Journal of Alzheimer's Disease - Volume 42, issue s4

Authors: Thal, Dietmar Rudolf | Attems, Johannes | Ewers, Michael

Article Type: Research Article

Abstract: Primary pathologies including amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) develop many years before the onset of dementia symptoms in Alzheimer's disease (AD). Age-related small vessel disease (SVD) is common in elderly subjects and may contribute to the clinical syndrome of AD. Each type of pathology shows a specific spatio-temporal sequence of spreading in the brain. Here, we review neuropathological and neuroimaging findings (PET tracers of Aβ and NFT, MRI markers of SVD) to assess whether staging of these primary pathologies is useful to predict clinical symptoms in AD. On the basis of neuropathological data, early stages of Aβ plaque …and NFT pathology distribution occur in preclinical AD, but advanced stages with spreading into further brain regions are associated with dementia symptoms. Amyloid PET presumably detects Aβ in advanced neuropathological Aβ stages, and increased global amyloid PET uptake is associated with clinical worsening in non-demented subjects. Tau PET may provide additional predictive value by detecting NFT in the allocortex. There is weak evidence that SVD is related to amyloid or NFT pathology. Global volume of MRI-assessed white matter hyperintensities (WMH) contribute in addition to biomarker levels of Aβ to predict cognitive decline. Regional differences of the effect of WMH on cognition have been demonstrated but are not yet established as a biomarker in AD. In conclusion, biomarkers for amyloid and tau pathology allow a distinction between early and advanced stages of AD, but a subgroup of pathologically identified preclinical AD cases is not identified by the currently available biomarkers. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarker, diagnosis, early detection, magnetic resonance imaging, neurofibrillary tangles, plaques, positron emission tomography, small vessel disease

DOI: 10.3233/JAD-141461

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S421-S429, 2014

Authors: de la Torre, Jack C.

Article Type: Review Article

Abstract: The incidence rate in Alzheimer's disease (AD) is expected to quadruple worldwide by 2050. To limit this impending socio-medical calamity, a fulcrum change from how AD is presently managed is crucial. The present approach has not averted the stress of AD on medical resources nor reduced the already cost-strained government health care programs. Since substantial evidence indicates that sporadic AD is directly associated with vascular risk factors, a strategic plan is proposed to target this association and markedly reduce the onset of AD. This plan would establish in-house heart-brain clinics devoted to identifying, detecting, and preventing the progression of vascular …risk factors that predispose to cognitive impairment and development of AD. The heart-brain clinics would be staffed with a multidisciplinary group of neurologists, psychologists, neuroradiologists, cardiovascular specialists, and technical personnel Their goal would be to apply and interpret non-invasive, cost-effective multidiagnostic testing of heart and brain function in outpatient asymptomatic and symptomatic patients at risk of dementia. Multidiagnostic testing would permit better risk stratification, medical decision-making, and a tailored intervention of patients at-risk of dementia than the present monotherapeutic approach. Personalized intervention, moreover, should achieve better patient compliance and outcome through periodic follow-up visits to the clinics where the medical plan of action could be monitored and modified as needed. Multidisciplinary heart-brain clinics will be costly at first but eventually should become cost-effective while providing an invaluable medical service to an aging population and possibly extending years of full-health lived in those at risk of dementia. Show more

Keywords: Alzheimer's disease, cognitive impairment, detection, heart-brain clinics, multidiagnostic testing, prevention, vascular risk factors

DOI: 10.3233/JAD-141560

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S431-S442, 2014

Authors: van Buchem, Mark A. | Biessels, Geert Jan | Brunner la Rocca, Hans Peter | de Craen, Anton J.M. | van der Flier, Wiesje M. | Ikram, M. Arfan | Kappelle, L. Jaap | Koudstaal, Peter J. | Mooijaart, Simon P. | Niessen, Wiro | van Oostenbrugge, Robert | de Roos, Albert | van Rossum, Albert C. | Daemen, Mat J.A.P.

Article Type: Review Article

Abstract: While both cardiac dysfunction and progressive loss of cognitive functioning are prominent features of an aging population, surprisingly few studies have addressed the link between heart and brain function. This is probably due to the monodisciplinary approach to these problems by cardiologists, neurologists, and geriatricians. Recent data indicate that autoregulation of cerebral flow cannot always protect the brain from hypoperfusion when cardiac output is reduced or atherosclerosis is prominent. This suggests a close link between cardiac function and large vessel atherosclerosis on the one hand and brain perfusion and cognitive functioning on the other. In a national research program, we …will test the hypothesis that impaired hemodynamic status of both heart and brain is an important and potentially reversible cause of vascular cognitive impairment (VCI) offering promising opportunities for treatment. Using a multidisciplinary approach, we will address the following questions: 1) To what extent do hemodynamic changes contribute to VCI? 2) What are the mechanisms involved? 3) Does improvement of the hemodynamic status lead to improvement of cognitive dysfunction? To this end we will perform clinical studies in elderly patients with clinically manifest VCI, carotid occlusive disease, or heart failure and evaluate their cardiac and large vascular function, atherosclerotic load, and cerebral perfusion with a comprehensive magnetic resonance imaging protocol and thoroughly test their cognitive function. We will also analyze epidemiological data from the Rotterdam Study. Show more

Keywords: Atherosclerosis, heart, magnetic resonance imaging, vascular cognitive impairment

DOI: 10.3233/JAD-141542

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S443-S451, 2014

Authors: Poggesi, Anna | Salvadori, Emilia | Valenti, Raffaella | Nannucci, Serena | Ciolli, Laura | Pescini, Francesca | Pasi, Marco | Fierini, Fabio | Donnini, Ida | Marini, Sandro | Chiti, Guido | Rinnoci, Valentina | Inzitari, Domenico | Pantoni, Leonardo

Article Type: Research Article

Abstract: Background and objective: Services dedicated to patients with cognitive and behavioral consequences of cerebrovascular diseases are not well established. In this paper, we report on the general organization of such a service (the Florence VAS-COG Clinic) after 9 years of activity, updating a previous work related to the first 5 years. Methods: The Florence VAS-COG clinic, started in 2006, is an outpatient service dedicated to the assessment and follow-up of patients with cerebrovascular diseases and related cognitive, psychiatric, and behavioral disturbances. The staff involved in the clinic is composed of certified neurologists, one neuropsychologist, and neurology residents. The …diagnostic protocol includes detailed personal and family history, general and neurologic examinations, and functional, neuropsychological, and neuroimaging assessment. After this work-up, comprehensive diagnoses are made. Results: From January 2006 to March 2014, 600 patients (mean age 67.3 years ± 13.9; 52% females) have been evaluated in the clinic. Cognitive impairment, including mild cognitive impairment and dementia, mainly of vascular origin, was the most common (36.4%) diagnostic category, followed by suspected or confirmed familial micro-angiopathy (35.8%). Compared to the first years of activity, we are now facing the need of augmenting the number of visits due to increasing request and to better implement the multidisciplinarity of the team. Efforts are currently directed towards the definition of management protocols in pharmacological and non-pharmacological strategies. Conclusions: The establishment of a VAS-COG clinic represents an important step for the appreciation of the patient clinical needs and for the implementation of screening, diagnostic, and treatment options in the field of the neuropsychiatric consequences of cerebrovascular diseases. Show more

Keywords: Dementia, mild cognitive impairment, outpatient clinic, post-stroke aphasia, post-stroke depression, small vessel disease, stroke, vascular cognitive impairment

DOI: 10.3233/JAD-141569

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S453-S461, 2014

Authors: Anstey, Kaarin J. | Eramudugolla, Ranmalee | Dixon, Roger A.

Article Type: Review Article

Abstract: The development and integration of risk assessment and clinical risk management for Alzheimer's disease (AD) and dementia is a rapidly emerging field of research and practice. At present, risk management is the only available approach with potential for a large impact on the projected rates of dementia, given population aging. This review describes six available risk assessment tools, including those developed specifically for AD and those for dementia. These tools differ along several important dimensions, including whether they (a) include clinical measures, (b) require a clinician's ratings, (c) are predominantly self-report, (d) are independently validated, and (e) are available online. …A narrative review of recently identified risk factors not included in these instruments is included, indicating future directions for risk assessment. Finally, consideration is given to the prioritization of risk advice according to the ease of risk modification and the potential for synergies among risk factors. Show more

Keywords: Alzheimer's disease, cognitive decline, prevention, risk assessment, risk factor

DOI: 10.3233/JAD-141248

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S463-S473, 2014

Authors: Polidori, Maria Cristina

Article Type: Review Article

Abstract: Malnutrition-, obesity-, and Alzheimer's disease (AD)-related burden to patients and society are among the main public health challenges of our time in both developed and developing countries. Poor nutrition as part of an unhealthy lifestyle is one of the modifiable risk factors for AD, and its improvement has been the recent focus of several interventional and epidemiologic studies. There is an impressive body of evidence supporting the beneficial role of balanced nutrition in lowering the risk of dementia, but despite worldwide dementia epidemics, lack of information still leads to (too) late diagnosis and (symptomatic) interventions. The aim of this work …is to critically summarize knowledge on the preventive effects of natural nutrition against AD onset and to present a multidimensional and individualized approach aimed at delaying AD onset in community dwellers with subjective and mild cognitive complaints. Show more

Keywords: Alzheimer's disease, antioxidant, clinical trial, counseling, mild cognitive impairment, natural nutrition, oxidative stress

DOI: 10.3233/JAD-141539

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S475-S482, 2014

Authors: Hampstead, Benjamin M. | Mosti, Caterina B. | Swirsky-Sacchetti, Thomas

Article Type: Review Article

Abstract: Projections indicate that the prevalence of Alzheimer's disease (AD) and other dementias will increase two to three fold in the coming decades. As a result, there has been considerable interest in identifying methods that maintain or enhance cognitive functioning in these older adults. Existing pharmacological agents are limited in this respect and disease-modifying agents are years away from being available. Cognitively based interventions (i.e., cognitive training, cognitive rehabilitation) hold particular promise for maximizing patients' functioning, are relatively inexpensive, and have virtually no side effects. Everyday life is complex and multifaceted, which means that a personalized approach is essential for maximizing …and prolonging functioning in each patient. Unfortunately, little is known about the factors contributing to such an approach. The current review first identifies several lifestyle factors that have been shown to be neuroprotective as well as risk factors that may ultimately contribute to the efficacy of different cognitive intervention techniques. There is a critical need to understand the conditions under which individual techniques are effective; an issue examined through characteristic examples across the AD spectrum. While limited at this time, there is some evidence of the long-term benefits of cognitive intervention. We conclude by describing several critical areas of investigation and proposing a clinically oriented framework for both furthering cognitive intervention research and providing patient-centered care. Show more

Keywords: Aging, biomarker, cognitive rehabilitation, cognitive training, learning, memory, mild cognitive impairment

DOI: 10.3233/JAD-141476

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S483-S493, 2014

Authors: Wang, Ze

Article Type: Review Article

Abstract: Searching for biomarkers sensitive to early Alzheimer's disease (AD) and its progression has been a research priority for two decades. MRI has been increasingly used for this endeavor because of its capability of detecting both structural and functional brain patterns without injecting external contrast agent or radioactive tracers. Recent work has shown sensitivity of hippocampal volume and regional cerebral blood flow for differentiating prodromal AD from normal controls as well as AD. This review provides a summary for the existing literature describing the applications of either or both modalities in early AD studies as well as disease progression assessment. The …various findings in the reviewed studies lead to a conclusion of assessing hippocampal volume and arterial spin labeling cerebral blood flow as potential markers for disease detection, and progression monitoring though longitudinal studies are still lacking to fully examine their sensitivity and specificity. Show more

Keywords: Arterial spin labeling, cerebral blood flow, diagnosis, grey matter volume, hippocampus, imaging

DOI: 10.3233/JAD-141419

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S495-S502, 2014

Authors: Zeki Al Hazzouri, Adina | Yaffe, Kristine

Article Type: Review Article

Abstract: Cognitive decline and dementia are a major cause of disability and mortality among older adults. Cross-sectional evidence from observational studies suggests that greater arterial stiffness is associated with worse cognitive performance. These associations have been observed on measures of global cognition and across multiple domains of cognition. Epidemiologic evidence on the association between arterial stiffness and rate of cognitive decline has been less definitive, and very few studies have investigated the risk of developing dementia. This review summarizes the current research on arterial stiffness and cognition, issues around measurement, and the effect that potential intervention might have on the course …of cognitive aging. The evidence on pharmacological and non-pharmacological (exercise, nutrition, etc.) interventions in older adults with arterial stiffness is promising. Yet there are no studies or trials that directly evaluate how interventions of arterial stiffness reduce or prevent cognitive impairment and risk of developing dementia. More research is needed to elucidate the causal link between arterial stiffness and cognitive decline and dementia, and to identify whether potential interventions to prevent or reduce arterial stiffness may benefit cognitive health of the elderly. Show more

Keywords: Aging, arterial stiffness, cognitive decline, dementia, epidemiology

DOI: 10.3233/JAD-141563

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S503-S514, 2014

Authors: Rodríguez-Gómez, Octavio | Palacio-Lacambra, M. Eugenia | Palasí, Antoni | Ruiz-Laza, Agustín | Boada-Rovira, Mercè

Article Type: Review Article

Abstract: The incidence of dementia is rapidly increasing in developed countries due to social and demographic changes. This trend is expected to worsen in the coming decades, with the number of cases possibly even tripling in the next 25 years. Therefore Alzheimer's disease (AD) prevention is becoming a global health priority. Our knowledge of the pathophysiological process leading to the development of pathological brain lesions that characterize AD has increased exponentially in recent years. However, the phenotypic expression of AD not only depends on the development of senile plaques and neurofibrillary tangles but other factors also play a role. Thus, over …the last few decades, epidemiological studies have revealed several risk factors for developing AD, such as vascular or lifestyle related factors. Having the current knowledge on AD, two different strategies have been developed for the prevention of AD: one is based on primary prevention by acting on modifiable risk factors, the other is a pathophysiology-driven approach aimed to identify individuals in a preclinical stage of the disease and treating them with drugs purporting to act on molecular targets of the amyloid cascade. Several promising trials with these approaches are currently ongoing and results are expected in the next few years. The intrinsic limitations in the design of preventive trials should be overcome through a global effort involving healthy population, healthcare professionals, governments, industry, and scientific institutions. This exertion will be more than compensated if we can make AD a preventable disease. Show more

Keywords: Alzheimer's disease, anti-amyloid therapy, multidomain approach, preclinical Alzheimer's disease, preventive clinical trials, primary prevention, secondary prevention, vascular risk factors

DOI: 10.3233/JAD-141479

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S515-S523, 2014

Authors: Auchter, Allison | Williams, Justin | Barksdale, Bryan | Monfils, Marie H. | Gonzalez-Lima, Francisco

Article Type: Research Article

Abstract: Chronic cerebral hypoperfusion, a risk factor for mild cognitive impairment and Alzheimer's disease, affects mitochondrial respiration and memory consolidation. Therefore, drugs that improve mitochondrial function may be appropriate cognitive treatments for cerebral hypoperfusion. Methylene blue (MB) crosses the blood-brain barrier and at low doses serves as an electron cycler in the mitochondrial electron transport chain. Previous studies implicate MB in both memory enhancement and neuroprotection. We treated rats that underwent permanent bilateral carotid occlusion (2VO) or sham surgery with daily 4 mg/kg USP MB or saline for one month. Animals went through a battery of behavioral tests, including open field, …visual water maze, and odor-recognition tasks. 2VO rats showed worse performance in the visual water task without showing differences in general motor activity, visually guided swimming ability or odor recognition. Daily MB attenuated the deficits in visual learning and memory that resulted from cerebrovascular insufficiency. During training on three different discrimination problems in the visual water task, all animals were able to reach a criterion of 8/10 correct trials, but 2VO animals took longer to learn each problem and showed lower performance in a challenging memory probe. However, animals that received daily post-session MB performed significantly better than saline-treated subjects both during training and during the memory probe. This is the first study to demonstrate that MB attenuates learning and memory deficits caused by carotid occlusion. The results suggest that MB may be beneficial for conditions involving chronic cerebral hypoperfusion, such as mild cognitive impairment, vascular dementia, and Alzheimer's disease. Show more

Keywords: Carotid occlusion, cerebral hypoperfusion, cognitive impairment, memory enhancement, methylene blue

DOI: 10.3233/JAD-141527

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S525-S535, 2014

Authors: Grammas, Paula | Martinez, Joseph M.

Article Type: Review Article

Abstract: The Alzheimer's disease (AD) epidemic proceeds unabated. Estimates suggest 5.4 million Americans and 36 million people worldwide have AD. No single mechanism or pathologic mediator can account for AD progression. Currently no disease modifying therapies are available. There is a large literature documenting an association among cardiovascular risk factors (CVRFs), especially diabetes and hypoxia, with increased AD incidence. CVRFs directly impair vascular function and could mediate cerebrovascular dysfunction in AD. This is important as cerebrovascular dysfunction precedes cognitive decline and onset of neurodegenerative changes in AD and AD animal models. In this review we present evidence that thrombin may be …a heretofore unexplored target for AD therapy. This idea is based on the following observations. Thrombin is elevated in the brain and cerebral microvasculature in AD, is directly neurotoxic, and causes pro-inflammatory effects in endothelial cells, microglia, and astrocytes. Diabetes- and hypoxia-induced cerebrovascular effects are mediated by thrombin. Thrombin inhibitors block the effects of hypoxia on brain endothelial cells and reduce vascular inflammation in transgenic AD mice. Based on reports that reducing cerebrovascular expression of inflammatory proteins in AD mice is associated with improved cognition, we propose thrombin inhibitors could prove useful for improving cognition in AD patients. The next generation of AD therapeutics should not focus on single target drugs but rather employ a multi-component cocktail approach. We propose thrombin inhibitors be considered as potential contributors to the dementia therapy pharmacopeia. The urgent need for disease-modifying drugs in AD demands new thinking about disease pathogenesis and exploration of novel drug targets. Show more

Keywords: Alzheimer's disease, cardiovascular risk factors, cerebral microvasculature, cognitive decline, dabigatran, thrombin, thrombin inhibitors

DOI: 10.3233/JAD-141557

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S537-S544, 2014

Authors: Rafii, Michael S.

Article Type: Review Article

Abstract: In 2013, the Food and Drug Administration released draft guidance on drug development for early-stage Alzheimer's disease (AD). This guidance builds on the understanding that AD is a progressive disease with symptoms appearing long after neurodegeneration has begun. Preclinical AD relies on the conceptual distinction made between the presence of AD pathological processes and clinically observable symptoms. With the advent of new biomarkers that allow for presymptomatic detection of AD pathology, there now exists an opportunity to design and conduct clinical trials of putative disease-modifying drugs in the earliest stages of the disease when they are thought to have the …greatest chance of success. As such, there are four clinical trials planned or underway for the secondary prevention of AD. Show more

Keywords: Clinical trials, preclinical Alzheimer's disease

DOI: 10.3233/JAD-141482

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S545-S549, 2014

Authors: Gates, Nicola J. | Sachdev, Perminder

Article Type: Research Article

Abstract: There is much interest in early intervention for the prevention or postponement of dementia in Alzheimer's disease (AD). The results of drug trials in this regard have thus far been disappointing, and non-pharmacological interventions are receiving increased attention. One such intervention is complex cognitive activity. Evidence from epidemiological studies suggests that participation in stimulating mental activities is associated with lowered dementia risk. The introduction of novel and complex cognitive interventions to healthy adults and those with cognitive impairment may represent an efficacious treatment option to improve cognition, lower dementia incidence, and slow rate of decline. This review examines the evidence …for restorative cognitive training (CT) and addresses a number of clinically relevant issues regarding cognitive benefit and its transfer and persistence. Although the number of randomized controlled trials is limited, preliminary evidence suggests that CT may provide immediate and longer term cognitive benefits which generalize to non-trained domains and non-cognitive functions, with supervised small group multi-domain training providing greatest benefits. Possible neuroplastic mechanisms are discussed, and recommendations for further research and clinical implementation provided. Show more

Keywords: Alzheimer's disease, cognitive intervention, cognitive training, treatment

DOI: 10.3233/JAD-141302

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S551-S559, 2014

Authors: García-Barroso, Carolina | Ugarte, Ana | Martínez, Martín | Rico, Alberto J. | Lanciego, José Luis | Franco, Rafael | Oyarzabal, Julen | Cuadrado-Tejedor, Mar | García-Osta, Ana

Article Type: Review Article

Abstract: Understanding the cellular and molecular processes involved in learning and memory will help in the development of safe and effective cognitive enhancers. The cAMP response element-binding (CREB) may be a universal modulator of processes required for memory formation, and increasing the levels of second messengers like cAMP and cGMP could ultimately lead to CREB activation. Phosphodiesterase (PDE) inhibitors regulate signaling pathways by elevating cAMP and/or cGMP levels, and they have been demonstrated to improve learning and memory in a number of rodent models of impaired cognition. The aim of this review is to summarize the outstanding progress that has been …made in the application of PDE inhibitors for memory dysfunction. In addition, we have introduced some recent data we generated demonstrating that tadalafil could be considered as an optimal candidate for drug re-positioning and as a good candidate to enhance cognition. Show more

Keywords: Cerebrospinal fluid, cGMP, memory enhancement, phosphodiesterase, tadalafil

DOI: 10.3233/JAD-141341

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S561-S573, 2014

Authors: O'Caoimh, Rónán | Kehoe, Patrick Gavin | Molloy, D. William

Article Type: Review Article

Abstract: With the rising prevalence of cognitive impairment worldwide, clinicians are facing important challenges managing dementia, particularly Alzheimer's disease, the most prevalent dementia subtype. Given that current treatments mainly offer symptomatic improvement, without altering disease progression, the challenge now is to identify and integrate new therapeutic strategies. Hypertension is increasingly recognized as a modifiable risk factor for mild cognitive impairment (MCI), the precursor of dementia. The renin angiotensin aldosterone system (RAAS) is central to blood pressure regulation and medications targeting RAAS inhibition are associated with reduced rates of both cognitive and functional decline in those with MCI and dementia. Angiotensin converting …enzyme inhibitors and angiotensin receptor blockers are widely prescribed anti-hypertensives acting on the RAAS, and there is growing evidence that they act centrally, possibly exerting their effects independent of their blood pressure lowering properties. The relationship is complex however, and given the risks associated with hypotension particularly in older adults, treatment with these agents may not benefit all. Additionally, current evidence is limited to preclinical and observational studies such that there is now a pressing need to confirm preliminary studies with properly conducted randomized control trials. Here, we review some of the salient and complex aspects of these observations to date. Show more

Keywords: Alzheimer's disease, angiotensin converting enzyme inhibitors, dementia, hypertension, mild cognitive impairment, renin angiotensin aldosterone system

DOI: 10.3233/JAD-141284

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S575-S586, 2014