In Alzheimer's disease (AD), pathological processes start in the brain long before clinical dementia. Biomarkers reflecting brain alterations may therefore indicate disease at an early stage, enabling early diagnosis. This raises several ethical questions and the potential benefits of early diagnosis must be weighted against possible disadvantages. Currently, there are few strong arguments favouring early diagnosis, due to the lack of disease modifying therapy. Also, available diagnostic methods risk erroneous classifications, with potentially grave consequences. However, a possible benefit of early diagnosis even without disease modifying therapy is that it may enable early decision making when patients still have full decision competence, avoiding problems of hypothetical consents. It may also help identifying patients with cognitive dysfunction secondary to other diseases that may be responsive to treatment already today.
Exponentially growing biological and bioinformatics data sets present a challenge and an opportunity for researchers to contribute to the understanding of the genetic basis of phenotypes. Due to breakthroughs in microarray technology, it is possible to simultaneously monitor the expressions of thousands of genes, and it is imperative that researchers have access to the clinical data to understand the genetics and proteomics of the diseased tissue. This technology could be a landmark in personalized medicine, which will provide storage for clinical and genetic data in electronic health records (EHRs). In this paper, we explore the computational and ethical challenges that emanate from the intersection of bioinformatics and healthcare informatics research. We describe the current situation of the EHR and its capabilities to store clinical and genetic data and then discuss the Genetic Information Nondiscrimination Act. Finally, we posit that the synergy obtained from the collaborative efforts between the genomics, clinical, and healthcare disciplines has potential to enhance and promote faster and more advanced breakthroughs in healthcare.
bioinformatics; healthcare informatics; data mining; electronic health records; Genetic Information Nondiscrimination Act; privacy
Pharmacological cognitive enhancers (PCEs) are used to improve cognitive functions, such as attention, learning, memory and planning in patients with impairments in cognition resulting from traumatic brain injury (TBI) or from neuropsychiatric disorders such as Alzheimer's disease (AD), mild cognitive impairment, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Moreover, PCEs have been shown to improve cognition in healthy volunteers with no psychiatric disorders. This article describes the rationale behind the need for their use in neuropsychiatric patients and illustrates how PCEs can ameliorate cognitive impairments, improve quality of life and wellbeing, and therefore reduce the economic burden associated with these disorders. We also describe evidence that PCEs are being used as cognitive enhancers by healthy people. Crucially, as the lifestyle use of these drugs becomes very popular in the healthy population, a final aim is to present an overview of the current and future neuroethical considerations of enhancing the healthy brain. As information regarding their actual use, benefits and harms in various healthy populations is currently lacking, we propose research that aims to obtain relevant empirical data, monitor the short- and long-term effectiveness and side-effects, and initiate accurate surveys to determine current patterns and quantity of usage of PCE drugs by healthy people. Furthermore, in order to instigate a dialogue between neuroethics and neuropsychopharmacology, we urge scientists to explore and communicate the social and ethical implications of their research to the public. Finally, we discuss and highlight other means of enhancing cognition in both patients and healthy adults, including education and physical exercise.
Atomoxetine; methylphenidate; modafinil; neuroethics; pharmacological cognitive enhancers
Clinical research on Alzheimer disease (AD) is much needed but requires the participation of patients with substantial cognitive impairment who have difficulty providing informed consent. Despite decades of debate, policies regulating such research are not well-defined. Although numerous studies have underscored the difficulties of obtaining informed consent for clinical research from patients compromised by AD, there is also increasing evidence that such individuals and their surrogates can make decisions about research participation that are consistent with the patients’ values. Policy discussions and future research should consider how the ethical reservations about enrolling incapacitated patients in research could be mitigated by developing ways to promote the congruence between surrogates’ decisions and patients’ values.
Breakthrough in treatment of Alzheimer's disease with a shift from irrational dangerous chelation therapy to rational safe evidence based oral zinc therapy. Evidence based medicine: After synthesizing the best available clinical evidence I conclude that oral zinc therapy is a conscientious choice for treatment of free copper toxicosis in individual patients with Alzheimer's disease. Hypothesis 1: Age related free copper toxicosis is a causal factor in pathogenesis of Alzheimer's disease. There are 2 neurodegenerative diseases with abnormalities in copper metabolism: (a) the juvenile form with degeneration in the basal ganglia (Wilson's disease) and (b) the age related form with cortical neurodegeneration (Alzheimer's disease). Initially the hypothesis has been that neurodegeneration was caused by accumulation of copper in the brain but later experiences with treatment of Wilson's disease led to the conviction that free plasma copper is the toxic form of copper: it catalyzes amyloid formation thereby generating oxidative stress, free radicals and degeneration of cortical neurons. Hypothesis 2: Oral zinc therapy is an effective and safe treatment of free copper toxicosis in Alzheimer's disease. Proposed dosage: 50 mg elementary zinc/day. Warning: Chelation therapy is irrational and dangerous in treatment of copper toxicosis in Alzheimer's disease.
In later years, sex selection has become of importance for prevention of X-linked diseases in families at risk. There is today a potential to perform sperm selection before fertilization by taking advantage of the chromosomal heterogamy of spermatozoa, and before implantation by preimplantation genetic diagnosis (PGD). The methods of sex determination by separating spermatozoa are, in our opinion, still not safe enough for routine clinical use. Apart from the technical problems and possible associated risks, which first must be better evaluated, the most critical questions are ethical or legal. We support the use of sex selection by PGD in X-linked severe disease, but due to the potential risks of misuse, we are not prepared to support a more liberal attitude as long as the discriminated sex in nearly all parts of the world are women.
PGD; sex selection; social sexing; spermatozoa; X chromosome; Y chromosome
Children and adolescents with multiple sclerosis (MS) are reported to show high rates of relapse early in the course of the disease as well as cognitive deterioration over time. Immunomodulatory therapies developed for adult MS patients are currently the standard first-line agents for most paediatric MS patients. Available data indicate that the three interferon-beta preparations and glatiramer acetate are safe and well tolerated in children and adolescents with MS, and provide preliminary indications of efficacy in terms of relapse rate reduction. However, these treatments are only partly effective and their routes of administration can be bothersome, particularly for children. Emerging therapies for MS offer promise for improved disease control and long-term clinical outcome, with the advantage of an oral administration for some of them. The future approval of these new medications requires clinical trial consideration of such therapies in the paediatric population. Many of these new agents carry a higher risk for serious adverse events with increased toxicity and still undefined long-term side effects. There are ethical issues as well as issues related to feasibility that must be borne in mind when planning investigation trials for new pharmacological agents in the paediatric population, including immunological maturity, key period of exposure to numerous community-acquired infections, neurodevelopmental factors, in addition to short-term and long-term age-related toxicities. Furthermore, the lack of a large enough paediatric MS population worldwide limits some designs and the feasibility of participation in all the studies. Emerging new therapies have the potential to optimize the care of both paediatric and adult patients with MS. Future treatment trials in children and adolescents with MS will require a multicentre design, definition and selection of key outcome measures, and identification of the most promising therapies. Risks versus benefits of each specific treatment should be weighed and comprehensively discussed.
adolescence; childhood; clinical trials; ethics; immunomodulatory treatment; immunosuppression; multiple sclerosis; new therapies; recruitment
Contrary to early views, we now know that systemic inflammatory/immune responses transmit to the brain. The microglia, the resident “macrophages” of the brain’s innate immune system, are most responsive, and increasing evidence suggests that they enter a hyper-reactive state in neurodegenerative conditions and aging. As sustained over-production of microglial pro-inflammatory mediators is neurotoxic, this raises great concern that systemic inflammation (that also escalates with aging) exacerbates or possibly triggers, neurological diseases (Alzheimer’s, prion, motoneuron disease). It is known that inflammation has an essential role in the progression of Alzheimer’s disease (AD), since amyloid-β (Aβ) is able to activate microglia, initiating an inflammatory response, which could have different consequences for neuronal survival. On one hand, microglia may delay the progression of AD by contributing to the clearance of Aβ, since they phagocyte Aβ and release enzymes responsible for Aβ degradation. Microglia also secrete growth factors and anti-inflammatory cytokines, which are neuroprotective. In addition, microglia removal of damaged cells is a very important step in the restoration of the normal brain environment, as if left such cells can become potent inflammatory stimuli, resulting in yet further tissue damage. On the other hand, as we age microglia become steadily less efficient at these processes, tending to become over-activated in response to stimulation and instigating too potent a reaction, which may cause neuronal damage in its own right. Therefore, it is critical to understand the state of activation of microglia in different AD stages to be able to determine the effect of potential anti-inflammatory therapies. We discuss here recent evidence supporting both the beneficial or detrimental performance of microglia in AD, and the attempt to find molecules/biomarkers for early diagnosis or therapeutic interventions.
microglia; amyloid-β; Alzheimer’s disease; inflammation; NSAIDs; annexin A1; immunity
The Human Genome Project (HGP) is regarded by many as one of the major scientific achievements in recent science history, a large-scale endeavour that is changing the way in which biomedical research is done and expected, moreover, to yield considerable benefit for society. Thus, since the completion of the human genome sequencing effort, a debate has emerged over the question whether this effort merits to be awarded a Nobel Prize and if so, who should be the one(s) to receive it, as (according to current procedures) no more than three individuals can be selected. In this article, the HGP is taken as a case study to consider the ethical question to what extent it is still possible, in an era of big science, of large-scale consortia and global team work, to acknowledge and reward individual contributions to important breakthroughs in biomedical fields. Is it still viable to single out individuals for their decisive contributions in order to reward them in a fair and convincing way? Whereas the concept of the Nobel prize as such seems to reflect an archetypical view of scientists as solitary researchers who, at a certain point in their careers, make their one decisive discovery, this vision has proven to be problematic from the very outset. Already during the first decade of the Nobel era, Ivan Pavlov was denied the Prize several times before finally receiving it, on the basis of the argument that he had been active as a research manager (a designer and supervisor of research projects) rather than as a researcher himself. The question then is whether, in the case of the HGP, a research effort that involved the contributions of hundreds or even thousands of researchers worldwide, it is still possible to “individualise” the Prize? The “HGP Nobel Prize problem” is regarded as an exemplary issue in current research ethics, highlighting a number of quandaries and trends involved in contemporary life science research practices more broadly.
Human Genome Project; Nobel Prize; Research ethics; Fairness of reward mechanism in biomedical research
This article focuses on the prospects and ethics of using neuroimaging to predict Alzheimer’s disease (AD). It is motivated by consideration of the historical roles of science in medicine and society, and considerations specifically contemporary of capabilities in imaging and aging, and the benefits and hope they bring. A general consensus is that combinations of imaging methods will ultimately be most fruitful in predicting disease. Their roll-out into translational practice will not be free of complexity, however, as culture and values differ in terms of what defines benefit and risk, who will benefit and who is at risk, what methods must be in place to assure the maximum safety, comfort, and protection of subjects and patients, and educational and policy needs. Proactive planning for the ethical and societal implications of predicting diseases of the aging brain is critical and will benefit all stakeholders— researchers, patients and families, health care providers, and policy makers.
neuroimaging; Alzheimer’s disease; aging; prediction; neuroethics
Synaptic dysfunction is one of the earliest events in the pathogenesis of Alzheimer’s disease. However, the molecular mechanisms underlying synaptic defects in AD are largely unknown. We report here that Aβ, the main component of senile plaques, induced a significant decrease in dynamin 1, a protein that is essential for synaptic vesicle recycling, and hence, for memory formation and information processing. The Aβ-induced dynamin 1 decrease occurred in the absence of overt synaptic loss and was also observed in the Tg2576 mouse model of Alzheimer’s disease. In addition, our results provided evidence that the Aβ-induced decrease in dynamin 1 was likely the result of a calpain-mediated cleavage of dynamin 1 protein and possibly the down-regulation of dynamin 1 gene expression. These data suggest a mechanism to explain the early cognitive loss without a major decline in synapse number observed in Alzheimer’s disease, and propose a novel therapeutic target for Alzheimer’s disease intervention.
Although it is now generally acknowledged that new biomedical technologies often produce new definitions and sometimes even new concepts of disease, this observation is rarely used in research that anticipates potential ethical issues in emerging technologies. This article argues that it is useful to start with an analysis of implied concepts of disease when anticipating ethical issues of biomedical technologies. It shows, moreover, that it is possible to do so at an early stage, i.e. when a technology is only just emerging. The specific case analysed here is that of ‘molecular medicine’. This group of emerging technologies combines a ‘cascade model’ of disease processes with a ‘personal pattern’ model of bodily functioning. Whereas the ethical implications of the first are partly familiar from earlier—albeit controversial—forms of preventive and predictive medicine, those of the second are quite novel and potentially far-reaching.
Concept of disease; Ethics; Emerging technology; Epistemology; Molecular medicine; Personalized medicine; Health technology assessment
End stage dementia is a particularly difficult aspect of care for patients with Alzheimer's disease and related dementias. In care institutions, caregivers and family are concerned by treatment decision-making for an acute life threatening complication occurring in Alzheimer patients at the end of life. How should the best treatment pathway be decided: to treat or not to treat? Which arguments are used for decision-making? These are mainly ethical questions which are currently difficult to express and investigate.
Cross sectional multicentre study of clinical cases involving 67 health centres (university hospitals, general hospitals, local hospitals and homes for the elderly) in the east of France. The method was based on the "card sorting" technique, with a set of 36 cards, each labelled with a different item relating to arguments for treatment decision-making. For each clinical case, medical staff and carers expressed in a meeting the pieces of information which they believed had been taken into account in the decision. Each participant received a card game, selected fewer than ten and ranked them according to the importance they attached to each one. All selected cards were then put on the table anonymously for participants, respecting the order of importance of the cards in each pile. Lastly, all games were photographed together in order to analyse occurrence and order frequencies. The cards were then classified on the table by frequency to open the discussion. Discussion time, which was conducted by the head carer of the department, concerned the clinical situation of the patient based on the shared responses.
During team meetings, the "card sorting" method was quickly adopted by professionals as a tool to assist with discussion beyond the context of the study. The participants were not compelled to mention their feelings in relation to a case, and it is significant that the anonymity which we tried to maintain so that each person felt "listened to" without value judgement was very often discarded by the individuals themselves.
Granulovacuolar degeneration involves the accumulation of large, double membrane-bound bodies within certain neurons during the course of Alzheimer’s disease and other adultonset dementias. Because of the two-layer membrane morphology, it has been proposed that the bodies are related to autophagic organelles. The aim of this study was to test this hypothesis, and determine the approximate stage at which the pathway stalled in Alzheimer’s disease.
Spatial colocalization of autophagic and endocytic markers with casein kinase 1 delta, a marker for GVD bodies, was evaluated in hippocampal sections prepared from postmortem Braak stage IV and V Alzheimer’s disease cases using double-label confocal fluorescence microscopy.
GVD bodies colocalized weakly with early-stage autophagy markers LC3 and p62, but strongly with late-stage marker LAMP1 (lysosome-associated membrane protein 1), which decorated their surrounding membranes. GVD bodies also colocalized strongly with CHMP2B (charged multivesicular body protein 2B), which colocalized with the core granule, but less strongly with lysosomal marker cathepsin D.
The resultant immunohistochemical signature suggests that GVD bodies contain late-stage autophagic markers, and accumulate at the nexus of autophagic and endocytic pathways. . The data further suggest that failure to complete autolysosome formation may be an important correlate of GVD body accumulation.
Alzheimer’s disease; granulovacuolar degeneration; autophagy; endocytosis; lysosome
To investigate possible differences in pupil dilation and light reflex in Alzheimer’s disease patients that can be attributed to the age of onset of the disease, a statistical comparison was made of pupil dilation and light reflex among early- and late-onset Alzheimer’s disease, Down syndrome, and patients with vascular dementia, and normal controls. The subjects included 53 probable Alzheimer’s disease outpatients, including both early-onset type (AD: n=21) and late-onset type (SD: n=32). They were compared with normal controls (n=15), Down syndrome patients (DS: n=6), and patients with vascular dementia (VD: n=9). All subjects and controls were dark-eyed Japanese. Pupil dilation and light reflex were tested in 21 AD and 32 SD patients, and were compared with those in the control subjects; 6 DS and 9 VD patients. The measured maximum increase in pupil diameter after instilling a mixture of anticholinergic and α -adrenergic stimulating drugs (Midrin-P®), in one eye was significantly greater in AD and DS than in the controls. However, there was no difference among SD, VD, and controls, suggesting a stronger pupil response to these drugs in AD than in SD. Pupil movement in response to light became significantly smaller and faster after instillation of the drugs in Alzheimer’s disease patients. The above findings may be useful for the early detection of Alzheimer’s disease.
Alzheimer’s disease; Down syndrome; pupil; tropicamide; light reflex
Since fisal year 1991, the U.S. Human Genome Project has spent $170.6 million in federal funds to help isolate genes associated with Huntington's disease, amyotrophic lateral sclerosis, neurofibromatosis types 1 and 2, myotonic dystrophy, and fragile X syndrome and to localize genes that predispose people to breast cancer, colon cancer, hypertension, diabetes, and Alzheimer's disease. Now comes the hard part. Biology's 21st century megaproject starts to look relatively manageable compared to another challenge facing the enterprise: sorting out ethical, legal, and social issues associated with using this information. "The Human Genome Project," wrote Senior Editor Barbara Jasny in the October 1 Science editorial, stretches "the limits of the technology and the limits of our ability to ethically and rationally apply genetic information to our lives."
Alzheimer’s disease is thought to be caused by an imbalance between amyloid-β (Aβ) production and clearance leading to Aβ accumulation in the Central Nervous System (CNS). Aβ production and clearance are key targets in the development of disease modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer’s disease. Using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of patients with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer’s disease compared to controls. On average, there were no differences in Aβ42 or Aβ40 production rates. Thus, the common late-onset form of Alzheimer’s disease may involve an overall impairment of Aβ clearance.
The scientific evidence of plasticity, or the brain’s dynamic ability to alter its organization and activation throughout one’s lifetime, has increased significantly over the last decade. This analytic review evaluates selected evidence regarding the persistence of plasticity in people with early-stage Alzheimer’s disease (AD). Functional neuroimaging provides persuasive evidence of plasticity throughout aging as well as the early stages of dementia, including the possibility of a heightened response during the prodromal period of AD. Behavioral outcomes research demonstrates the ability of people with early-stage AD to relearn previously forgotten information or otherwise improve cognitive abilities following a cognition-focused intervention. Both of these bodies of evidence support the existence of compensatory processes at work, even in the presence of dementia-related pathology. This retained ability of the brain to adapt to neurodegenerative disease in an attempt to maintain function may provide a valuable opportunity for intervention, particularly in the prodromal or earliest stages of AD.
Alzheimer’s disease is characterised by the inappropriate death of brain cells and accumulation of the Aβ peptide in the brain. Thus, it is possible that there are fundamental differences between Alzheimer’s disease patients and healthy individuals in their abilities to clear Aβ from brain fluid and to protect neurons from Aβ toxicity. In the present study, we examined (1) the cytotoxicity of Alzheimer’s disease cerebrospinal fluid (CSF) compared to control CSF, (2) the ability of Alzheimer’s disease and control CSF to protect cells from Aβ toxicity and to promote cell-mediated clearance of Aβ and lastly (3) the effects of extracellular chaperones, normally found in CSF, on these processes. We show that the Alzheimer’s disease CSF samples tested were more toxic to cultured neuroblastoma cells than normal CSF. In addition, the Alzheimer’s disease CSF samples tested were less able to protect cells from Aβ-induced toxicity and less efficient at promoting macrophage-like cell uptake when compared to normal CSF. The addition of physiologically relevant concentrations of the extracellular chaperones, clusterin, haptoglobin and α2-macroglobulin into CSF protected neuroblastoma cells from Αβ1-42 toxicity and promoted Αβ1-42 uptake in macrophage-like cells. These results suggest that extracellular chaperones are an important element of a system of extracellular protein folding quality control that protects against Aβ toxicity and accumulation.
Aβ; Alzheimer’s disease; CSF; Extracellular chaperones
Numerous studies show that the pathology of Alzheimer's disease is present decades before a clinical diagnosis of dementia can be made. Given the likelihood that agents will become available that reliably delay onset and/or slow progression of Alzheimer's disease, it will be important to detect preclinical Alzheimer's disease as early as possible for maximal treatment effect. Detection of individuals by sensitive cognitive measures provides one way to identify people who are at high risk of developing clinical Alzheimer's disease. However, it is likely that those with considerable brain or cognitive reserve will be able to mask cognitive deficits until very close to the onset of the dementia, rendering such cognitive measures insensitive. Optimum biomarkers for Alzheimer's disease therefore need to target the severity of underlying brain pathology independently of brain reserve. Findings are presented showing the importance of higher education and larger brain size in masking the underlying disease pathology.
Alzheimer's disease; biomarkers; prevention
Following a brief introduction and discussion of the pathological features of Alzheimer's disease, the main emphasis of this review article will be the genetic factors that have been implicated in this disease. These can be divided into two main categories. First, the three genes in which mutations are known to result in early onset autosomal dominant familial Alzheimer's disease will be discussed. These are well characterised but account for only a small proportion of Alzheimer's disease cases. Late onset, sporadic Alzheimer's disease is more common and evidence suggests that there is a genetic component to this type of disease. A number of genetic risk factors have been implicated that might increase the risk of developing sporadic disease. Many of these are controversial and studies have shown conflicting results, which are discussed in this section. Finally, a brief discussion of some of the mechanisms suggested to play a role in the pathogenesis of Alzheimer's disease is included. It is hoped that this will show why particular genes have been implicated in Alzheimer's disease and how they might be able to influence the development of the disease.
Alzheimer's disease (AD) is the most common neurodegenerative disease featuring progressive impairments in memory, cognition, and behavior and ultimately leads to death. The histopathological changes of Alzheimer's disease include neuronal and synaptic loss, formation of extracellular senile plaques and intracellular neurofibrillary tangles in brain. Multiple lines of evidence indicate that oxidative stress not only strongly participates in an early stage of Alzheimer's disease prior to cytopathology, but plays an important role in inducing and activating multiple cell signaling pathways that contribute to the lesion formations of toxic substances and then promotes the development of Alzheimer's disease. Many years of studies show that antioxidant therapies have enjoyed general success in preclinical studies. Therefore, this paper mainly focuses on the recent developments of common used antioxidant therapies for Alzheimer's disease and thus provides indications for future potential antioxidant therapeutic strategies of neurodegenerative diseases.
Translational medicine describes the transfer of basic in vitro and in vivo data into human applications. In the light of low rates of market approvals for new medical entities, better strategies to predict the risk of drug development should be used to increase output and reduce costs. Recently, a scoring system to assess the translatability of early drug projects has been proposed. Here eight drugs from different therapeutic areas have been subjected to a retrospective test-run in this system fictively located at the phase II-III transition. The scores gained here underline the importance of biomarker quality which is pivotal to decrease the risk of the project in all cases. This is particularly evident for gefitinib. The EGFR mutation status is a breakthrough biomarker to predict therapeutic success which made this compound clinically acceptable, and this is plausibly reflected by a considerable increase of the translatability score. For psychiatric and Alzheimer's drugs, and for a CETP-inhibitor, the lack of suitable biomarkers and animal models is reflected by a low translatability score, well correlating with the excessive translational risk in these areas. These case studies document the apparent utility of the scoring system, at least under retrospective conditions, as the scores correlate with the outcomes at the level of market approval. Prospective validation is still missing, but these case studies are encouraging.
Dabigatran; Ipilimumab; Gefitinib; Vilazodone; Latrepirdine; Semagacestat; Translatability Score; Translational medicine; Drug development
Early screenings involving biomarkers and use of potential disease-modifying therapies (DMTs) may have significant humanistic implications for treatment strategies in Alzheimer’s disease.
Markov models simulated transitions of patient cohorts beginning in predementia, a hypothetical early stage of Alzheimer’s disease marked by objective cognitive impairment/memory complaints without functional impairment, and followed for 10 years. Hypothetical cohorts of 10,000 patients included those who were treated with standard of care (donepezil) upon reaching mild–moderate Alzheimer’s disease, a DMT in predementia, and a DMT in mild-moderate Alzheimer’s disease. Transition probabilities were based on data from the Alzheimer’s Disease Neuroimaging Initiative and published clinical data, and estimated for the hypothetical DMT. In each disease stage (predementia, mild, moderate, or severe), time was computed and costs were estimated using literature review and published data, and published data provided mortality rates. The impact of screening was evaluated using positive predictive value (patients identified as predementia truly at risk for transition to dementia).
Earlier treatment yielded modest gains in total life-years; however, the distribution was skewed towards milder disease. Assuming a 25% reduction in the annual risk of progression, treating predementia patients with DMT increased life-years in predementia to mild states on average from 3.2 to 4.2, while life-years spent in moderate-to-severe Alzheimer’s disease decreased from 2.6 to 2.2. Average time in the community increased from 4.4 to 5.4 years, while time in long-term care declined from 1.3 to 0.9 years. This impact grows as the advantage of the novel agent increases. Screening accuracy had significant implications for cost-effectiveness.
If screening can accurately identify predementia patients at risk for progression, earlier treatment with DMTs has the potential benefit to patients of prolonging time in milder disease, reducing time spent with more severe disease, increasing time in the community, and reducing time in long-term care.
Alzheimer’s disease; Markov model; disease-modifying therapy; donepezil; standard of care; predementia
A challenge in developing informative neuroimaging biomarkers for early diagnosis of Alzheimer's disease is the need to identify biomarkers that are evident before the onset of clinical symptoms, and which have sufficient sensitivity and specificity on an individual patient basis. Recent literature suggests that spatial patterns of brain atrophy discriminate amongst Alzheimer's disease, mild cognitive impairment (MCI) and cognitively normal (CN) older adults with high accuracy on an individual basis, thereby offering promise that subtle brain changes can be detected during prodromal Alzheimer's disease stages. Here, we investigate whether these spatial patterns of brain atrophy can be detected in CN and MCI individuals and whether they are associated with cognitive decline. Images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used to construct a pattern classifier that recognizes spatial patterns of brain atrophy which best distinguish Alzheimer's disease patients from CN on an individual person basis. This classifier was subsequently applied to longitudinal magnetic resonance imaging scans of CN and MCI participants in the Baltimore Longitudinal Study of Aging (BLSA) neuroimaging study. The degree to which Alzheimer's disease-like patterns were present in CN and MCI subjects was evaluated longitudinally in relation to cognitive performance. The oldest BLSA CN individuals showed progressively increasing Alzheimer's disease-like patterns of atrophy, and individuals with these patterns had reduced cognitive performance. MCI was associated with steeper longitudinal increases of Alzheimer's disease-like patterns of atrophy, which separated them from CN (receiver operating characteristic area under the curve equal to 0.89). Our results suggest that imaging-based spatial patterns of brain atrophy of Alzheimer's disease, evaluated with sophisticated pattern analysis and recognition methods, may be useful in discriminating among CN individuals who are likely to be stable versus those who will show cognitive decline. Future prospective studies will elucidate the temporal dynamics of spatial atrophy patterns and the emergence of clinical symptoms.
early Alzheimer's disease; mild cognitive impairment; neuroimaging; ageing; SPARE-AD