Journal of Alzheimer's Disease - Volume 32, issue 3

Authors: de la Torre, Jack C.

Article Type: Editorial

DOI: 10.3233/JAD-2012-120830

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 517-518, 2012

Authors: Polidori, M. Cristina | Pientka, Ludger | Mecocci, Patrizia

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, cardiac diseases, cognitive impairment, dementia, diabetes, hypercholesterolemia, hypertension, metabolic syndrome, obesity, vascular risk factors

DOI: 10.3233/JAD-2012-120871

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 521-530, 2012

Authors: Tolppanen, Anna-Maija | Solomon, Alina | Soininen, Hilkka | Kivipelto, Miia

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, blood pressure, cholesterol, diabetes mellitus, epidemiology, metabolic syndrome X, obesity, risk factors, stroke, vascular diseases

DOI: 10.3233/JAD-2012-120802

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 531-540, 2012

Authors: Rabkin, Simon W.

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, arterial stiffness, cognitive impairment, dementia

DOI: 10.3233/JAD-2012-120757

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 541-549, 2012

Authors: de la Torre, Jack C.

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, atherosclerosis, brain hypoperfusion, cerebral blood flow, cerebral hemodynamics, cognition, diabetes, hypertension, Poiseuille's law, vascular risk factors

DOI: 10.3233/JAD-2012-120793

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 553-567, 2012

Authors: Toda, Noboru | Okamura, Tomio

Article Type: Review Article

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. Show more

Keywords: Acetylcholinesterase inhibitor, Alzheimer's disease, cerebral blood flow, endothelial dysfunction, nitric oxide, parasympathetic nitrergic nerve

DOI: 10.3233/JAD-2012-120670

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 569-578, 2012

Authors: Shah, Raj C. | Schneider, Julie A. | Leurgans, Sue | Bennett, David A.

Article Type: Review Article

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 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 other common age-related neuropathologies. Show more

Keywords: Diffuse plaque, hemoglobin, macroscopic infarction, Lewy body, microscopic infarction, neuritic plaque, neurofibrillary tangle, neuropathology

DOI: 10.3233/JAD-2012-120952

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 579-586, 2012

Authors: Sanchez, Alma | Tripathy, Debjani | Yin, Xiangling | Desobry, Katheryn | Martinez, Joseph | Riley, Jarred | Gay, Dylan | Luo, Jinau | Grammas, Paula

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, cerebrovascular, COX-2, hypoxia, inflammation, iNOS, p38 MAPK

DOI: 10.3233/JAD-2012-120829

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 587-597, 2012

Authors: Cortes-Canteli, Marta | Zamolodchikov, Daria | Ahn, Hyung Jin | Strickland, Sidney | Norris, Erin H.

Article Type: Review Article

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. Show more

Keywords: Blood brain barrier, blood coagulation, cerebral amyloid angiopathy, fibrinogen, hemostasis, thrombosis

DOI: 10.3233/JAD-2012-120820

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 599-608, 2012

Authors: Kennelly, Sean | Collins, Orla

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, amyloid, antihypertensive, dementia, hypertension, hypotension, orthostatic hypotension

DOI: 10.3233/JAD-2012-120748

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 609-621, 2012