing the effects of hypertension on small vessel disease in the brain.
 

TBI and AD: Vascular Coag-Inflammatory Pathways and Therapeutic Targets
Barry W. Festoff, MD, University of Kansas Medical Center and pHLOGISTIX LLC

Vascular, coagulation and inflammatory pathways converge in traumatic brain injury (TBI) and Alzheimer's disease (AD). Evolution has placed coagulation and innate immune cascades in close proximity to one another and they co-evolved to provide an advantage against invading pathogens. Procoagulants are proinflammatory and vice versa, namely that anti-coagulants are anti-inflammatory. The serine proteinase thrombin is a key player in both clotting and inflammatory pathways, the latter via cleavage activation of proteinase-activated receptors (PARs), which can be distinguished by PAR-specific agonist and antagonist peptides, PARAPs. The blood-brain barrier (BBB) becomes defective following TBI and is also involved in AD, where both amyloid Aβ and tau participate. Thrombin affects the BBB, as it does other barriers, inducing many endothelial cell (EC) responses that regulate hemostasis, thrombosis and vessel wall pathophysiology. One of these, EC intercellular gap formation and vascular permeability is a cardinal feature of inflammation and is regulated by an EC proteoglycan, thrombomodulin (TM). Understanding and controlling thrombin's influences may be an important therapeutic target in both TBI and AD. Aspects of thrombin inflammatory signaling up- and downstream of PARs in the brain by TM are a major focus of pHLOGISTIX. TM has another target, HMGB1, separate from thrombin, that is also prominent in TBI, BBB disruption, and possibly AD as well. In this discussion we approach this via in vitro and in vivo experiments.
 

Leukocyte Plugging of Capillaries Reduces Brain Blood Flow in Mouse Models of Alzheimer's Disease
Chris B. Schaffer, PhD, Cornell University

Alzheimer's disease (AD) is characterized by aggregates of amyloid-beta, which eventually accumulates into dense plaques scattered throughout the brain. Clinical research and experimental work suggest that cerebral blood flow is impaired in AD, although the mechanisms involved are not fully elucidated. We used in vivo two-photon excited fluorescence microscopy to examine cortical blood flow in aged mouse models of AD in an effort to identify mechanisms for impaired cortical blood flow. We found that the fraction of capillaries that are not flowing in AD mice (median of 2%) is greatly elevated as compared to age-matched wild-type animals (median of 0%). We further determined that these capillary stalls are caused by monocytes that are firmly stuck in individual capillary segments, suggesting an inflammation mediated mechanism. Because a single stalled capillary will impact the blood flow in downstream vessels, we estimate that this phenomena could lead to blood flow decreases of ~20%, potentially contributing to cognitive dysfunction in AD and reducing clearance of amyloid-beta from the brain.
 

Fibrinogen and β-amyloid Association Alters Thrombosis and Fibrinolysis: A Possible Contributing Factor to Alzheimer's Disease
Sidney Strickland, PhD, The Rockefeller University

Alzheimer's disease (AD) is a neurodegenerative disorder in which vascular pathology plays an important role. Since the β-amyloid peptide (Aβ) is a critical factor in this disease, we examined its relationship to fibrin clot formation in AD. In vitro and in vivo experiments showed that fibrin clots formed in the presence of Aβ are structurally abnormal and resistant to degradation. Fibrin(ogen) was observed in blood vessels positive for amyloid in mouse and human AD samples, and intravital brain imaging of clot formation and dissolution revealed abnormal thrombosis and fibrinolysis in AD mice. Moreover, depletion of fibrinogen lessened cerebral amyloid angiopathy pathology and reduced cognitive impairment in AD mice. These experiments suggest that one important contribution of Aβ to AD is via its effects on fibrin clots, implicating fibrin(ogen) as a potential critical factor in this disease.
 

Guarding Vascular Health with High Density Lipoproteins
Cheryl Wellington, PhD, University of British Columbia

High-density lipoprotein (HDL) is the principal facilitator of reverse cholesterol transport, a critical pathway of lipid metabolism whereby excess cholesterol is mobilized from peripheral tissues and delivered to the liver and steroidogenic organs for catabolism/removal and utilization. High levels of HDL-cholesterol (HDL-C) are consistently associated with reduced risk of coronary artery disease, atherosclerosis and cardiovascular events. ApoA-I, which comprises approximately 70% of the protein content of HDL, promotes cholesterol efflux via the lipid transporter ABCA1. Although apoA-I is not synthesized by glia or neurons, it is present in cerebrospinal fluid (CSF) at levels comparable to CSF apoE, which translates to approximately 0.1-0.5% of plasma apoA-I levels. In CSF, apoA-I- and apoE are on distinct lipoprotein particles. CNS apoA-I is believed to originate from two potential sources; secretion of apoA-I from cerebral vascular endothelial cells and/or translocation of plasma apoA-I across the blood brain barrier. Emerging evidence supports the involvement of apoA-I in maintaining cognitive and cerebrovascular health. Human epidemiological studies suggest that low levels of plasma HDL-C, especially in midlife, are associated with increased AD risk. Furthermore, AD mice that lack apoA-I have impaired spatial learning and elevated cerebrovascular amyloid deposition, whereas transgenic over-expression of apoA-I protects from age-associated learning and memory deficits and selectively decrease cerebrovascular amyloid load. These observations demonstrate a key role for apoA-I in regulating cerebrovascular amyloid metabolism. HDL also exerts direct anti-inflammatory and anti-thrombotic effects, stimulates nitric oxide synthesis, and promotes endothelial repair by enhancing the mobilization of endothelial progenitor cells. Despite this plethora of beneficial effects in cardiovascular medicine, the association of HDL with human AD remains poorly understood. This is due in part to limitations in study design, the profound heterogeneity of HDL particles, and the relatively poor association of HDL-C levels with HDL function. We have developed an indirect measure of HDL's cholesterol efflux capacity that is based on the rate at which a patient's circulating HDL particles can generate substrate for the cholesterol transporter ABCA1. Our assay can be used as an index of HDL's efflux capacity that is predictive of clinical states, including atherosclerosis, diabetes, and obesity. I will discuss the potential applicability of this novel assay of HDL function for AD.