Alzheimer's Disease: Detection, Prevention, and Preclinical Treatment (Guest Editor: Jack C. de la Torre)
Pages S327-S328
Preface
Jack C. de la Torre
Detection, Prevention, and Pre-Clinical Treatment of Alzheimer’s Disease
Detection
Pages S329-S338
Review
Blossom C.M. Stephan, Carol Brayne
Risk Factors and Screening Methods for Detecting Dementia: A Narrative Review
Abstract: Accurate detection of individuals with cognitive impairment and dementia in addition to identification of those at high risk of future disease is important to guide clinical care, and has research implications regarding clinical trial recruitment and development of dementia preventative strategies. In this narrative review, we describe new proposed criteria for early diagnosis of Alzheimer’s disease (AD). We also explore risk factors for dementia and evaluate methods for screening for increased risk of incident disease. We highlight variability in different diagnostic approaches. Additional work needs to be done to validate new methods across different settings (such as population-based, primary care, and memory clinics), age, and ethnic groups. Having an accurate method to assess for dementia and predict risk in routine clinical care will aid decision making and could ultimately lead to disease prevention.
Pages S339-S352
Review
Carol Yim-lui Cheung, Yi-Ting Ong, M. Kamran Ikram, Christopher Chen, Tien Yin Wong
Retinal Microvasculature in Alzheimer’s Disease
Abstract: Although cerebral small vessel disease has been implicated in the development of Alzheimer’s disease (AD), the cerebral microcirculation is difficult to visualize directly in vivo. As the retina and the brain share similar embryological origin, anatomical features and physiological properties with the cerebral small vessels, the retinal vessels thus offer a unique and easily accessible “window” to study the correlates and consequences of cerebral small vessel diseases in vivo. Retinal microvasculature can now be visualized, quantified and monitored non-invasively using state-of-the-art retinal imaging technology. Recent clinic- and population-based studies have demonstrated a link between retinal vascular changes and dementia, in particular AD, and cerebral small vessel disease. In this review, we summarize the current findings on retinal vascular changes such as retinopathy signs and changes in novel retinal vascular network parameters and retinal vascular caliber with dementia, cognitive dysfunction and cerebral small vessel disease, and discuss possible future research to further evaluate whether retinal vascular imaging might help to elucidate vascular mechanisms contributing to the development of AD and provide additional value in predicting who may be at risk of developing AD.
Pages S353-S363
Carole Dufouil, Sudha Seshadri, Geneviève Chêne
Cardiovascular Risk Profile in Women and Dementia
Abstract: There is growing evidence for the importance of cardiovascular risk factors in dementia development, including Alzheimer’s disease. As cardiovascular risk profiles vary greatly by gender, with men suffering a greater burden of cardiovascular risk in midlife, this could lead to differences in dementia risk. To explore current evidence on the association between components of the cardiovascular risk profile and dementia risk in women and men, we reviewed all studies reporting the risk of dementia associated with cardiovascular risk factors stratified by gender and found 53 eligible articles out of over 4,000 published since the year 2000. Consistent results were found: 1) for exposures acting specifically in women: overweight/obesity (harmful) and physical activity (protective), and 2) for exposures acting similarly in women and men: moderate alcohol (protective) and hypertension, diabetes, and depression (harmful). A modified effect of tobacco or high cholesterol/statin use remained controversial. Available data do not allow us to assess whether selection of men with healthier cardiovascular profile (due to cardiovascular death in midlife) could lead in late life either to a difference in the distribution of risk factors or to a differential effect of these risk factors by gender. We recommend that results on dementia risk factors, especially cardiovascular ones, be reported systematically by gender in all future studies. More generally, as cardiovascular risk profiles evolve over time, more attention needs to be paid to the detection and correction of cardiovascular risk factors, as early as possible in the life course, and as actively in women as in men.
Pages S365-S374
Review
Tomek Aleš, Urbanová Barbora, Hort Jakub
Utility of Transcranial Ultrasound in Predicting Alzheimer’s Disease Risk
Abstract: Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized by an increasing incidence. One of the pathologic processes that underlie this disorder is impairment of brain microvasculature. Transcranial ultrasound is a non-invasive examination of cerebral blood flow that can be employed as a simple and useful screening tool for assessing the vascular status of brain circulation in preclinical and clinical stages of AD. The objective of this review is to explore the utility of using a transcranial ultrasound to diagnose AD. With transcranial ultrasound, the most frequently studied parameters are cerebral blood flow velocities and pulsatility indices, cerebrovascular reserve capacity, and cerebral microembolization. On the basis of current knowledge, we recommend using as a transcranial Doppler sonography screening method of choice the assessment of cerebrovascular reserve capacity with breath-holding test.
Pages S375-S382
Sylvie Belleville, Céline Fouquet, Simon Duchesne, D. Louis Collins, Carol Hudon and the CIMA-Q group
Detecting Early Preclinical Alzheimer’s Disease via Cognition, Neuropsychiatry, and Neuroimaging: Qualitative Review and Recommendations for Testing
Abstract: In this paper, we review studies that have investigated whether neuropsychological, neuropsychiatric, and neuroimaging measures predict decline to Alzheimer’s disease (AD). Prospective neuropsychological studies indicate that cognitive performance may be an excellent indicator of future progression from mild cognitive impairment (MCI) to AD, particularly when episodic memory is combined with tasks relying on executive control and language tasks. Research on neuropsychiatric symptoms reveal that depression, apathy, anxiety, and sleep disturbances can contribute to predictive models, though their sensitivity is typically lower than that found with cognitive measures. Finally, different structural brain imaging markers reveal excellent predictive accuracy. The paper discusses issues that will have to be addressed in future studies. First, it will be necessary to increase the evaluation of combined markers, as this may considerably improve predictive accuracy. Second, it will be necessary to move to earlier stages than MCI in order to expand the detection window. Third, processes of compensation and plasticity will have to be better investigated as research moves into earlier stages. The Consortium for the early identification of AD-Quebec (CIMA-Q) is presented as an instance of this approach, and potential batteries of measures are proposed.
Pages S383-S391
Review
Maria Mataró, Juan José Soriano-Raya, Jorge López-Olóriz, Júlia Miralbell, Rosalia Dacosta-Aguayo
Cerebrovascular Markers in Lowered Cognitive Function
Abstract: Cerebrovascular disease (CVD) is a major cause of age-related cognitive decline and dementia. The identification of cognitive-related cerebrovascular markers is crucial in the early detection of individuals at high risk of cognitive decline. In vivo markers of CVD can help to characterize the underlying pathology, stage the progression of the disease, as well as identify and monitor candidates who could benefit from preventive interventions. We review the most common cerebrovascular markers of cognitive decline in subclinical individuals. These include neuroimaging, sonographic, and blood markers.
Pages S393-S400
Review
Marion Mortamais, Artero Sylvaine, Karen Ritchie
White Matter Hyperintensities as Early and Independent Predictors of Alzheimer’s Disease Risk
Abstract: There is growing evidence that vascular health plays a significant role in the etiology of clinical Alzheimer’s disease (AD). Understanding the timing of vascular changes in relation to progression from cognitive impairment to AD has become of increasing importance, being both possible pre-clinical markers and potentially modifiable risk factors. White matter hyperintensities (WMH) detected in vivo with magnetic resonance imaging, are commonly used to assess cerebrovascular burden in cognitive impairment and appear to be associated with an increased risk of cognitive decline due to many causes. The present review examines specifically the association between WMH and AD and its related biomarkers. Overall, current findings across the literature suggest that WMH may predict AD at least a decade before the clinical stage of the disease, independently of biomarkers of AD pathology, thus indicating that vascular factors may constitute important targets for pre-clinical detection and intervention.
Pages S401-S410
Review
Angelo Scuteri, HongYu Wang
Pulse Wave Velocity as a Marker of Cognitive Impairment in the Elderly
Abstract: Carotid-femoral pulse wave velocity (PWV), an index of large artery stiffness, is a good proxy of arterial aging and also an independent marker of cardiovascular disease. A consistently growing number of studies has shown a significant inverse association of arterial aging and cognitive function: the greater the PWV, the lower the cognitive performance (and the greater its decline over time)-regardless of heterogeneity in study populations, sample size, and measure of cognitive functions adopted in each study. Therefore the epidemiological evidence and the biological plausibility require adoption of strategies to foster the routine measurement of PWV and cognitive function measurements in each and every older subject, particularly those at higher cardiovascular risk. Consistently, limited available healthcare resources should be progressively shifted from a sterile differential diagnosis between Alzheimer-type and vascular dementia to interventions aimed to reduce PWV and, thus, to prevent dementia before its onset or to decrease its rate of progression.
Pages S411-S419
Review
Christina E. Wierenga, Chelsea C. Hays, Zvinka Z. Zlatar
Cerebral Blood Flow Measured by Arterial Spin Labeling MRI as a Preclinical Marker of Alzheimer’s Disease
Abstract: There is growing recognition that cerebral hypoperfusion is related to the pathogenesis of Alzheimer’s disease (AD), implicating the measurement of cerebral blood flow (CBF) as a possible biomarker of AD. The ability to identify the earliest and most reliable markers of incipient cognitive decline and clinical symptoms is critical to develop effective preventive strategies and interventions for AD. Arterial spin labeling (ASL) magnetic resonance imaging (MRI) measures CBF by magnetically labeling arterial water and using it as an endogenous tracer. Studies using ASL MRI in humans indicate that CBF changes are present several years before the development of the clinical symptoms of AD. Moreover, ASL-measured CBF has been shown to distinguish between cognitively normal individuals, adults at risk for AD, and persons diagnosed with AD. Some studies indicate that CBF may even be sensitive for predicting cognitive decline and conversion to mild cognitive impairment and AD over time. Taken together, evidence suggests that the current staging models of AD biomarker pathology should incorporate early changes in CBF as a useful biomarker, possibly present even earlier than amyloid-β accumulation. Though still a research tool, ASL imaging is a promising non-invasive and reliable method with the potential to serve as a future clinical tool for the measurement of CBF in preclinical AD.
Pages S421-S429
Dietmar Rudolf Thal, Johannes Attems, Michael Ewers
Spreading of Amyloid, Tau, and Microvascular Pathology in Alzheimer’s Disease: Findings from Neuropathological and Neuroimaging Studies
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 independently from biomarker levels of Aβ to 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.
Prevention
Pages S431-S442
Review
Jack C. de la Torre
In-House Heart-Brain Clinics to Reduce Alzheimer’s Disease Incidence
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.
Pages S443-S451
Review
Mark A. van Buchem, Geert Jan Biessels, Hans Peter Brunner la Rocca, Anton J.M. de Craen, Wiesje M. van der Flier, M. Arfan Ikram, L. Jaap Kappelle, Peter J. Koudstaal, Simon P. Mooijaart, Wiro Niessen, Robert van Oostenbrugge, Albert de Roos, Albert C. van Rossum, Mat J.A.P. Daemen
The Heart-Brain Connection: A Multidisciplinary Approach Targeting a Missing Link in the Pathophysiology of Vascular Cognitive Impairment
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.
Pages S453-S461
Anna Poggesi, Emilia Salvadori, Raffaella Valenti, Serena Nannucci, Laura Ciolli, Francesca Pescini, Marco Pasi, Fabio Fierini, Ida Donnini, Sandro Marini, Guido Chiti, Valentina Rinnoci, Domenico Inzitari, Leonardo Pantoni
The Florence VAS-COG Clinic: A Model for the Care of Patients with Cognitive and Behavioral Disturbances Consequent to Cerebrovascular Diseases
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.
Pages S463-S473
Review
Kaarin J. Anstey, Ranmalee Eramudugolla, Roger A. Dixon
Contributions of a Risk Assessment Approach to the Prevention of Alzheimer’s Disease and Dementia
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.
Pages S475-S482
Review
Maria Cristina Polidori
Preventive Benefits of Natural Nutrition and Lifestyle Counseling against Alzheimer’s Disease Onset
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.
Pages S483-S493
Review
Benjamin M. Hampstead, Caterina B. Mosti, Thomas Swirsky-Sacchetti
Cognitively-Based Methods of Enhancing and Maintaining Functioning in Those at Risk of Alzheimer’s Disease
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.
Pages S495-S502
Review
Ze Wang
Characterizing Early Alzheimer’s Disease and Disease Progression Using Hippocampal Volume and Arterial Spin Labeling Perfusion MRI
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.
Pages S503-S514
Review
Adina Zeki Al Hazzouri, Kristine Yaffe
Arterial Stiffness and Cognitive Function in the Elderly
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.
Pages S515-S523
Review
Octavio Rodríguez-Gómez, M. Eugenia Palacio-Lacambra, Antonio Palasí-Franco, Agustín Ruiz-Laza, Mercè Boada-Rovira
Prevention of Alzheimer’s Disease: A Global Challenge for Next Generation Neuroscientists
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.
Pre-Clinical Treatment
Pages S525-S535
Allison Auchter, Justin Williams, Bryan Barksdale, Marie H. Monfils, Francisco Gonzalez-Lima
Therapeutic Benefits of Methylene Blue on Cognitive Impairment during Chronic Cerebral Hypoperfusion
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.
Pages S537-S544
Review
Paula Grammas, Joseph M. Martinez
Targeting Thrombin: An Inflammatory Neurotoxin in Alzheimer’s Disease
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. Next generation 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.
Pages S545-S549
Review
Michael S. Rafii
Preclinical Alzheimer’s Disease Therapeutics
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.
Pages S551-S559
Nicola J Gates, Perminder Sachdev
Is Cognitive Training an Effective Treatment for Preclinical and Early Alzheimer’s Disease?
Abstract: There is much interest in early intervention for the prevention or postponement of dementia in Alzheimer’s disease (AD). The results of drugs 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.
Pages S561-S573
Review
Carolina García-Barroso, Ana Ugarte, Martín Martínez, Alberto J. Rico, José Luis Lanciego, Rafael Franco, Julen Oyarzabal, Mar Cuadrado-Tejedor*, Ana García-Osta* *These authors contributed equally to this work.
Phosphodiesterase Inhibition in Cognitive Decline
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.
Pages S575-S586
Review
Rónán O’Caoimh, Patrick Gavin Kehoe, D. William Molloy
Renin Angiotensin Aldosterone System Inhibition in Controlling Dementia-Related Cognitive Decline
Abstract: With the rising prevalence of cognitive impairment worldwide clinicians are facing important challenges managing dementia, particularly Alzheimer’s disease (AD), 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, and established AD. 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 AD. 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.
