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

Authors: Gons, Rob A.R. | van Oudheusden, Lucas J.B. | de Laat, Karlijn F. | van Norden, Anouk G.W. | van Uden, Inge W.M. | Norris, David G. | Zwiers, Marcel P. | van Dijk, Ewoud | de Leeuw, Frank-Erik

Article Type: Research Article

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. Show more

Keywords: Cerebral small vessel disease, cognition, corpus callosum, diffusion tensor imaging, hypertension, white matter

DOI: 10.3233/JAD-2012-121006

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 623-631, 2012

Authors: Marshall, Randolph S.

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, cerebral autoregulation, cerebral blood flow, cerebral hemodynamics, cognitive impairment, vascular cognitive impairment

DOI: 10.3233/JAD-2012-120949

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 633-642, 2012

Authors: Costanza, Alessandra | Xekardaki, Aikaterini | Kövari, Enikö | Gold, Gabriel | Bouras, Constantin | Giannakopoulos, Panteleimon

Article Type: Review Article

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 a 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. Show more

Keywords: Alzheimer's disease, lacunes, multi-infarct dementia, oldest old, subcortical vascular burden

DOI: 10.3233/JAD-2012-120835

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 643-652, 2012

Authors: Pase, Matthew P.

Article Type: Review Article

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. Show more

Keywords: Aging, arterial stiffness, blood pressure, cognitive, dementia, hypertension, memory, pulse wave velocity, stroke, vascular

DOI: 10.3233/JAD-2012-120565

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 653-663, 2012

Authors: van Norden, Anouk G.W. | van Uden, Inge W.M. | de Laat, Karlijn F. | van Dijk, Ewoud J. | de Leeuw, Frank-Erik

Article Type: Research Article

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. Show more

Keywords: Aging, cerebral small vessel disease, cognition, diffusion tensor imaging, imaging, lacunar infarcts, magnetic resonance imaging, microbleeds, white matter lesions

DOI: 10.3233/JAD-2012-120784

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 667-676, 2012

Authors: Zhang, Quan | Stafford, Randall B. | Wang, Ze | Arnold, Steven E. | Wolk, David A. | Detre, John A.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, arterial spin labeling, cerebral blood flow, magnetic resonance imaging, perfusion, vascular cognitive impairment, white matter lesions

DOI: 10.3233/JAD-2012-120964

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 677-687, 2012

Authors: Silvestrini, Mauro | Viticchi, Giovanna | Altamura, Claudia | Luzzi, Simona | Balucani, Clotilde | Vernieri, Fabrizio

Article Type: Review Article

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.

Keywords: Alzheimer's disease, vascular markers, vascular risk factors

DOI: 10.3233/JAD-2012-121240

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 689-698, 2012

Authors: Bell, Robert D.

Article Type: Review Article

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. Show more

Keywords: APOE4, blood-brain barrier, cardiovascular, LRP1, MEOX2, MYOCD, neurovascular, RAGE, SRF

DOI: 10.3233/JAD-2012-121060

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 699-709, 2012

Authors: Dhikav, Vikas | Anand, Kuljeet Singh

Article Type: Review Article

Abstract: The hipppocampus 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. Show more

Keywords: Alzheimer's disease, diabetes mellitus, hippocampal atrophy, hyperlipidemia, hypertension, vascular risk factors

DOI: 10.3233/JAD-2012-120928

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 711-718, 2012

Authors: Qiu, Chengxuan

Article Type: Review Article

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 this devastating disorder. Show more

Keywords: Alzheimer's disease, cerebrovascular disease, epidemiology, neurodegeneration, prevention, randomized controlled trials, vascular risk factors

DOI: 10.3233/JAD-2012-120922

Citation: Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 721-731, 2012