Several progressive neurologic disorders begin with cognitive decline or parkinsonism, notably Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). We used positron emission tomography (PET) in attempts to differentiate these disorders.
We performed PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) to examine blood-to-brain ligand transport (K(1)) and striatal monoaminergic presynaptic binding (distribution volume [DV]) in 25 DLB, 30 PD, and 25 AD patients and 57 elderly controls (NC).
[11C]DTBZ DV was decreased significantly in caudate nucleus, anterior putamen, and posterior putamen in DLB and PD compared with AD and NC. DLB and PD groups showed an anterior-to-posterior gradient of binding loss relative to NC, least in caudate nucleus and largest in posterior putamen. The gradient was significantly steeper in PD than DLB. Both PD and DLB showed significantly greater interhemispheric striatal binding asymmetry than NC, and PD had greater asymmetry than DLB. Cerebral cortical [11C]DTBZ K(1) was decreased diffusely by 4% to 8% in PD. Larger K(1) deficits occurred in AD and DLB temporoparietal and prefrontal association cortices and posterior cingulate cortex. Greater reduction of K(1) occurred in occipital cortex in DLB than AD. Receiver operating characteristic curve analyses distinguished DLB from AD more effectively on the basis of striatal DV than occipital K(1) and distinguished DLB from PD more effectively on the basis of cerebral cortical K(1) than striatal DV patterns. Overall, 90% of cases were properly classified by combining these measures.
PET with [11C]DTBZ can differentiate DLB from both PD and AD in a single neuroimaging study.
The costs of care for patients with Alzheimer's disease are correlated with key measures of disease severity. This relationship is important in the economic evaluation of new treatments and is used to translate treatment efficacy into effects on costs through economic modeling. We aimed to identify what measures of disease severity are the most important predictors of societal costs of care and whether their relationship differs across countries.
Interviews were conducted with 1222 patient and caregiver pairs residing in the community or in residential care settings in Spain, Sweden, United Kingdom, and the United States. Assessments included costs of care (Resource Utilization in Dementia) and key disease severity measures: cognitive function (Mini-Mental State Examination), ability to perform Activities of Daily Living (ADL-ability, Disability Assessment for Dementia [DAD]), and behavioral symptoms (Neuropsychiatry Inventory (NPI)-severity).
ADL-ability was the most important predictor of societal costs of care of community-dwelling patients in all countries. A one-point decrease in DAD resulted in a 1.4% increase in costs of care in Spain, United Kingdom, and the United States on average, and a 2% increase in Sweden. This translated into a 45% increase from a standard deviation decrease in DAD on average. NPI-severity and Mini-Mental State Examination were also significant predictors but with lesser effect. Although mean costs of care differed across countries, the important predictors were the same.
ADL-ability is the most important predictor of societal costs of care in community dwellings irrespective of country and should therefore be central in the economic evaluation of Alzheimer's disease therapies.
Early, accurate diagnosis of dementia with Lewy bodies (DLB), in particular its differentiation from Alzheimer's disease, is important for optimal management, providing patients/carers with information about the likely symptomatology and illness course, allowing initiation of effective pharmacotherapy, and avoiding the consequences of neuroleptic sensitivity. Clinical diagnosis of DLB has high specificity but low sensitivity. Clinical trials of [(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computed tomography ([(123)I]FP-CIT SPECT) indicate high positive and negative percent agreement with reference to clinical diagnosis, and high sensitivity and specificity in patients with neuropathologically confirmed diagnoses of DLB. An abnormal [(123)I]FP-CIT SPECT image in patients fulfilling criteria for possible DLB advances the certainty of a diagnosis to probable DLB. [(123)I]FP-CIT SPECT, by identifying the striatal dopaminergic deficit, can be a valuable diagnostic aid and can provide support to a clinical diagnosis of DLB in patients with dementia. The technique is likely to be of particular utility in patients with dementia with an uncertain diagnosis.
To evaluate the contributions of amyloid-positive (Am+) and medial temporal atrophy-positive (MTA+) scans to the diagnostic classification of prodromal and probable Alzheimer's disease (AD).
(18)F-flutemetamol-labeled amyloid positron emission tomography (PET) and magnetic resonance imaging (MRI) were used to classify 10 young normal, 15 elderly normal, 20 amnestic mild cognitive impairment (aMCI), and 27 AD subjects. MTA+ status was determined using a cut point derived from a previous study, and Am+ status was determined using a conservative and liberal cut point.
The rates of MRI scans with positive results among young normal, elderly normal, aMCI, and AD subjects were 0%, 20%, 75%, and 82%, respectively. Using conservative cut points, the rates of Am+ scans for these same groups of subjects were 0%, 7%, 50%, and 93%, respectively, with the aMCI group showing the largest discrepancy between Am+ and MTA+ scans. Among aMCI cases, 80% of Am+ subjects were also MTA+, and 70% of amyloid-negative (Am-) subjects were MTA+. The combination of amyloid PET and MTA data was additive, with an overall correct classification rate for aMCI of 86%, when a liberal cut point (standard uptake value ratio = 1.4) was used for amyloid positivity.
(18)F-flutemetamol PET and structural MRI provided additive information in the diagnostic classification of aMCI subjects, suggesting an amyloid-independent neurodegenerative component among aMCI subjects in this sample.
Demonstration of a disease-modifying effect of a therapeutic agent on Alzheimer's disease (AD) requires a trial lasting for at least 18 months. An understanding of expected rates of adverse events (AEs), overall discontinuations, and discontinuations due to AEs, serious AEs, and deaths would be useful in planning such trials.
We examined safety information for patients taking placebo from five published 18-month AD trials and for patients from the Alzheimer's Disease Neuroimaging Initiative study.
AEs reported consistently across multiple studies were dyspnea (occurring in 5.3%-5.8% of patients), headache (4.0%-5.5%), constipation (4.3%-4.7%), nausea (2.0%-5.8%), joint swelling (3.6%-3.7%), vomiting (3.6%-3.7%), and anxiety (3.2%-3.6%). Larger multinational studies, as compared with smaller studies with fewer sites and geographies, demonstrated greater overall discontinuations (24.6%-33.0% vs 8.2%-21.0%) and greater discontinuations due to AEs (9.5%-11.6% vs 2.7%-3.2%). Rates of death (1.8%-2.4%) and SAEs (19.9%-21.2%) were consistent across 18 month published studies and in ADNI; fall was the most common SAE (2.6%-4.0%) where SAEs were reported.
In general, comparable types of AEs, frequency of deaths, and serious AEs were seen for patients taking placebo in five randomized, controlled 18-month AD trials and in Alzheimer's Disease Neuroimaging Initiative, whereas rates of discontinuations were more variable. Evaluation across studies was complicated by inconsistent methods of reporting safety information. Evaluation of large databases of placebo patients from therapeutic AD trials is needed to further enhance the understanding of expected safety outcomes in clinical trials of AD patients.
We wished to develop a highly selective positron emission tomography (PET) imaging agent targeting PHF-tau in human Alzheimer's disease (AD) brains.
To screen potential tau binders, human AD brain sections were used as a source of native paired helical filament (PHF)-tau and Aβ rather than synthetic tau aggregates or Aβ fibrils generated in vitro to measure the affinity and selectivity of [(18)F]T807 to tau and Aβ. Brain uptake and biodistribution of [(18)F]T807 in mice were also tested.
In vitro autoradiography results show that [(18)F]T807 exhibits strong binding to PHF-tau-positive human brain sections. A dissociation constant (Kd) of [(18)F]T807 (14.6 nM) was measured using brain sections from the frontal lobe of AD patients. A comparison of autoradiography and double immunohistochemical staining of PHF-tau and Aβ on adjacent sections demonstrated that [(18)F]T807 binding colocalized with immunoreactive PHF-tau pathology, but did not highlight Aβ plaques. In vivo studies in mice demonstrated that [(18)F]T807 was able to cross the blood-brain barrier and washed out quickly.
[(18)F]T807 demonstrates high affinity and selectivity to PHF-tau as well as favorable in vivo properties, making this a promising candidate as an imaging agent for AD.
Florbetapir ((18)F) for brain amyloid positron emission tomography (PET) imaging has been recently approved in Europe to estimate β-amyloid neuritic plaque density in the brain when the subject is still alive. Such density is one of the key issues for the definitive diagnosis of Alzheimer's disease (AD) at autopsy. This capability of florbetapir ((18)F) is regarded as a significant improvement in the diagnostic procedures for adult patients with cognitive impairment who are being evaluated for AD and other causes of cognitive impairment. The current paper highlights the specific characteristics of the European marketing authorization of florbetapir ((18)F).
Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG-PET) thus far rarely has been used to advance the development of new treatments for Alzheimer's disease (AD). Now that FDG-PET with standard acquisition protocols for dementia is widely available, change in cerebral glucose metabolism is a feasible outcome variable for clinical drug trials. Individual analysis of FDG-PET results also might prove valuable. FDG-PET can detect metabolic changes very early in the course of AD and identify subjects for earlier treatment. FDG-PET reliably distinguishes AD from frontotemporal dementia so that only those most likely to benefit are enrolled in trials. Finally, objectively identifying phenotypic variations of AD with FDG-PET might have pathogenic and prognostic implications that can be used for personalized treatment approaches. The judicious use of FDG-PET is needed to accelerate the evaluation of promising new drugs and more rationally target treatments for dementing diseases.
The association between lifelong body mass index (BMI) and cognitive function has not been comprehensively studied.
In more than 2000 men and women born in 1946, we tested associations between BMI gain at 15, 20, 26, 36, 43, and 53 years with respect to the previous measure (gain at age 15 years with respect to BMI at age 11 years), and semantic fluency (animal naming) and cognitive reserve (the National Adult Reading Test) at age 53 years, and verbal memory (word list recall) and speed/concentration (letter cancellation) at ages 43 and 53 years. Measures of BMI gain were adjusted in stages for childhood intelligence, education, socioeconomic position (SEP), lifestyle, and vascular risk factors.
Independent of childhood intelligence, BMI gain between ages 26 and 36 years was associated with lower memory scores (β per SD increase in BMI in men = −0.11; 95% confidence interval [CI]: −0.19, −0.02), verbal fluency (β in women = −0.11; 95% CI: −0.20, −0.02), and lower National Adult Reading Test score (β in women = −0.08; 95% CI: −0.15, −0.01), but not with speed/concentration (β in men = 0.02; 95% CI: −0.11, 0.07). Associations were largely explained by educational attainment and SEP (P ≥ .10). However, BMI gain at 53 years in men was independently associated with better memory (β = 0.12; 95% CI: 0.03, 0.22), and both underweight (β = −1.54; 95% CI: −2.52, −0.57) and obese (β = −0.30; 95% CI: −2.52, −0.57) women at 53 years had significantly lower memory scores.
The adverse effect of higher BMI gain on midlife cognitive function and cognitive reserve is independent of childhood intelligence but not of education and SEP. The independent association between greater BMI gain in midlife and better cognitive function deserves further investigation.
This study compares age-specific and overall prevalence rates for dementia and Alzheimer's disease (AD) in two nonoverlapping, population-based cohorts of elderly African Americans in Indianapolis in 2001 and 1992.
We used a two-stage design. The first stage involves the Community Screening Interview for Dementia (CSI-D). The CSI-D scores are grouped into good, intermediate, and poor performance before selection for clinical assessment. Diagnoses were performed using standard criteria in a consensus diagnosis conference; clinicians were blind to performance groups. In 1992, interviewers visited randomly sampled addresses to enroll self-identified African Americans aged > or =65 years. Of 2582 eligible, 2212 enrolled (9.6% refused, and 4.7% were too sick). In 2001, Medicare rolls were used for African Americans aged >70 years. Of 4260 eligible, 1892 (44%) enrolled, 1999 (47%) refused, and the remainder did not participate for other reasons.
The overall age-adjusted prevalence rate for dementia at age > or =70 years in 2001 was 7.45% (95 confidence interval [CI], 4.27-10.64), and in the 1992 cohort, this prevalence rate was 6.75% (95% CI, 5.77-7.74). The overall age-adjusted prevalence rate at age > or =70 years for AD in the 2001 cohort was 6.77% (95% CI, 3.65-9.90), and for the 1992 cohort, it was 5.47% (95% CI, 4.51-6.42). Rates for dementia and AD were not significantly different in the two cohorts (dementia, P = .3534; AD, P = .2649).
We found no differences in the prevalence rates of dementia and AD between 1992 and 2001, despite significant differences in medical history and medical treatment within these population-based cohorts of African American elderly.
To better understand the status of frontotemporal dementia (FTD) research, and identify opportunities to accelerate translational research, we analyzed international funding for FTD and related dementias between 1998 and 2008.
Search terms were compiled to define the clinical spectrum of FTD and all known mechanisms. Funders were asked to return grants that contained these search terms in the title or abstract. Grants were classified according to the most reasonably achieved stated aim using a classification scheme of research activities that was developed to map grants along the continuum from basic research to clinical trials of treatments.
This analysis captured 613 grants ($432,167,275), from 19 private and public funders from 7 countries and the European Union. National Institutes of Health contributed $360 million (MM), 53% of grants and 83% of total funding. Foundations contributed $43 MM, 35% of grants and 10% of total funding, an increase in recent years. A total of $319 MM (74%, funding) went toward basic research, of which 10% was dedicated to preclinical treatment development, clinical treatment evaluation, and developing detection, diagnostic, and imaging technologies and reagents.
FTD received moderate funding over the past decade, which has decreased almost five-fold during this period. A sizable proportion of FTD funding supported mechanisms shared with Alzheimer's disease. Few programs advanced past validating target models and into drug discovery and preclinical development, indicating that the knowledge gained from recent research has still not advanced into treatment development. Quantitative analysis of funding highlighted under-resourced areas as well as redundant efforts, enabling a more strategic approach toward advancing FTD drug discovery and development.
Alzheimer's disease (AD) is the most common cause of dementia; the main risk factors are age and several recently identified genes. A major challenge for AD research is the early detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy ((1)H-MRS), a noninvasive technique that evaluates brain chemistry in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD.
We studied 75 subjects from the largest multigenerational pedigree in the world (∼5000 people) that segregates a unique form of early-onset Alzheimer's disease (EOAD) caused by a fully penetrant mutation in the Presenilin-1 gene (PSEN1 p.Glu280Ala [E280 A]). Forty-four subjects were carriers of the mutation, and 31 were noncarriers. Seventeen carriers had either mild cognitive impairment (MCI) or early-stage AD (collectively MCI-AD). In right and left parietal white mater and parasagittal parietal gray matter (RPPGM and LPPGM) of the posterior cingulate gyrus and precuneus, we measured levels of the brain metabolites N-acetylaspartate (NAA), inositol (Ins), choline (Cho), and glutamate-glutamine complex (Glx) relative to creatine (Cr) levels (NAA/Cr, Ins/Cr, Cho/Cr, and Glx/Cr, respectively) with two-dimensional (1)H-MRS. Using advanced recursive partition analysis and random forest analysis, we built classificatory decision trees for both mutation carrier status and the presence of MCI-AD symptoms, fitting them to (1)H-MRS data while controlling for age, educational level, and sex.
We found that (1) the combination of LPPGM Cho/Cr <0.165 and RPPGM Glx/Cr >1.54 fully excluded carriers; (2) LPPGM Cho/Cr >0.165, RPPGM Glx/Cr <1.54, and left parietal white mater NAA/Cr >1.16 identified asymptomatic carriers with sensitivity of 97.7% and specificity of 77.4%; and (3) RPPGM NAA/Cr >1.05 defined asymptomatic subjects (independent of carrier status) with sensitivity of 100% and a specificity of 96.6%.
Brain metabolites measured by (1)H-MRS in the posterior cingulate gyrus and precuneus are optimally sensitive and specific potential noninvasive biomarkers of subclinical emergence of AD caused by the PSEN1 p.Glu280Ala (E280 A) mutation.
The Australian Pharmaceutical Benefits Scheme (PBS) first subsidized cholinesterase inhibitors (CEIs) for Alzheimer's disease in 2001, introducing a novel therapy for a previously untreatable common condition. This study aims to determine Australian rates of CEI use and to assess equality of access to treatment based on socioeconomic status and geographic remoteness.
Pharmaceutical claims records were used to identify all Australians prescribed CEIs between January 2003 and December 2010. Age-standardized and sex-adjusted index prescription rates were derived using the total Australian population as the denominator to examine temporal trends and the impacts of socioeconomic and geographic disadvantage on CEI index prescription rates.
Index prescription rates peaked in 2004 at 92.5 per 100,000 person-years, declining to between 70.2 and 73.5 for years 2006 to 2010. Rates were highest in the 85- to 89-year age group and 2.6-fold higher in the least socioeconomic disadvantaged population when compared with the most disadvantaged population. In major cities in Australia, index prescription rates were 1.4 to 1.7 times greater compared with remote areas.
Increasing geographic remoteness and socioeconomic disadvantage are associated with lower CEI index prescription rates, indicating inequities in the management of Alzheimer's disease in Australia.
The aim of this report was to estimate the worldwide cost of dementia in 2005 from a societal viewpoint.
Costs were estimated by combining prevalence estimates, country and region specific data on Gross Domestic Product per person, and average wage with results from previously published cost-of-illness studies in different countries. Direct medical and nonmedical costs as well as costs for informal care were included.
The total worldwide societal cost of dementia, on the basis of a dementia population of 29.3 million persons, was estimated to be US$315.4 billion in 2005, including US$105 billion for informal care (33%). Seventy-seven percent of the total costs occurred in the more developed regions, with 46% of the prevalence.
Worldwide costs for dementia are enormous, and informal care constitutes a major cost component, in particular in less developed regions. The health economics of dementia is a highly relevant area for further research.
A comprehensive and useful initiative has been performed by our Canadian colleagues. The subjects presented are under active discussion in many countries, with the goal of direct applications in daily clinical practice. The review provided by this special issue of the Journal will therefore be very useful for all. In this commentary we will not discuss all papers, but will underline only some important points concerning mild cognitive impairment and the diagnosis and management of Alzheimer's disease.
There are many groups and organizations across the government, private, and nonprofit sectors that are passionately engaged in the fight against Alzheimer's disease (AD), but they have constraints on their funding and scope and, therefore, cannot tackle the problem holistically. Addressing the complexities of this epidemic strategically will require the collective efforts of committed stakeholders. Individuals and organizations must work together to identify mutual interests and forge new relationships and partnerships. Through this network of stakeholders, known as a megacommunity, individual members can support and expand their objectives and impact through the combined knowledge and resources in the megacommunity network. Leaders Engaged on Alzheimer's Disease (LEAD) is an example of a megacommunity tackling the toughest issues facing AD patients and their families. LEAD is currently comprised of more that thirty individuals and organizations committed to sharing information and coordinating action across organizational boundaries.
Frequent review and update of guidelines are necessary for them to remain current and useful for clinical practices. This second revision of the postdiagnostic management of Alzheimer's disease (AD) guideline by the California Workgroup was prompted by significant advances in knowledge about appropriate care management, including pharmacologic and nonpharmacologic approaches to treatment of the disease, accompanying behavioral problems, and functional decline. The focus remains explicitly on primary care, where the majority of it occurs for those with AD and other dementias.
In all, 40 experts in dementia care were recruited from a variety of disciplines across California. Four workgroups were created that reviewed recent research findings from a total of 569 publications since 2002. The revised Guideline incorporates 305 new references, including 11 state and federal laws, in addition to 78 references from the previous version.
The Guideline is divided into four sections that address postdiagnostic management: (1) assessment, (2) treatment, (3) patient and family education and support, and (4) legal considerations associated with AD. Significant revisions and changes in each area and the underlying research to support the recommendations are presented in this article. New topics related to early stage and end-of-life were identified and recommendations were developed for these specific populations.
The Guideline recommendations provide a framework to inform and improve medical care for AD by primary health care providers.
A federally funded, nonprofit research and development corporation is needed to directly address preventing cognitive impairment and Alzheimer's disease. The corporation would bring resources to bear on the crisis by directly managing and expanding informatics, research, prevention, treatment development, and health care, with the overarching goals of preventing, delaying, and minimizing cognitive impairments and behavioral effects and prolonging and enhancing quality of life. The undertaking will have profound and unanticipated salutary effects. This proposal-modest as it is-responds to President Obama's call for bold and swift action to create jobs, to lay a new foundation for growth, restoring and advancing science, by using technology "to raise health care's quality and lower its costs" . It supports the administration's goal to help families continue to pursue their work, with health care that works and with a retirement that is dignified; and it should not be judged by whether it is too big but by whether it works .
This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.
A key component of the mission of the National Institute on Aging (NIA) is to diminish the public-health burden posed by diseases of aging, and Alzheimer’s disease (AD) in particular. The NIA’s Division of Neuroscience (formerly the Neuroscience and Neuropsychology of Aging Program) has a longstanding interest and commitment to supporting translational research for AD that goes back to 1991 when the first AD Drug Discovery Request for Applications (RFA) was issued. In 2004, as a result of a process aimed at establishing measureable agency performance goals, the Office of Management and Budget selected the following performance target goal for the NIA: ‘‘To identify at least one intervention that would delay the onset or slow the progression of AD by 2013.’’ In response to this charge, the NIA’s Division of Neuroscience began a series of program-development activities and initiatives aimed at creating a robust AD translational research program. Here we provide a summary of the NIA’s current translational research initiatives and related programs.** In 2004, the NIA launched an exploratory R21 grants program for early drug discovery for AD (http://grants.nih.gov/ grants/guide/pa-files/PAS-06-261.html), in collaboration with the Institute for the Study of Aging/Alzheimer’s Drug Discovery Foundation (ISOA/ADDF; www.alzdiscovery. org). In 2005, a U01 cooperative agreement program was initiated for preclinical drug development of small molecules and biologics for the treatment of AD, mild cognitive impairment (MCI), and age-related cognitive decline (http://grants. nih.gov/grants/guide/pa-files/PAR-08-266.html). Funding for these initiatives was secured through an NIA director’s set-aside through the end of 2009, at which point the support will likely transition to mainstream NIA funding. These programs provide a critical investment in the early steps of AD drug discovery and preclinical drug development, because they are the most risky steps and are unlikely to be pursued by the pharmaceutical industry.
Despite enormous worldwide public and private interest in improving the prevention and treatment of Alzheimer's disease (AD), we have not made as much of an impact as we would like, and the number of affected individuals continues to grow. Even more alarmingly, whereas global efforts to identify AD cases and to develop new treatments are increasing, patient-care options are disappearing, so that even if a highly efficacious therapy or prevention approach arose, it would not be used effectively. As a first step toward organizing a better way forward, we should establish AD centers of excellence that mandate both patient care and research in the same setting. These centers would benefit from changes in public health policies related to chronic-disease surveillance, Center for Medicare and Medicaid Services funding for the care of chronic diseases, institutional review boards, good clinical practice guidelines, National Institutes of Health regulations for the use of research funds, Food and Drug Administration guidelines for the approval of AD drugs, and Department of Commerce regulations related to patent protection of AD diagnostic aids and treatments. This new form of AD centers of excellence would also provide direct care to many patients and their families, model care for communities and medical trainees, enhance the voluntary recruitment of AD patients to clinical trials, and improve our understanding of AD and its management.
Autosomal dominant familial Alzheimer's disease (FAD) of young onset due to alterations in the PSEN1, APP, and PSEN2 genes is a fully-penetrant and devastating condition. As the subsequent development of AD in persons inheriting such genes is essentially certain, the condition provides a unique opportunity to perform informative studies of interventions with potential for preventing the disease. Though feasible, there are many challenges to such an endeavor including the fact that most persons at-risk for FAD do not desire to know their genetic status. Other challenges include the time course over which a preventative treatment would need to be administered and potential limitations to the degree to which the knowledge gained might be validly generalized to the more common late-onset AD. In this paper we discuss issues of study design including power estimates, protocols in which subjects' genetic status is not revealed to them, and the advantage of one-time interventions such as vaccinations. Though addressed in the context of FAD, many of the issues discussed are relevant to other fully-penetrant autosomal dominant degenerative illnesses such as Huntington's disease. We also discuss important next steps including the performance of pre-clinical studies in model systems appropriate for FAD and the recently funded international Dominantly Inherited Alzheimer Network (DIAN). The goals of the DIAN are to characterize the natural history of FAD and to establish the infrastructure that would be required to perform meaningful studies in this rare, widely dispersed, but informative population.
A major barrier to progress in Alzheimer's disease treatment research is the increasingly difficult task of recruiting elderly participants into clinical trials. We conducted an anonymous online survey of 676 adults (average age, 50 years) to examine perceived trust in different components of our healthcare-delivery and clinical-research systems, as well as willingness to participate in clinical trials. Respondents indicated the greatest amount of trust in family members, followed by family physicians. Only 3% of respondents "completely" trusted clinical researchers, whereas 62% of respondents trusted them "somewhat" to care for them during the course of a clinical trial. Trust in clinical researchers was modestly negatively correlated with income (r = -0.165, P < .001), but was not significantly related to sex, race, or education. Respondents indicated the least amount of trust in industry sponsors, followed by regulatory authorities.
The focus of the 2008 Leon Thal Symposium was to identify issues and changes that might be facilitated by government agencies, industry, or the academic research community that might move the field forward: “Big Asks” for fundamental shifts in the way we deal with Alzheimer's disease (AD) research. These items are therefore aimed at macro rather than molecular changes, but their impact will carry to the molecular level of research to increase our understanding of etiology and treatment of AD and associated disorders.
Because no effective curative approaches are available, preventive approaches in the field of Alzheimer's disease (AD) are needed. We present the design of the ongoing Multidomain Alzheimer Preventive Trial (MAPT) Study. Several previous studies suggested that many factors may be involved in the occurrence of AD at late ages. Because of the probable multifactorial nature of AD, it seems logical to initiate multidomain interventions to examine their potential synergistic effects. The MAPT Study aims to evaluate the efficacy of a multidomain intervention (nutritional, physical, and cognitive training) and omega 3 treatment in the prevention of cognitive decline in frail elderly persons aged 70 years or over. The study also collects imaging and biological data that could be used in future AD prevention and treatment trials.
The MAPT Study is a 3-year, randomized, controlled trial conducted by university hospital practitioners specializing in memory disorders in four French cities (Bordeaux, Limoges, Montpellier, and Toulouse). The study plans to enroll 1200 frail elderly subjects on the basis of at least one of the following criteria: subjective memory complaint spontaneously expressed to a general practitioner, limitation in one instrumental activity of daily living (IADL), and slow walking speed. To demonstrate the protective effect of interventions, subjects are randomized into one of the following four groups: omega 3 alone, multidomain intervention alone, omega 3 plus multidomain intervention, or placebo (n = 300 each). The principal outcome measure is a change in cognitive function at 3 years, as determined by the Grober and Buschke Test.
The MAPT Study is the first preventive trial involving multidomain interventions. Final results should be available in 2013.
Among the many contributions of Leon Thal to the field of Alzheimer’s disease (AD) research was his leadership in developing the clinical trial network required for accelerating the testing of new potential therapies. He co-founded the Alzheimer’s Disease Cooperative Study to serve the public need for promising new treatments for AD . The Leon Thal Symposium, held in December 2008, was structured around five major public policy initiatives designed to advance the study of new therapeutics for AD. Participants in the symposium were charged with formulating specific recommendations for an action plan for the Alzheimer’s Study Group (ASG). The final recommendations will be used by the ASG as part of the National Strategic Plan for Alzheimer’s, which will be forwarded to the 111th U.S. Congress . We propose in this commentary that recommendations for the strategic plan include the Medicare program to increase public awareness of AD clinical trials and provide information on how potential study participants can enter AD clinical trials. (Medicare is the largest U.S. health insurance program and covers nearly 40 million Americans. It is for people aged 65 years or older, some disabled people younger than age 65, and people with end-stage renal disease.)
Advancing the development of drugs for the prevention and treatment of Alzheimer's disease (AD) is dependent on the ability of investigators to identify, recruit, and retain appropriate subjects in clinical trials. Innovations in care that link primary-care providers with AD researchers can help overcome barriers to early, specific diagnosis and access to research studies. Collaborative care provides a new paradigm for the mutual benefit of patients, providers, and AD research. Recommendations to achieve this goal include funding clinical centers of excellence in AD, linked with community physicians to utilize clinical care and initial evaluations as early entry points for patients into AD research, and funding mini-fellowships for community physicians. Reimbursement for dementia care should be expanded to include periodic cognitive assessments for at-risk individuals, medically directed dementia education, and diagnostic imaging and biomarkers. These innovations can simultaneously improve the translation of research advances, and benefit AD research.
As the field of aging and dementia evolves, it becomes apparent that there are likely multiple underlying continua of clinical and pathological substrates that characterize progression. On the clinical side, there is a natural progression from normal cognition through mild cognitive impairment (MCI) to dementia. Correspondingly, on the neuropathological side, there is a gradual accumulation of pathological markers that likely develop over years and probably decades. The challenge is to develop reliable and valid correspondences between the clinical features and the underlying neuropathological markers that are consistent and meaningful. Numerous studies have demonstrated that clinically normal individuals, late in life, can harbor significant pathology in the brain, and, conversely, some individuals who are demented have relatively little demonstrable pathology[1–3]. The correlations are imperfect.
Currently, we make arbitrary distinctions among clinical categories such as normal aging, MCI and dementia. While we all recognize the artificiality of dividing a continuum into discrete categories, the exercise does serve a purpose in allowing us to communicate the clinical significance of findings to patients and also promotes interactions among physicians and scientists[4–6]. Similarly, from a neuropathological perspective, we make arbitrary distinctions regarding the meaningfulness of the development of amyloid deposits in the brain and the spread of neurofibrillary tangles throughout the brain. Again, while certain demarcations are necessary for communication, the clinical significance of the development and spread of these markers needs to be clarified. As mentioned, the clinical-pathological correspondence between these two continua is variable.
This type of discussion begs for the development of a collection of persons across the age spectrum on whom extensive demographic, clinical, imaging and biomarker data would be available. It is only through the longitudinal study of all of these measures in concert that we will be able to untangle these important questions regarding the development and progression of diseases of aging.
There is growing consensus in the field of Alzheimer's disease (AD) research that it may be difficult to develop drugs that can reverse the neuronal damage caused by the disease once symptoms are severe enough to be diagnosable. Therefore, the goal has shifted toward identification of individuals earlier in the disease process, when symptoms are very mild, as well as identification of asymptomatic, high-risk individuals so that they can be targeted for prevention and early intervention.
In other fields, risk indices are often used to identify individuals who are asymptomatic but high-risk. Risk indices, also known as prognostic models, are tools that are used to predict the likelihood that an individual will experience a given event within a given time frame. Usually, this is accomplished by combining information from several different individual risk factors into a summary score. The prognostic accuracy of risk indices is typically assessed based on the area under the receiver operating characteristic (ROC) curve, also known as the c statistic . The ROC curve is a graph of the true-positive rate (sensitivity) by the false-positive rate (1-specificity), and it is related to the relative probability that in all possible pairs of subjects in which one had the outcome and one didn't, the one with the outcome would receive a higher risk score. The c statistic may range from 0 to 1, with 0.5 reflecting predictive accuracy no better than chance and 1 reflecting perfect discrimination.
The Framingham Heart Index is one of the most commonly used risk indices. It uses a combination of age, sex, blood pressure, cholesterol, and smoking status to identify individuals who are currently free of overt coronary heart disease but, based on their risk factor profile, have a high risk of experiencing a major coronary event within 10 years (c statistic, 0.79) [2,3]. Similarly, the Breast Cancer Risk Assessment Tool uses information about a woman's age, race, reproductive history, family history of breast cancer, and biopsy history to predict her risk of developing invasive breast cancer within five years (c statistic, 0.58) [4,5]. Risk indices also are available to predict risk of mortality [6,7], disability , nursing home placement , and diabetes [10,11], among many other conditions and disorders.
Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27-28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia. The deliberations of LTS'09 included presentations and reviews of different approaches (algorithms, biomarkers, or measures) for identifying asymptomatic individuals at elevated risk for AD who would be candidates for longitudinal or prevention studies. The key nested recommendations of LTS'09 included: (1) establishment of a National Database for Longitudinal Studies as a shared research core resource; (2) launch of a large collaborative study that will compare multiple screening approaches and biomarkers to determine the best method for identifying asymptomatic people at risk for AD; (3) initiation of a Global Database that extends the concept of the National Database for Longitudinal Studies for longitudinal studies beyond the United States; and (4) development of an educational campaign that will address public misconceptions about AD and promote healthy brain aging.
The purpose of this study was to update the previous estimate of the worldwide cost of dementia in 2005 to 2009.
The cost model is based on prevalence estimates, country and region-specific data on Gross Domestic Product per person and average wage, with results from previously published cost-of-illness studies in different countries. Prevalence figures are updated to 2009 and costs were adjusted to 2009 constant US dollars ($).
The total worldwide societal cost of dementia, based on a dementia population of 34.4 million demented persons, was estimated to $422 billion in 2009, including $142 billion for informal care (34%).
The worldwide cost of dementia has increased by 34% (18% in fixed prices) between 2005 and 2009.
The published proceedings of the second Annual Leon Thal Symposium (Alzheimers Dement 2009;5:85-92) have added to the open discussion among leaders in this field, with respect to the development of a national strategy for accelerating the discovery of preventative interventions for Alzheimer's disease. One of the recommended "action steps" detailed in that report centers on the establishment of a National Institutional Review Board for neurodegenerative diseases. The purpose of this new ethical oversight panel would be to increase the efficiency with which large-scale multi-site trials are conducted. This essay expands on this recommendation, and two potential organizational models are briefly considered. A well-designed, highly-qualified, and responsive National Institutional Review Board for neurodegenerative diseases would serve the direct interest of protecting the rights, welfare, and safety of our older citizens, who so generously contribute their time, energy, and comfort to advance research to discover new treatments for this devastating disease.
There is a significant need for reliable molecular biomarkers to aid in Alzheimer's disease (AD) clinical diagnosis. RNA transcriptional profiling, although extensively applied for biomarker development in other diseases, is first defining its role in AD. Application of this technology has the sensitivity and power to provide sufficient information for the development of tests to determine disease severity, progression, heterogeneity, and potential for therapeutic response in the AD population. In order to bring forth the potential of this technology, however, the community needs to make a concerted effort to begin sample collection as soon as patients/subjects are identified. Only then can these powerful technologies be applied in a well controlled study for the development of novel diagnostics.