Journal of Alzheimer's Disease - Volume 20, issue 3

Authors: Sofi, Francesco | Macchi, Claudio | Abbate, Rosanna | Gensini, Gian Franco | Casini, Alessandro

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease characterized by cognitive and memory deterioration, with an increasing prevalence in the industrialized countries and an extraordinary cost of caring for patients. Due to the limited information available on the exact pathophysiology of the disease, over the last years there have been extensive efforts on the identification of possible risk factors, but no conclusive data have been obtained. Some risk factors have been identified but no clear evidence on what is clearly associated with the occurrence and progression of AD are available, and in particular no effective preventive strategies have …been found. One of the most intriguing and appealing lines of investigation is the association between lifestyle habits such as diet and dietary compounds and the occurrence of AD. In this review, we focus on studies that investigated the association between nutrition and AD, paying particular attention to the role of a dietary pattern such as a Mediterranean-like diet on the occurrence of such disease. Studies in support of Mediterranean diet as an optimal diet for prevention of cardiovascular and major chronic diseases has rapidly evolved. A recent meta-analysis from our group, comprising prospective studies that investigated the association between adherence to Mediterranean diet and health status, showed a significant association between a greater adherence to Mediterranean diet and a reduced risk of major chronic degenerative diseases, including AD. Moreover, the Mediterranean diet has been extensively reported to be associated with a favorable health outcome and a better quality of life. Show more

Keywords: Alzheimer's disease, health, Mediterranean diet, nutrition

DOI: 10.3233/JAD-2010-1418

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 795-801, 2010

Authors: Flicker, Leon

Article Type: Review Article

Abstract: There is increasing evidence that some lifestyle factors are linked to the development of Alzheimer's disease. Many of these are potentially modifiable and include smoking, physical activity, education, social engagement, cognitive stimulation, and diet. Modification of most of these factors has other health advantages, increasing the potential benefits of modifying the individual's lifestyle. Unfortunately, most of the current evidence is based on observational data, and where human trials have been performed they have used surrogate outcomes rather than the development of Alzheimer's disease. For many of these modifiable lifestyle factors, such trials may never be performed, and an individual's choice …may need to be based on the available evidence. Show more

Keywords: Alzheimer's disease, lifestyle, older people, prevention

DOI: 10.3233/JAD-2010-091624

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 803-811, 2010

Authors: Jefferson, Angela L.

Article Type: Review Article

Abstract: Heart failure has served as a clinically useful model for understanding how cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to clinical brain injury. This review summarizes more recent data suggesting that subtle cardiac dysfunction or low normal levels of cardiac function, as quantified by cardiac output, are related to cognitive and neuroimaging markers of abnormal brain aging in the absence of heart failure or severe cardiomyopathy. Additional work is required, but such associations suggest that reduced cardiac output may be a risk factor for Alzheimer's disease (AD) …and abnormal brain aging through the propagation or exacerbation of neurovascular processes, microembolism due to thrombosis, and AD neuropathological processes. Such mechanistic pathways are discussed in the context of a theoretical model that posits a direct pathway of injury between cardiac output and abnormal brain aging (i.e., reduced systemic blood flow disrupts cerebral blood flow homeostasis), contributing to clinical brain injury, independent of shared risk factors for both cardiac dysfunction and abnormal brain aging. Show more

Keywords: Alzheimer's disease, cardiac output, cardiovascular disease, cognition

DOI: 10.3233/JAD-2010-100081

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 813-821, 2010

Authors: Tierney, Mary C. | Lermer, Miriam A.

Article Type: Review Article

Abstract: The incidence and prevalence in those over age 65 of neurodegenerative disorders and chronic diseases, which often have deleterious effects on cognition, are rapidly increasing in western societies. Primary care physicians (PCPs) provide the majority of medical treatment for older people and in order to effectively care for their patients with suspected cognitive impairment, they must have tools that will allow them to accurately assess their patient's cognitive function. This knowledge will assist the PCPs in formulating a diagnosis of dementia or cognitive impairment and provide an indication of risk of progression to dementia. It will also assist with monitoring …response to treatment and care decisions, including medication management, capacity judgments, and the need for family involvement. Tests currently used in primary care, such as the Mini-Mental State Examination, do not accurately assess patients with mild cognitive impairments, and other tests more suitable for this purpose require further validation and may be too time-consuming in the primary care setting. A possible solution is the use of patient-administered computerized cognitive testing in the PCP's office. This systematic review identified eleven test batteries and three were judged potentially appropriate for cognitive assessment in the PCP's office. These three varied in their presentation format and the quality of cross-sectional validation studies, and none had longitudinal data for dementia prediction. Thus the existing test batteries show potential for use in primary care but further study is needed to demonstrate their feasibility and effectiveness in this setting. Show more

Keywords: Cognition, computers, mild cognitive impairment, neuropsychological tests, primary care

DOI: 10.3233/JAD-2010-091672

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 823-832, 2010

Authors: Waldstein, Shari R. | Wendell, Carrington Rice

Article Type: Review Article

Abstract: Cardiovascular (CV) diseases and their risk factors negatively impact the brain and neurocognitive function prior to stroke, dementia, or mild cognitive impairment (MCI). Indeed, a progression of neurocognitive and neurobiological impairments may be associated with increasingly severe manifestations of CV risk and disease. In samples ranging from children to elderly, a broad spectrum of CV risk factors, and both subclinical and clinical CV diseases, have been related to decrements in cognitive function and cognitive decline across multiple domains of performance including executive functions, attention, learning and memory, perceptuo-motor speed, and others. In contrast to the MCI literature, the possibility of …distinct subgroups has not been explored. Further, it remains unknown whether neurocognitive performance (or its pattern) per se can predict conversion to MCI and later dementia. We suggest that neurocognitive function may contribute to such prediction in concert with relevant radiological, genetic, biomedical, sociodemographic, and other data. To best do so, future research would benefit from inclusion of a breadth of neurocognitive tests that tap multiple domains of function and have historical sensitivity to vascular and neurodegenerative pathology, in addition to biological or radiological assessment of such pathology. Aggressive efforts at prevention and early intervention with CV risk may play a critical role in the prevention of MCI or dementia. Show more

Keywords: Brain, cardiovascular disease, cardiovascular risk factors, cognitive function, neuropsychology

DOI: 10.3233/JAD-2010-091591

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 833-842, 2010

Authors: Mosconi, Lisa | Berti, Valentina | Glodzik, Lidia | Pupi, Alberto | De Santi, Susan | de Leon, Mony J.

Article Type: Review Article

Abstract: The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to subtle brain changes occurring in the preclinical stage of the disease. Early diagnostics is necessary to identify and treat at risk individuals before irreversible neuronal loss occurs. In vivo imaging has long been used to evaluate brain structural and functional abnormalities as predictors of future AD in non-demented persons. Prior to development of amyloid-β (Aβ) tracers for positron emission tomography (PET), the most widely utilized PET tracer in AD was 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) PET. For over 20 years, FDG-PET has been used to …measure cerebral metabolic rates of glucose (CMRglc), a proxy for neuronal activity, in AD. Many studies have shown that CMRglc reductions occur early in AD, correlate with disease progression, and predict histopathological diagnosis. This paper reviews reports of clinical and preclinical CMRglc reductions observed in association with genetic and non-genetic risk factors for AD. We then briefly review brain Aβ PET imaging studies in AD and discuss the potential of combining symptoms-sensitive FDG-PET measures with pathology-specific Aβ-PET to improve the early detection of AD. Show more

Keywords: Amyloid-β, cerebral metabolic rate of glucose (CMRglc), normal aging, positron emission tomography, preclinical detection

DOI: 10.3233/JAD-2010-091504

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 843-854, 2010

Authors: Kitagawa, Kazuo

Article Type: Review Article

Abstract: Recent epidemiological studies have shown that hypertension is a significant risk factor for Alzheimer's disease (AD). Cerebral small vessel disease (CSVD) including silent cerebral infarction and white matter lesions could represent hypertensive target organ damage in the brain and may be reliable predictors for incident dementia. However, there have been few measures to classify those patients with CSVD who are at high risk for cognitive decline and dementia. Although cerebral hypoperfusion is central to the vascular hypothesis of AD, there have been no studies linking cerebral blood flow (CBF) and future cognitive decline. Using positron emission tomography, we have demonstrated …a moderate association between CBF under baseline conditions and cognitive decline during a 3-year follow-up study in 27 hypertensive patients (r=0.59, P=0.001). Findings from randomized clinical trials together with our results suggest that the preservation or improvement of CBF by anti-hypertensive treatment might be effective for the prevention of cognitive decline and dementia, especially in hypertensive patients with CSVD. Show more

Keywords: Cerebral blood flow, cerebral small vessel disease, cognitive decline, hypertension, positron emission tomography

DOI: 10.3233/JAD-2010-091324

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 855-859, 2010

Authors: de la Torre, Jack C.

Article Type: Review Article

Abstract: The dramatic rising incidence and costs of Alzheimer's disease (AD) require that research efforts and funding be primarily directed on either finding a cure or applying preventive measures to curb this disorder. A cure for AD appears unlikely when significant cognitive loss has occurred because the neuronal networks that controlled the perturbed cognitive abilities are either dead or irreversibly damaged and replacing them, even if it were technically possible, would not reconstruct the intellectual identity of the host. Prevention of risk factors to sporadic AD is a more realistic stratagem and treatment, when indicated, ideally should begin in cognitively intact …individuals as part of a mass screening effort. Prevention of modifiable risk factors to AD is cost-effective because it reduces hospice or hospital stay, repeated doctor visits, and long-term care. Presently, neurocognitive and neuroimaging tests are used with partial success in identifying persons at higher risk of AD but these tests can not pinpoint either a cause or a specific intervention that could attenuate disease progress. We previously proposed that carotid artery ultrasound +echocardiography together with ankle-brachail index (CAUSE+ABI) as mass screening tests in asymptomatic persons could detect not only cardio-cerebrovascular risk factors to AD, but also identify an indicated intervention. CAUSE+ABI are simple to perform, cost-effective, non-invasive, and reasonably accurate for the intended purpose. Additionally, detection of cardio-cerebrovasacular abnormalities long before expression of cognitive deterioration allows higher success rate with earlier treatment. Evidence-based medicine is recommended for optimizing clinical decision-making in evaluating AD risk factors and their treatment. Show more

Keywords: Alzheimer's disease, Alzheimer's risk factors, cognition, evidence-based medicine, neurodegeneration, prevention, ultrasound screen

DOI: 10.3233/JAD-2010-091579

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 861-870, 2010

Authors: Alsop, David C. | Dai, Weiying | Grossman, Murray | Detre, John A.

Article Type: Review Article

Abstract: Arterial spin labeling (ASL) enables the noninvasive, quantitative imaging of cerebral blood flow using standard magnetic resonance imaging (MRI) equipment. Because it requires no contrast injection, ASL can add resting functional information to MRI studies measuring atrophy and signs of ischemic injury. Key features of ASL technology that may affect studies in Alzheimer's disease are described. The existing literature describing ASL blood flow imaging applied to Alzheimer's disease and related dementia is reviewed, and the potential role of ASL in treatment and prevention studies of early Alzheimer's disease is discussed.

Keywords: Cerebral blood flow, diagnosis, imaging, magnetic resonance imaging, perfusion

DOI: 10.3233/JAD-2010-091699

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 871-880, 2010

Authors: van Rossum, Ineke A. | Vos, Stephanie | Handels, Ron | Visser, Pieter Jelle

Article Type: Review Article

Abstract: Disease modifying drugs for Alzheimer's disease (AD) are likely to be most effective when given in non-demented subjects. In this review we summarized biomarkers in cerebrospinal fluid (CSF) and blood that can predict AD-type dementia in subjects with mild cognitive impairment (MCI). In addition, we investigated whether these markers could reduce sample size and costs if used to select subjects for trials on the prevention of AD in subjects with MCI. A meta-analysis of markers that had been investigated in multiple studies showed that the combination of amyloid-β (Aβ1-42 and tau in CSF had the best predictive accuracy for …AD (odds ratio (OR) 18.1, 95% confidence interval (CI) 9.6–32.4). Aβ1-42 , total tau, and phosphorylated tau in CSF also predicted conversion, but with lower accuracy (OR 7.5 to 8.1). Plasma levels of Aβ1-40 , Aβ1-42 , the ratio Aβ1-42 /Aβ1-40 and homocysteine did not predict outcome. In a fictive trial design, the use of the combination of Aβ1-42 and tau in CSF in the selection of subjects could reduce sample size by 67% and trial costs by 60% compared to a trial in which unselected subjects with MCI would be enrolled. In conclusion, the combination of Aβ1-42 and tau in CSF is useful to select subjects for trials that aim to slow down the progression from MCI to AD-type dementia. Show more

Keywords: Alzheimer's disease, biomarkers, blood, cerebrospinal fluid, cost-benefit, decision analysis, mild cognitive impairment

DOI: 10.3233/JAD-2010-091606

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 881-891, 2010

Authors: Luzzi, Simona | Vella, Lucia | Bartolini, Marco | Provinciali, Leandro | Silvestrini, Mauro

Article Type: Review Article

Abstract: The relationship between cerebrovascular impairment and Alzheimer's disease is a controversial debate. An important and topical aspect in clinical research is the attempt to define the role of atherosclerosis and its determinants in the presentation and evolution of dementia. In this article, we discuss the evidence of the interaction between degenerative and vascular mechanisms in the pathogenesis of dementia. Moreover, we present data about the influence of hypertension and dyslipidemia, usually considered among the most important risk factors for atherosclerosis, on the evolution of Alzheimer's disease. The effects of antihypertensive and lipid-lowering drugs on cognitive impairment will be also discussed.

Keywords: Alzheimer's disease, atherosclerosis, cerebrovascular disease, dyslipidemia, hypertension

DOI: 10.3233/JAD-2010-091378

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 893-901, 2010

Authors: Duron, Emmanuelle | Hanon, Olivier

Article Type: Review Article

Abstract: Chronic hypertension is associated with an increased risk of both vascular dementia and Alzheimer's disease (AD). In this context, the role of anti-hypertensive therapy for the prevention and delay of cognitive decline and dementia is of central importance. Most longitudinal studies have shown a significant inverse association between anti-hypertensive therapies and dementia incidence and for some of these, particularly in AD. Seven randomized, double blind placebo-controlled trials have evaluated the benefit of antihypertensive treatments on cognition. Three of them found positive results in term of prevention of dementia (SYST-EUR) or cognitive decline (PROGRESS, HOPE). Others disclosed non-significant results (MRC, SHEP, …SCOPE, HYVET-COG). This discrepancy emphasizes the difficulty to perform such trials: the follow-up has to be long enough to disclose a benefit, a large number of patients is needed for these studies, and because of ethical reasons some anti-hypertensive treatments are often prescribed in the placebo group. Results of the two more recent meta-analyses are inconsistent, possibly due to methodological issues. Antihypertensive treatments could be beneficial to cognitive function by lowering blood pressure and/or by specific neuroprotective effect. Three main antihypertensive subclasses have been associated with a beneficial effect on cognitive function beyond blood pressure reduction (calcium channel blockers, angiotensin converting enzyme inhibitor, angiotensin-AT1-receptor-blockers). Further long-term randomized trials, designed especially to assess a link between antihypertensive therapy and cognitive decline or dementia are therefore needed with cognition as the primary outcome. A low blood pressure threshold that could be deleterious for cognitive function should also be determined. Show more

Keywords: Alzheimer's disease, a ntihypertensive therapy, cognitive decline, hypertension, longitudinal studies, meta-analyses, randomized controlled trials

DOI: 10.3233/JAD-2010-091552

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 903-914, 2010

Authors: Middleton, Laura E. | Yaffe, Kristine

Article Type: Review Article

Abstract: The prevalence of dementia is expected to increase dramatically over the upcoming decades due to the aging population. Since treatment is still short of a cure, preventative strategies are of the utmost importance. Stimulating activity (cognitive, physical, and social), vascular risk factors, and diet may be important in preventative strategies. Dementia risk may be modified by participation in stimulating activities. One study suggested that the cognitive, physical, and social components of activity were of equal importance to cognitive outcomes. However, while exercise interventions appear to benefit global cognition, the benefits from cognitive training appear to be domain specific. People with …vascular risk factors (hypertension, diabetes, dyslipidemia, and obesity) appear to be at higher risk for dementia than those without in observational and clinical trials. Controlled trials suggest that vascular risk management via some pharmaceutical interventions may benefit cognition, though results are inconsistent. Finally, people who adhere to a Mediterranean diet or who have high intake of antioxidants and omega-3 fatty acids have reduced likelihood of dementia in observational studies. However, supplementation in controlled trials has not generally proved successful at improving cognitive outcomes. A single supplement may be insufficient to prevent dementia; it may be that the overall diet is more important. Future large randomized controlled studies should examine whether interventions can reduce the risk of dementia and whether combining cognitive, physical, and social activity, vascular risk reduction, and dietary interventions might have additive or multiplicative effects. Show more

Keywords: Cognitive activity, dementia, diet, physical activity, prevention, social engagement, vascular risk

DOI: 10.3233/JAD-2010-091657

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 915-924, 2010

Authors: McGuinness, Bernadette | Passmore, Peter

Article Type: Review Article

Abstract: Evidence accumulating from biological and epidemiological studies suggests that high levels of serum cholesterol may promote the pathological processes that lead to Alzheimer's disease (AD). Lowering cholesterol in experimental animal models slows the expression of Alzheimer's pathology. These findings raise the possibility that treating humans with cholesterol lowering medications might reduce the risk of developing AD or help treat it. The statins (lovastatin, pravastatin, simvastatin, and others) are powerful cholesterol lowering agents of proven benefit in vascular disease. Several clinical studies comparing the occurrence of AD between users and non-users of statins suggested that risk of AD was substantially reduced …among the users. However, because these studies were not randomized trials, they provided insufficient evidence to recommend statin therapy. Cochrane reviews are based on the best available information about healthcare interventions and they focus primarily on randomized controlled trials (RCTs). On the issue of prevention, two randomized trials have been carried out and neither showed any reduction in occurrence of AD in patients treated with statins compared to those given placebo. Statins cannot therefore be recommended for the prevention of AD. Regarding treatment of AD, the large RCTs which have assessed this outcome have not published their results. Initial analysis from the studies available indicate statins have no benefit on the outcome measure ADAS-Cog but have a significant beneficial effect on MMSE as an outcome. We need to await full results from the RCTs before we can be certain. In addition statins were not detrimental to cognition in either systematic review. Show more

Keywords: Alzheimer's disease, cholesterol, cognitive impairment, dementia, statins

DOI: 10.3233/JAD-2010-091570

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 925-933, 2010

Authors: Murad, M. Hassan | Montori, Victor M.

Article Type: Review Article

Abstract: The two fundamental principles of evidence-based medicine indicate that a hierarchy of evidence exists and that evidence alone is never sufficient to make clinical decisions. Incorporation of factors other than evidence such as patients' values and preferences, clinical context, and resource allocation are essential factors for decision making. The knowledge of these principles orients the use of clinical care research by evidence users such as patients, clinicians, and policy makers; and also helps researchers create research protocols and agendas that produce evidence that fulfills the needs of these users. Examples of research in Alzheimer's disease are presented to illustrate how …evidence is produced, appraised and utilized. Show more

Keywords: Alzheimer's disease, evidence-based medicine, patients' values and preferences, quality of evidence, research methodology

DOI: 10.3233/JAD-2010-1419

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 935-942, 2010

Authors: Strobel, Gabrielle

Article Type: Editorial

DOI: 10.3233/JAD-2010-100013

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 943-948, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-100082

Citation: Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 949-951, 2010