Volume 32, Number 3, October 2012 - "Physiopathology of Vascular Risk Factors in Alzheimer’s Disease" (Guest Editor: Jack de la Torre)

Pages 517-518
Preface
Jack de la Torre
Physiopathology of Vascular Risk Factors in Alzheimer's Disease

Profiles and Epidemiology of vascular risk factors in Alzheimer’s disease

Pages 521-530
Review
M. Cristina Polidori, Ludger Pientka, Patrizia Mecocci
A Review of the Major Vascular Risk Factors Related to Alzheimer’s Disease
Abstract: The present review is dedicated to the epidemiology of vascular risk factors proven to play a role in facilitating onset and progression of cognitive impairment. These include hypertension, hypercholesterolemia, diabetes, obesity, atherosclerosis, and cardiac diseases. The targeted, chance-free identification and management of traditional vascular risk factors in midlife is a general public health strategy against the onset of mild to severe cognitive impairment in advanced age. This preventive action must be routinely carried out with outmost awareness by physicians in order to be effective. In advanced age, the individually shaped assessment and management of vascular risk factors assumes particular importance as some of them show a strong age-dependent pattern. The relative strategies with this purpose cannot be separated from a thorough lifestyle anamnesis including nutrition, physical exercise, and cognitive and social activities.

Pages 531-540
Review
Anna-Maija Tolppanen, Alina Solomon, Hilkka Soininen, Miia Kivipelto
Midlife Vascular Risk Factors and Alzheimer’s Disease: Evidence from Epidemiological Studies
Abstract: The shared risk factor profile between cardiovascular diseases and Alzheimer’s disease (AD), observations on vascular pathology in AD, and altered cerebral blood flow in AD brains have led to the suggestion that AD might be a vascular disorder with neurodegenerative consequences. Targeting vascular and metabolic risk factors could be an effective way to prevent AD. Higher body mass index, elevated blood pressure, serum cholesterol concentrations, and impaired glucose regulation have been associated with increased risk of AD. Interestingly, the associations between these factors measured at mid-life are stronger, or even opposite, than with the risk factors measured at late-life. This may reflect true differences in the association (i.e., mid-life risk factors being a better measure of vascular load during adulthood), reverse causality, or bias. The vascular risk factors can directly increase the susceptibility to AD, or the effect can be mediated via cardio- and cerebrovascular diseases.

Pages 541-549
Review
Simon W. Rabkin
Arterial Stiffness: Detection and Consequences in Cognitive Impairment and Dementia of the Elderly
Abstract: Arterial stiffness constitutes a reduction in the ability of large arteries to readily accommodate the increase in blood ejected from the heart during systole. Propagation of the pulse wave or pulse wave velocity (PWV) is a relatively simple, non-invasive, and reproducible method to determine arterial stiffness. There is mounting evidence that consistently implicates arterial stiffness in the pathogenesis of impaired cognitive function and dementia in the elderly. This paper summarizes this evidence. First, the majority (85%) of the twelve studies comprising over 6,000 individuals found a significant association between increased vascular stiffness and cognitive impairment in multivariate analysis after adjusting for age, educational level, and other factors that influence cognition. Second, higher pulse wave velocity, adjusted for age and other factors, was associated with a greater amount of white matter hyperintensities on brain imaging, indicating cerebral small-vessel disease. Third, studies consistently indicate that higher PWV is a significant predictor of subsequent cognitive decline. Fourth, some data support the proposition that arterial stiffness (PWV) increases progressively from persons with normal cognitive function to those with mild cognitive impairment, to Alzheimer’s disease, and then to vascular dementia. Fifth, there is some suggestion that antihypertensive drugs that have a more favorable effect to reduce vascular stiffness are more likely to reduce the occurrence of cognitive impairment. Taken together, these data suggest that artery stiffness may be a useful clinical tool to detect individuals at risk for cognitive impairment and dementia of the elderly.

Physiopathology of vascular risk factors in Alzheimer’s disease

Pages 553-567
Review
Jack C. de la Torre
Cerebral Hemodynamics and Vascular Risk Factors: Setting the Stage for Alzheimer’s Disease
Abstract: Considerable information is currently available from neuroimaging, pathological, and population-based prospective studies showing that vascular risk factors are independently associated with an increased risk of Alzheimer's disease (AD). Many of these studies indicate that vascular risk factors can predict the clinical development of cognitive dysfunction and AD onset. This review examines the role of cerebral hemodynamics and vasoactive molecules that contribute to the regulation of cerebral perfusion and how three common vascular risk factors to AD, namely, hypertension, diabetes type 2, and atherosclerosis, can alter cerebral blood flow (CBF) regulation and generate perfusion pressure deficits. It is proposed that these vascular risk factors (and presumably other vascular risk factors) initiate chronic brain hypoperfusion that ultimately impair signaling from neurons, astrocytes, and endothelial cells to vascular smooth muscle controlling vessel diameter. Impaired signaling involving vascular pathways in the elderly can attenuate vessel tone and deregulate CBF. Noxious cerebral hemodynamic responses to vascular risk factors and chronic brain hypoperfusion are partly explained by Poiseuille’s Law which states that miniscule changes in vessel diameter can have a dramatic effect on vessel resistance and on the rate of blood flow. Using Poiseuille’s model, even minor narrowing of arteriolar diameter can lead to major reductions in CBF and in suboptimal delivery of high energy nutrients to the brain, with lethal consequences to brain cells that participate in cognitive function. Regional brain cell loss sets the stage for age-related cognitive impairment and AD onset. Keeping cerebral hemodynamic homeostasis by careful management of vascular risk factors could be a decisive therapeutic target in the prevention of AD.

Pages 569-578
Review
Noboru Toda, Tomio Okamura
Cerebral Blood Flow Regulation by Nitric Oxide in Alzheimer’s Disease
Abstract: Cerebral hypoperfusion due to impaired bioavailability of nitric oxide (NO) synthesized by endothelial nitric oxide synthase and neuronal nitric oxide synthase leads to cognitive decline and neurodegeneration in Alzheimer’s disease (AD). Risk factors for endothelial dysfunction, such as inadequate lifestyle, cardiovascular/metabolic diseases, and aging, evokes cerebral hypoperfusion, impaired autoregulation, and increased production of amyloid-β peptides (Aβ) in association with vasculogenic memory loss and dementia. Decrease in parasympathetic nitrergic nerve activity also plays a role in cerebral hypoperfusion. Aβ is a functional obstacle to NO-mediated vasodilatation; therefore, it decreases cerebral blood flow. Generation of reactive oxygen species by Aβ is a major action in promoting NO degradation. Effective strategies for the prophylaxis or treatment of AD includes acetylcholinesterase inhibitors, drugs acting on the NO-cyclic GMP signaling pathway, antioxidants, peroxisome proliferator-activated receptor γ-agonists, and hydroxymethylglutaryl-CoA reductase inhibitors. Here our hypothesis about the mechanisms underlying the actions of acetylcholinesterase inhibitors in relation to NO-mediated cerebral blood flow is presented. Future detailed analyses of the relationship between cerebral blood flow regulation by constitutive NO and cognitive decline/neurodegeneration will provide clues for developing novel prophylactic measures and therapeutic means to alleviate AD.

Pages 579-586
Review
Raj C. Shah, Julie A. Schneider, Sue Leurgans, David A. Bennett
Association of Lower Hemoglobin Level and Neuropathology in Community-Dwelling Older Persons
Abstract: Lower hemoglobin levels have been associated with cognitive decline in older persons. The objective of this study was to investigate the relationship between lower hemoglobin levels and common, age-related neuropathologies associated with cognitive decline. Hemoglobin and neuropathology measures were available in 113 deceased, community-dwelling, older adults participating in the Rush Memory and Aging Project, a prospective, observational, clinical pathology study of aging. The mean hemoglobin level was 13.0 g/dL (SD=1.4) and was measured 3.2 (SD=1.3) years prior to death. Thirty-five participants had at least one chronic macroscopic infarction and twenty-nine had at least one chronic microscopic infarction. Eleven participants had Lewy bodies. The mean Alzheimer’s disease (AD) pathology score based on a summary measure of neuritic plaques, diffuse plaques, and neurofibrillary tangles was 0.56 unit (SD=0.56; range=0, 2.34). Using logistic regression models adjusted for age at death, gender, and education, each g/dL lower hemoglobin level increased the odds for having a chronic macroscopic infarction by 37% (95% CI=1.01, 1.86) but not for having a chronic microscopic infarction (OR=1.11; 95% CI=0.82, 1.52) or Lewy bodies (OR=1.07; 95% CI=0.68, 1.68). In an adjusted multiple regression model, hemoglobin level was not associated with the global AD pathology measure (parameter estimate=-0.02, SE=0.03, p=0.6). In secondary analyses, lower hemoglobin levels were associated with higher odds of having a chronic macroscopic infarction in a subcortical region but not with higher total subcortical chronic macroscopic infarction volume. In conclusion, lower hemoglobin levels appear to be associated with chronic macroscopic infarctions but not with other common age-related neuropathologies.

Pages 587-597
Research Report
Alma Sanchez, Debjani Tripathy, Xiangling Yin, Katheryn Desobry, Joseph Martinez, Jarred Riley, Dylan Gay, Jinau Luo and Paula Grammas
p38 MAPK: A Mediator of Hypoxia-Induced Cerebrovascular Inflammation
Abstract: Vascular perturbations and hypoxia are increasingly implicated in Alzheimer’s disease (AD) pathogenesis. Cerebral hypoxia induces a large number of inflammatory proteins in brain endothelial cells via signaling pathways that have not been defined. The p38 mitogen-activated protein kinase (MAPK) signaling system has been implicated in endothelial injury and inflammation. The objective of this study is to examine p38 MAPK levels in the cerebromicrovasulature in AD and AD animal models and determine the role of p38 MAPK signaling in hypoxia-mediated effects on brain endothelial cells. Western blot analysis of isolated human brain microvessels show that the phosphorylated (active) form of p38 MAPK (pp38 MAPK) is increased in vessels derived from AD brains compared to control-derived vessels. Similarly, immunofluorescent analysis reveals an increase in cerebrovascular pp38 MAPK as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in transgenic AD mice. Exposure of brain endothelial cells to hypoxia (2-6 hours) shows a time-dependent increase in pp38 MAPK. Examination of these cultures at 6 hours hypoxia shows that iNOS and COX-2 are significantly elevated and that the selective p38 MAPK inhibitor SB203580 significantly reduces the hypoxia-mediated increase in their expression. Inhibition of p38 MAPK in cultured brain endothelial cells also significantly decreases the hypoxia-induced increase in the inflammatory proteins, matrix metalloproteinase-2 and angiopoietin-2. These data demonstrate that pp38 MAPK is a key regulator of hypoxia in the cerebrovasculature and suggest that control of this signaling pathway could have therapeutic value in AD and other disorders where hypoxia is involved.

Pages 599-608
Review
Marta Cortes-Canteli, Daria Zamolodchikov, Hyung Jin Ahn, Sidney Strickland, Erin H. Norris
Fibrinogen and Altered Hemostasis in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) plaques, tau tangles, brain atrophy, and vascular pathology. Vascular defects include cerebrovascular dysfunction, decreased cerebral blood flow, and blood brain barrier (BBB) disruption, among others. Here, we review the evidence that links Aβ with the vascular pathology present in AD, with a specific focus on the hemostatic system and the clotting protein fibrinogen. Fibrinogen is normally found circulating in blood, but in AD it deposits with Aβ in the brain parenchyma and cerebral blood vessels. We found that Aβ and fibrin(ogen) interact, and their binding leads to increased fibrinogen aggregation, Aβ fibrillization, and the formation of degradation-resistant fibrin clots. Decreasing fibrinogen levels not only lessens cerebral amyloid angiopathy and BBB permeability, but it also reduces microglial activation and improves cognitive performance in AD mouse models. Moreover, a prothrombotic state in AD is evidenced by increased clot formation, decreased fibrinolysis, and elevated levels of coagulation factors and activated platelets. Abnormal deposition and persistence of fibrin(ogen) in AD may result from Aβ-fibrin(ogen) binding and altered hemostasis and could thus contribute to Aβ deposition, decreased cerebral blood flow, exacerbated neuroinflammation, and eventual neurodegeneration. Blocking the interaction between fibrin(ogen) and Aβ may be a promising therapeutic target for AD.

Pages 609-621
Review
Sean Kennelly, Orla Collins
Walking the Cognitive “Minefield” between High and Low Blood Pressure
Abstract: Vascular risk factors are implicated in the pathogenesis of Alzheimer’s disease (AD). There is an age-dependent relationship between blood pressure and the risk of AD. Given the potential temporal lag that can exist between the two conditions, longitudinal population studies offer the best opportunity to identify a causal relationship. Midlife hypertension increases the risk for AD, yet later-life hypertension does not appear to confer the same risk and may in fact be protective. Low diastolic blood pressure, especially in later-life, is associated with an increased risk of AD. Orthostatic hypotension and other neurocardiovascular syndromes may increase the risk for cognitive impairment and AD. Several physiopathological mechanisms may contribute to this increased risk. Dynamic blood pressure changes and impaired cerebrovascular autoregulation may result in cerebral hypoperfusion. Hypertensive patients also develop cerebral infarcts, resulting in diminished perfusion. Subsequent hypoxia driven pathways result in increased cerebral amyloid-β and phosphorylated tau protein accumulation. Treatment of elevated blood pressure with antihypertensive medications attenuates the risk of AD attributable to elevated midlife hypertension. Certain antihypertensive compounds have neuroprotective properties that may reduce the risk of AD, independent of their effects on blood pressure.

Pages 623-631
Research Report
Rob A.R. Gons, Lucas J.B. van Oudheusden, Karlijn F. de Laat, Anouk G.W. van Norden, Inge W.M. van Uden, David G. Norris, Marcel P. Zwiers, Ewoud van Dijk, Frank-Erik de Leeuw
Hypertension is Related to the Microstructure of the Corpus Callosum: The RUN DMC Study
Abstract: Vascular factors play a role in the etiology of Alzheimer’s disease (AD), presumably due to emergence of white matter lesions. However, important white matter structures involved in the etiology of AD, including the corpus callosum (CC), remain invariably free from macroscopical white matter lesions, although loss of microstructural integrity assessed with diffusion tensor imaging (DTI) has been described in the CC. Vascular factors have been related to these microstructural white matter changes too, but little is known about their effect on the CC. In 499 subjects with cerebral small vessel disease, aged 50-85 years, we cross-sectionally investigated the relation between hypertension, hypertension treatment status, the microstructural integrity of the CC using DTI, and the attendant cognitive performance. Fractional anisotropy and mean diffusivity were calculated in four substructures of the CC (genu, anterior body, posterior body, and splenium). Differences between groups were calculated with analysis of variance, adjusted for age, gender, and cardiovascular risk factors. Compared with normotensive subjects, hypertensive subjects had a lower fractional anisotropy in the splenium and a significant higher mean diffusivity in both the anterior body and the splenium; this was most noticeable in treated uncontrolled hypertensive subjects. Furthermore we found that microstructural integrity of the CC was related to global cognition. Of this relation, 14 to 60% was explained by the mediating effect of small vessel disease elsewhere in the white matter. Our findings indicate that adequate blood pressure treatment might postpone these changes and the attendant cognitive dysfunction.

Pages 633-642
Review
Randolph S. Marshall
Effects of Altered Cerebral Hemodynamics on Cognitive Function
Abstract: Cerebral hemodynamic impairment has come under examination over the years as an independent cause for cognitive dysfunction, but only recently has the advance of imaging and ultrasound technology permitted a fuller investigation of physiopathology. Beyond the impact of fixed structural lesions such as infarction and white matter hyperintensities, hemodynamic dysfunction, which includes hypoperfusion and altered cerebral autoregulation, may be independently associated with cognitive decline. More importantly, whereas vascular-related structural pathology may produce so-called vascular dementia, disorders of blood flow and blood flow regulation may also present clinically as mild cognitive impairment or even frank dementia, but may in fact be reversible. Hemodynamic effects may occur at the level of the cerebral hemisphere due to restricted flow through a large vessel of the neck or head, at a global level in the setting of cardiac failure, or intrinsically due to dysfunction of the endothelium in the microvasculature. This review surveys clinical, imaging, and physiological evidence for the association between hemodynamic abnormalities at these different levels and cognitive impairment.

Pages 643-652
Review
Alessandra Costanza, Aikaterini Xekardaki, Enikö Kövari, Gabriel Gold, Constantin Bouras, Panteleimon Giannakopoulos
Microvascular Burden and Alzheimer-Type Lesions Across the Age Spectrum 
Abstract: The occurrence of microvascular and small macrovascular lesions and Alzheimer’s disease (AD)-related pathology in the aging human brain is a well-described phenomenon. Although there is a wide consensus about the relationship between macroscopic vascular lesions and incident dementia, the cognitive consequences of the progressive accumulation of these small vascular lesions in the human brain are still matter of debate. Among the vast group of small vessel-related forms of ischemic brain injuries, the present review discusses the cognitive impact of cortical microinfarcts, subcortical gray matter and deep white matter lacunes, periventricular and diffuse white matter demyelinations, and focal or diffuse gliosis in old age. A special focus will be on the sub-types of microvascular lesions not detected by currently available neuroimaging studies in routine clinical settings. After providing a critical overview of in vivo data on white matter demyelinations and lacunes, we summarize the clinicopathological studies performed by our center in large cohorts of individuals with microvascular lesions and concomitant AD-related pathology across two age ranges (the younger old, 65-85 years old, versus the oldest old, nonagenarians and centenarians). In conjunction with other autopsy datasets, these observations fully support the idea that cortical microinfarcts are the only consistent determinant of cognitive decline across the entire spectrum from pure vascular cases to cases with combined vascular and AD lesion burden.

Pages 653-663
Review
Matthew P. Pase
Modifiable Vascular Markers for Cognitive Decline and Dementia: The Importance of Arterial Aging and Hemodynamic Factors
Abstract: Uncovering modifiable predictors of cognitive decline and dementia is crucial for early detection and prevention. Although high mid-life brachial blood pressure is considered a risk factor for later-life cognitive impairment, other non-invasive indices of arterial health, closely associated with aging, may improve risk stratification. This review discusses the contribution of vascular aging to cognitive decline, dementia, and brain pathology. Modifiable vascular markers are evaluated with respect to their prognostic value and ease of measurement. The notion of mitigating cognitive decline through improving cardiovascular health is also discussed. Anticipated mechanisms imply causal pathways between large artery stiffness, pulsatile pressures, and cognitive impairment through damage to small cerebral vessels. Accumulating evidence from human clinical studies now supports this mechanistic understanding. Aortic stiffness, measured as carotid-femoral pulse wave velocity, has been shown to predict cognitive decline in numerous studies. Aortic and carotid pulsatile pressures are also associated with cognitive impairment and brain pathology. Clinical evidence linking large arterial aging to dementia and associated pathology is scarce and requires further investigation. Future research is also required to investigate the extent to which the risk of cognitive decline can be perturbed by interventions that improve arterial health.

Diagnostics of vascular risk factors in Alzheimer’s disease

Pages 667-676
Research Report
Anouk GW van Norden*, Inge WM van Uden*, Karlijn F de Laat, Ewoud J van Dijk, Frank-Erik de Leeuw *Both authors contributed equally to this study.
Cognitive Function in Small Vessel Disease: The Additional Value of Diffusion Tensor Imaging to Conventional Magnetic Resonance Imaging: The RUN DMC Study
Abstract: The structural integrity of the cerebral white matter, including that of the white matter lesions (WML) and of the surrounding normal appearing white matter (NAWM), can be assessed with diffusion tensor imaging (DTI), which is suggested to be of added value in the explanation of cognitive dysfunction in cerebral small vessel disease (SVD). We investigated the value of DTI of NAWM and WML in addition to conventional magnetic resonance imaging (MRI) parameters in the variance of cognitive performance in subjects with SVD. 499 individuals with SVD, 50-85 years, without dementia, underwent MRI scanning, including a DTI sequence. Grey matter, white matter (WM), and WML volume, number of microbleeds, lacunar and territorial infracts, and mean diffusivity (MD) and fractional anisotropy (FA) in NAWM, WML, and total WM were related to cognitive performance in multivariate regression analyses, after adjustment for age, gender, and education. All MRI parameters together accounted for 1-6% of the variance in cognitive function on top of 22-36% already explained by age, gender, and level of education. Both mean MD and FA of the NAWM, WML, and total WM did not substantially contribute to the explained variance of cognitive function, to that already explained by conventional MRI parameters. When considered separately, the MD of the (NA)WM had the strongest association with cognitive performance. In conclusion, DTI of NAWM and WML has limited additional value to conventional MRI parameters in the etiological explanation of the variance in cognitive function among individuals with SVD.

Pages 677-687
Research Report
Quan Zhang, Randall B. Stafford, Ze Wang, Stephen E. Arnold, David A. Wolk, John A Detre
Microvascular Perfusion Based on Arterial Spin Labeled Perfusion MRI as a Measure of Vascular Risk in Alzheimer’s Disease
Abstract: There is growing recognition of an interaction between cerebrovascular disease and Alzheimer’s disease, but the mechanisms of this interaction remain poorly understood. While macroscopic stroke can clearly produce cognitive deficits and accelerate Alzheimer’s disease, the prevalence and implications of microvascular disease in Alzheimer’s disease pathogenesis has been harder to define. At present, white matter (WM) lesions, primarily defined as hyperintensities seen on T2-weighted magnetic resonance imaging (MRI), provide the best biomarker of cerebrovascular disease at the microvascular level. However, T2 hyperintensities in WM can also be caused by other mechanisms such as inflammation. Arterial spin labeled (ASL) perfusion MRI provides a noninvasive approach for quantifying cerebral blood flow (CBF). We explored CBF measurements with ASL in AD patients, mild cognitive impairment patients, and an age-matched control group to determine if CBF in gray matter or WM could be correlated with WM lesions, or to stratify patients by microvascular disease severity. In a retrospective sample, we were able to obtain credible measures of WM CBF using ASL MRI and observed trends suggesting that WM CBF may provide a useful biomarker of microvascular disease. Future prospective studies in larger cohorts with optimized ASL MRI protocols will be needed to validate these observations.

Pages 689-698
Review
Mauro Silvestrini, Giovanna Viticchi, Claudia Altamura, Simona Luzzi, Clotilde Balucani, Fabrizio Vernieri
Cerebrovascular Assessment for the Risk Prediction of Alzheimer’s Disease
Abstract: Increasing evidence is emerging that vascular disease and its risk factors play a role in the development of Alzheimer’s disease (AD) and affect the probability of an adverse outcome. The aims of this review are to explore the relationship between vascular risk factors and AD and to discuss the potential use of vascular markers in the clinical approach to cognitive impairment. Moreover, we present evidence about the potential use of ultrasonographic and neuroradiologic markers of cognitive impairment in order to establish possible treatment strategies in subjects with a clinical profile at risk of developing AD.

Pages 699-709
Review
Robert D. Bell
The Imbalance of Vascular Molecules in Alzheimer’s Disease
Abstract: The vascular system plays an integral role during Alzheimer’s disease (AD). Both systemic circulatory changes and alterations directly within the brain vasculature have been suggested to contribute to both the onset and progression of neurological conditions such as AD. It is now well established that vascular risk factors including hypertension, diabetes, obesity, atherosclerosis, metabolic syndrome, and stroke significantly increase one’s risk of later developing AD. Research within the last decade has begun to identify specific vascular molecules associated with such risk factors as well as elucidate the biological role they may play in the pathological processes linked to AD. This review aims to provide an overview of some of the key molecules within vascular cells and circulating in blood that have been identified to be altered in AD pathogenesis. In particular, the vascular-specific transcription factors MEOX2, MYOCD, and SRF, genetic risk factor APOE4, transport proteins LRP1 and RAGE, and circulating molecules such as sLRP1, homocysteine, and albumin are discussed. I aim to clarify how these identified vascular molecules may help to predict, explain, and influence the incidence AD. A strong emphasis is placed on the concept that these molecules play overlapping roles in cardiovascular disease progression, neurovascular dysfunction, and amyloid-β pathology. The studies reviewed here have identified vascular-based molecular targets in AD and thus provide new therapeutic avenues for the treatment of this devastating disease.

Pages 711-718
Review
Vikas Dhikav, Kuljeet Singh Anand
Are Vascular Factors Linked to the Development of Hippocampal Atrophy in Alzheimer’s Disease?
Abstract: The hippocampus is a brain structure located deep in the temporal lobe and is notable for its susceptibility to neurotoxic stimuli. It plays a vital role in governing learning and memory. It has been shown to be damaged by variety of factors, e.g., hypoxia, hypoperfusion, hypoglycemia, stress, and seizures, and the list of such factors keeps growing with time. Recently, the role of vascular factors in Alzheimer’s disease in causing significant hippocampal damage has started emerging. Vascular factors are known to cause cerebral microlesions and contribute to many more brain pathologies. Though evidence supporting their effects on causing regional brain atrophy is mixed, several studies are indicating that medial temporal lobe may be particularly vulnerable to the damage caused by cardiovascular risk factors. Considering the association between neurodegeneration and vascular factors, a more rigorous scientific evaluation of the correlation between these two has been suggested.

Interventions to vascular risk factors in Alzheimer’s disease

Pages 721-731
Review
Chengxuan Qiu
Preventing Alzheimer’s Disease by Targeting Vascular Risk Factors: Hope and Gap
Abstract: Alzheimer’s disease (AD) is a major cause of functional dependence, poor quality of life, institutionalization, and mortality among elderly people. As a multifactorial disorder, AD has been frequently linked to vascular risk factors (e.g., smoking, hypertension, obesity, diabetes, hyperlipidemia, and inflammation) in numerous prospective cohort studies of the general population. Systematic reviews and meta-analyses of prospective studies have from the life-course perspective revealed an age-dependent association with the risk of AD for several vascular risk factors such as high blood pressure, obesity, and high total cholesterol, such that possessing these factors in mid-life, but not necessarily in late-life, is associated with an increased risk of AD. The biological plausibility for vascular risk factors to be involved in the pathogenesis and clinical manifestation of Alzheimer syndrome is partly supported by population-based neuroimaging and neuropathological studies. However, randomized controlled trials that target those major cardiovascular risk factors (e.g., antihypertensive, cholesterol-lowering, and anti-inflammatory therapies) have generally failed to prove as efficacious preventative approaches for AD. To bridge the gap, the multifactorial nature of AD and the proper time-window for intervention should be taken into account in the future when designing preventative interventions against the devastating disorder.

Pages 733-740
Review
Edo Richard, Eric P. Moll van Charante, Willem A. van Gool
Vascular Risk Factors as Treatment Target to Prevent Cognitive Decline
Abstract: Epidemiological studies have consistently shown that vascular risk factors including hypertension, diabetes, obesity, hypercholesterolemia, smoking, and lack of physical exercise are associated with an increased risk of cognitive decline and dementia. Neuroradiological and neuropathological studies have confirmed the importance of cerebrovascular lesions in the etiology of late onset dementia. We have reviewed the literature and conclude that up until now randomized controlled clinical trials targeting individual risk factors and assessing cognitive decline or dementia as an outcome have not convincingly shown that treatment of vascular risk factors can actually prevent or postpone cognitive decline and dementia. New studies targeting several vascular risk factors at the same time and using cognitive decline or dementia as primary outcome might answer the question whether cognitive decline can really be postponed or even prevented. The design of such studies is not straightforward and long follow-up is required. In this review we discuss several pertinent methodological issues that need to be addressed to achieve an optimal design of new randomized controlled trials.

Pages 741-752
Research Report
Julio C. Rojas, Aleksandra K. Bruchey, Francisco Gonzalez-Lima
Low-Level Light Therapy Improves Cortical Metabolic Capacity and Memory Retention
Abstract: Cerebral hypometabolism characterizes mild cognitive impairment and Alzheimer’s disease. Low-level light therapy (LLLT) enhances the metabolic capacity of neurons in culture through photostimulation of cytochrome oxidase, the mitochondrial enzyme that catalyzes oxygen consumption in cellular respiration. Growing evidence supports that neuronal metabolic enhancement by LLLT positively impacts neuronal function in vitro and in vivo. Based on its effects on energy metabolism, it is proposed that LLLT will also affect the cerebral cortex in vivo and modulate higher-order cognitive functions such as memory. In vivo effects of LLLT on brain and behavior are poorly characterized. We tested the hypothesis that in vivo LLLT facilitates cortical oxygenation and metabolic energy capacity and thereby improves memory retention. Specifically, we tested this hypothesis in rats using fear extinction memory, a form of memory modulated by prefrontal cortex activation. Effects of LLLT on brain metabolism were determined through measurement of prefrontal cortex oxygen concentration with fluorescent quenching oximetry and by quantitative cytochrome oxidase histochemistry. Experiment 1 verified that LLLT increased the rate of oxygen consumption in the prefrontal cortex in vivo. Experiment 2 showed that LLLT-treated rats had an enhanced extinction memory as compared to controls. Experiment 3 showed that LLLT reduced fear renewal and prevented the reemergence of extinguished conditioned fear responses. Experiment 4 showed that LLLT induced hormetic dose-response effects on the metabolic capacity of the prefrontal cortex. These data suggest that LLLT can enhance cortical metabolic capacity and retention of extinction memories, and implicate LLLT as a novel intervention to improve memory.

Pages 753-763
Review
Carlos A. Feldstein
Association Between Chronic Blood Pressure Changes and Development of Alzheimer’s Disease
Abstract: Epidemiological studies suggest an association between chronic blood pressure (BP) changes and Alzheimer’s disease (AD). In particular, there is growing evidence that hypertensive people that do not have their BP adequately treated and controlled in midlife are more likely to develop AD in late-life. It has been hypothesized that cerebrovascular disease is a common pathway which connects hypertension and AD in individuals with apolipoprotein E genotype through brain hypoperfusion and hypoxia. This could accelerate amyloid-ß aggregation that disrupts cell-to-cell connectivity and leads to eventual brain neuron loss. Also, high BP contributes to worsen AD by raising oxidative stress and inflammatory response. Aging-related structural and functional disturbances appear to exacerbate the deleterious effect of chronic hypertension on cerebral blood flow autoregulation. There is evidence suggesting that some antihypertensive drug classes reduce the risk and progression of AD more than others. Further prospective randomized studies comparing different classes of antihypertensive drugs are needed to provide more evidence regarding their effects on AD risk. Hypotension could be a consequence of the incident dementia and conversely deteriorate the outcome of AD by worsening brain hypoperfusion. Frequent home BP monitoring should be carried out in AD patients to detect harmful orthostatic hypotension.

Pages 765-772
Review
Florence Richard, Florence Pasquier
Can the Treatment of Vascular Risk Factors Slow Cognitive Decline in Alzheimer’s Disease Patients?
Abstract: Dementia is a widespread disorder with major medical, economic, and societal costs.
Controlling vascular conditions could be one way of delaying the progression of Alzheimer’s disease (AD). In fact, vascular risk factors are implicated in AD occurrence. However, it has not been clearly determined whether these vascular factors also affect disease progression itself and thus whether controlling vascular conditions can slow this progression. The treatment of vascular risk factors could have an impact on disease progression by slowing the development of the vascular component. In the present article, we review the potential value of managing hypertension, diabetes, hypercholesterolemia, or global vascular risk factors in AD patients.

Pages 773-788
Hypothesis
Charles T. Ambrose
Neuroangiogenesis: A Vascular Basis for Alzheimer’s Disease and Cognitive Decline During Aging
Abstract: Angiogenesis directs development of the brain's microcirculation during antenatal and postnatal development, but its role later in life is less well recognized. I contend that during senescence a reduced cerebral capillary density accounts in part for the vascular cognitive impairment observed in many older persons and possibly for some forms of Alzheimer's disease. I propose that neuroangiogenesis is essential throughout adult life for maintaining the microcirculation of the cerebral cortex and elsewhere in the brain and that it commonly declines with old age. To support this hypothesis I have examined the neurological literature for relevant studies on cerebral capillary density and neuroangiogenesis throughout the three stages of life and in persons with senile dementias. Finally, I discuss therapeutic approaches employing angiogenic factors for treating vascular cognitive impairment and Alzheimer’s disease.

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