RESUMO
Recent approvals of amyloid immunotherapy drugs for early Alzheimer's disease (AD) have been highly controversial. In this piece, we consider challenges from the clinical, population health, and health systems perspectives to the role that the new AD drugs might be expected to play, now and in the future, in alleviating the morbidity caused by AD in the population. Clinically, short-term effects are small, adverse events are frequent, treatment regimens are burdensome, and, crucially, long-term effects are unknown. At a population level, there is always likely to be a trade-off between breadth of access and magnitude of benefit for any given individual. At a health system level, roll out of treatment even for only narrowly-defined patient groups will involve considerable resources to identify and treat eligible patients, with profound opportunity costs. Our considered view on current evidence is that there are challenges from each perspective to imagining a foreseeable future in which amyloid immunotherapy significantly alleviates AD morbidity at scale. HIGHLIGHTS: Recent approvals of Alzheimer's drugs have met with excitement but also controversy. Trial effects are small, adverse effects concerning, and long-term effects unknown. Results from trial cohorts may not generalize to broader, more complex patients. Significant resource requirements of eligibility assessment and drug administration. Use in "presymptomatic" populations is not supported by current evidence.
RESUMO
INTRODUCTION: Risk prediction models aim to identify those at high risk to receive targeted interventions. We aimed to identify the proportion of future dementia cases that would be missed by a high-risk screening program. METHODS: We identified validated dementia risk prediction models from systematic reviews. We applied these to European Prospective Investigation of Cancer Norfolk, a large population-based cohort of 30,387 individuals with 29 years of linked healthcare data. RESULTS: A maximum of 16.0% (14.7,17.2) and 31.9% (30.2,33.5) of cases arose from the highest risk decile and quintiles, respectively. For every 1000 people considered to be at high risk, a maximum of 235 (215, 255) developed dementia. DISCUSSION: Seven in every 10 cases of dementia arose from people at normal risk, and eight in every 10 people at high risk did not develop dementia. Individual-level prevention approaches targeted at high-risk groups are unlikely to produce large reductions in disease incidence at the population level. HIGHLIGHTS: Dementia, a significant public health challenge, is not an inevitability of aging; risk reduction is possible. Several dementia risk prediction models have been validated in the general population, and these aim to identify people at high risk of the disease who can then be targeted with primary prevention interventions. An alternative prevention approach is to focus on interventions that reduce risk across the population, irrespective of risk status. In our study, seven out of every ten people who developed dementia during 29 year follow-up were classed as 'normal-risk' (rather than 'high risk') at baseline. Eight out of every ten people who were at high risk at baseline did not go on to develop dementia. Even if effective, dementia risk reduction efforts based upon targeted high-risk approaches are unlikely to reduce incidence of disease at the population level.
RESUMO
The epidemiological neuropathology perspective of population and community-based studies allows unbiased assessment of the prevalence of various pathologies and their relationships to late-life dementia. In addition, this approach provides complementary insights to conventional case-control studies, which tend to be more representative of a younger clinical cohort. The Cognitive Function and Ageing Study (CFAS) is a longitudinal study of cognitive impairment and frailty in the general United Kingdom population. In this review, we provide an overview of the major findings from CFAS, alongside other studies, which have demonstrated a high prevalence of pathology in the ageing brain, particularly Alzheimer's disease neuropathological change and vascular pathology. Increasing burdens of these pathologies are the major correlates of dementia, especially neurofibrillary tangles, but there is substantial overlap in pathology between those with and without dementia, particularly at intermediate burdens of pathology and also at the oldest ages. Furthermore, additional pathologies such as limbic-predominant age-related TDP-43 encephalopathy, ageing-related tau astrogliopathy and primary age-related tauopathies contribute to late-life dementia. Findings from ageing population-representative studies have implications for the understanding of dementia pathology in the community. The high prevalence of pathology and variable relationship to dementia status has implications for disease definition and indicate a role for modulating factors on cognitive outcome. The complexity of late-life dementia, with mixed pathologies, indicates a need for a better understanding of these processes across the life-course to direct the best research for reducing risk in later life of avoidable clinical dementia syndromes.
Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Estudos Longitudinais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Encéfalo/patologia , Tauopatias/patologiaRESUMO
An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.
Assuntos
Doença de Alzheimer , Esclerose Lateral Amiotrófica , Demência Frontotemporal , Humanos , Doença de Alzheimer/patologia , Demência Frontotemporal/patologia , Esclerose Lateral Amiotrófica/patologia , Proteínas de Ligação a DNA/genéticaRESUMO
The association between sex/gender and aging-related cognitive decline remains poorly understood because of inconsistencies in findings. Such heterogeneity could be attributable to the cognitive functions studied and study population characteristics, but also to differential selection by dropout and death between men and women. We aimed to evaluate the impact of selection by dropout and death on the association between sex/gender and cognitive decline. We first compared the statistical methods most frequently used for longitudinal data, targeting either population estimands (marginal models fitted by generalized estimating equations) or subject-specific estimands (mixed/joint models fitted by likelihood maximization) in 8 studies of aging: 6 population-based studies (the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) Study (1996-2009), Personnes Âgées QUID (PAQUID; 1988-2014), the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study (2003-2016), the Three-City Study (Bordeaux only; 1999-2016), the Washington Heights-Inwood Community Aging Project (WHICAP; 1992-2017), and the Whitehall II Study (2007-2016)) and 2 clinic-based studies (the Alzheimer's Disease Neuroimaging Initiative (ADNI; 2004-2017) and a nationwide French cohort study, MEMENTO (2011-2016)). We illustrate differences in the estimands of the association between sex/gender and cognitive decline in selected examples and highlight the critical role of differential selection by dropout and death. Using the same estimand, we then contrast the sex/gender-cognitive decline associations across cohorts and cognitive measures suggesting a residual differential sex/gender association depending on the targeted cognitive measure (memory or animal fluency) and the initial cohort selection. We recommend focusing on subject-specific estimands in the living population for assessing sex/gender differences while handling differential selection over time.
Assuntos
Envelhecimento Cognitivo , Disfunção Cognitiva , Idoso , Envelhecimento/psicologia , Cognição , Disfunção Cognitiva/epidemiologia , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Testes Neuropsicológicos , População BrancaRESUMO
Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aß phase = 0 (lacking detectable Aß plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.
Assuntos
Doença de Alzheimer , Demência Frontotemporal , Doenças do Sistema Nervoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Amiloide , Autopsia , Proteínas de Ligação a DNA , Humanos , Masculino , Placa Amiloide/patologiaRESUMO
Background: There is renewed interest in whether sex differences in dementia risk exist, and what influence social and biological factors have. Objective: To review evidence from the Cognitive Function and Ageing Studies (CFAS), a multi-center population-representative cohort study in the UK; focusing on dementia and cognition, incorporating findings on participants' health and social circumstances. Methods: After identifying all CFAS publications, the results of all sex-stratified primary analyses of CFAS data were narratively reviewed. Results: Of 337 publications, 94 report results by sex (including null findings), which are summarized by theme: dementia epidemiology, cognition, mental health, health expectancy, social context and biological resource (including neuropathology). Conclusions: Where differences are found they most commonly favor men; however, greater mortality in men may confound associations with age-related outcomes. This 'survival bias' may explain findings of greater risk of dementia and faster cognitive decline in women. Age-specific dementia incidence was similar between sexes, although reduced incidence across study generations was more pronounced in men. Mood disorders were more prevalent in women, but adjusting for disability and deprivation attenuated the association. Prominent findings from other cohorts that women have more Alzheimer's disease pathology and greater risk of dementia from the Apolipoprotein E É4 allele were not observed, warranting further investigation. The 'male-female health-survival paradox' is demonstrated whereby women live longer but with more comorbidity and disability. Examining why health expectancies changed differently over two decades for each sex (interacting with deprivation) may inform population interventions to improve cognitive, mental and physical health in later life.
Assuntos
Envelhecimento , Cognição , Demência , Caracteres Sexuais , Humanos , Demência/epidemiologia , Masculino , Feminino , Envelhecimento/psicologia , Cognição/fisiologia , Estudos de Coortes , Idoso , Reino Unido/epidemiologia , Idoso de 80 Anos ou maisRESUMO
Lack of guidance for interpreting the definitions of endangered and threatened in the U.S. Endangered Species Act (ESA) has resulted in case-by-case decision making leaving the process vulnerable to being considered arbitrary or capricious. Adopting quantitative decision rules would remedy this but requires the agency to specify the relative urgency concerning extinction events over time, cutoff risk values corresponding to different levels of protection, and the importance given to different types of listing errors. We tested the performance of 3 sets of decision rules that use alternative functions for weighting the relative urgency of future extinction events: a threshold rule set, which uses a decision rule of x% probability of extinction over y years; a concave rule set, where the relative importance of future extinction events declines exponentially over time; and a shoulder rule set that uses a sigmoid shape function, where relative importance declines slowly at first and then more rapidly. We obtained decision cutoffs by interviewing several biologists and then emulated the listing process with simulations that covered a range of extinction risks typical of ESA listing decisions. We evaluated performance of the decision rules under different data quantities and qualities on the basis of the relative importance of misclassification errors. Although there was little difference between the performance of alternative decision rules for correct listings, the distribution of misclassifications differed depending on the function used. Misclassifications for the threshold and concave listing criteria resulted in more overprotection errors, particularly as uncertainty increased, whereas errors for the shoulder listing criteria were more symmetrical. We developed and tested the framework for quantitative decision rules for listing species under the U.S. ESA. If policy values can be agreed on, use of this framework would improve the implementation of the ESA by increasing transparency and consistency.
Assuntos
Tomada de Decisões Gerenciais , Técnicas de Apoio para a Decisão , Espécies em Perigo de Extinção/legislação & jurisprudência , Extinção Biológica , Formulação de Políticas , Teorema de Bayes , Entrevistas como Assunto , Medição de Risco/métodos , Estados UnidosRESUMO
The need for regulatory approval of new therapies for the treatment of Alzheimer's disease-a progressive neurodegenerative condition-has made the assessment of treatment efficacy an urgent priority for discussion and investigation in the field. In the first part of this Personal View, we summarise current views on what constitutes a clinically meaningful benefit from treatment for Alzheimer's disease, including the concept of a minimum treatment effect against which to compare trial outcomes and its limitations. Considering existing and divergent definitions of clinically meaningful change, we define this concept in the second part of the Personal View by proposing a new approach that consecutively considers whether a treatment benefit for Alzheimer's disease is noticeable, valuable, and worthwhile in the context of costs and risks. This approach could be a useful foundation from which the field can move forwards on this issue and address existing gaps in understanding.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population. METHODS: We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies. FINDINGS: The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42]). INTERPRETATION: Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted. FUNDING: Gates Ventures.
Assuntos
Doença de Alzheimer , Aterosclerose , Angiopatia Amiloide Cerebral , Encefalite Límbica , Masculino , Feminino , Humanos , Idoso , Idoso de 80 Anos ou mais , Prevalência , Autopsia , Estudos TransversaisRESUMO
A disconnect has developed over the past two decades between neurological and neuroscientific research, which have seen notable innovation and development, and our increasing understanding of the role of social and commercial determinants of health, including the health of the nervous system. Over the next two decades, grounding neurological research in public health and epidemiological principles can bring about a paradigm shift, away from reductionism, over-medicalisation, and health inequities towards neurological research that reduces inequalities and has true relevance to the populations it aims to serve. People who are involved in neurological and neuroscientific research and practice, as clinicians, researchers, publishers, and funders, can create change by being more aware of the social and commercial determinants of health, reprioritising research funding, and advocating for greater neurological health equity.
Assuntos
Saúde Pública , Pesquisadores , HumanosRESUMO
In 2006, we used the U.S. Coast Guard's Automatic Identification System (AIS) to describe patterns of large commercial ship traffic within a U.S. National Marine Sanctuary located off the coast of Massachusetts. We found that 541 large commercial vessels transited the greater sanctuary 3413 times during the year. Cargo ships, tankers, and tug/tows constituted 78% of the vessels and 82% of the total transits. Cargo ships, tankers, and cruise ships predominantly used the designated Boston Traffic Separation Scheme, while tug/tow traffic was concentrated in the western and northern portions of the sanctuary. We combined AIS data with low-frequency acoustic data from an array of nine autonomous recording units analyzed for 2 months in 2006. Analysis of received sound levels (10-1000 Hz, root-mean-square pressure re 1 microPa +/- SE) averaged 119.5 +/- 0.3 dB at high-traffic locations. High-traffic locations experienced double the acoustic power of less trafficked locations for the majority of the time period analyzed. Average source level estimates (71-141 Hz, root-mean-square pressure re 1 microPa +/- SE) for individual vessels ranged from 158 +/- 2 dB (research vessel) to 186 +/- 2 dB (oil tanker). Tankers were estimated to contribute 2 times more acoustic power to the region than cargo ships, and more than 100 times more than research vessels. Our results indicate that noise produced by large commercial vessels was at levels and within frequencies that warrant concern among managers regarding the ability of endangered whales to maintain acoustic contact within greater sanctuary waters.