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The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine (e.g., oncology), and is becoming a unifying concept common to all neurodegenerative diseases, not just AD. The present document is consistent with this principle. Our intent is to present objective criteria for diagnosis and staging AD, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care. These criteria are not intended to provide step-by-step clinical practice guidelines for clinical workflow or specific treatment protocols, but rather serve as general principles to inform diagnosis and staging of AD that reflect current science. HIGHLIGHTS: We define Alzheimer's disease (AD) to be a biological process that begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms. Early-changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers [especially phosphorylated tau 217]) map onto either the amyloid beta or AD tauopathy pathway; however, these reflect the presence of ADNPC more generally (i.e., both neuritic plaques and tangles). An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. Later-changing Core 2 biomarkers (biofluid and tau PET) can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms. An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages.
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Enfermedad de Alzheimer , Biomarcadores , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Humanos , Biomarcadores/líquido cefalorraquídeo , Estados Unidos , Progresión de la Enfermedad , Encéfalo/patología , Encéfalo/diagnóstico por imagen , National Institute on Aging (U.S.) , Proteínas tau/líquido cefalorraquídeoRESUMEN
Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life. Neuronal α-synuclein disease is defined by the presence of pathological n-αsyn species detected in vivo (S; the first biological anchor) regardless of the presence of any specific clinical syndrome. On the basis of this definition, we propose that individuals with pathological n-αsyn aggregates are at risk for dopaminergic neuronal dysfunction (D; the second biological anchor). Our biological definition establishes a staging system, the neuronal α-synuclein disease integrated staging system (NSD-ISS), rooted in the biological anchors (S and D) and the degree of functional impairment caused by clinical signs or symptoms. Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). The presence of clinical manifestations marks the transition to stage 2 and beyond. Stage 2 is characterised by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. A biological definition of neuronal α-synuclein disease and an NSD-ISS research framework are essential to enable interventional trials at early disease stages. The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated. Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.
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Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Sinucleinopatías , Humanos , alfa-Sinucleína/genética , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/genética , Enfermedad por Cuerpos de Lewy/diagnóstico , Sinucleinopatías/diagnóstico , Cuerpos de Lewy , SíndromeRESUMEN
Well-defined and reliable clinical outcome assessments are essential for determining whether a drug provides clinically meaningful treatment benefit for patients. In 2015, FDA convened a workshop, "Assessing Neurocognitive Outcomes in Inborn Errors of Metabolism." Topics covered included special challenges of clinical studies of inborn errors of metabolism (IEMs) and other rare diseases; complexities of identifying treatment effects in the context of the dynamic processes of child development and disease progression; and the importance of natural history studies. Clinicians, parents/caregivers, and participants from industry, academia, and government discussed factors to consider when developing measures to assess treatment outcomes, as well as tools and methods that may contribute to standardizing measures. Many issues examined are relevant to the broader field of rare diseases in addition to specifics of IEMs.
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Pruebas de Estado Mental y Demencia/normas , Errores Innatos del Metabolismo/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud , Enfermedades Raras/tratamiento farmacológico , Cuidadores , Niño , Desarrollo Infantil , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Humanos , National Institutes of Health (U.S.) , Padres , Tecnología de Sensores Remotos , Estados Unidos , United States Food and Drug AdministrationRESUMEN
There is a paucity of data regarding trends in dementia and its subtype prevalence in Japan. Our aims in the current paper are to: (1) summarize epidemiological studies of dementia in Japan including relevant details of study protocol and diagnostic criteria, (2) compare the age-specific prevalence of all-cause dementia among studies, and (3) assess the trends in Alzheimer's disease (AD) versus vascular dementia (VaD) over time. We reviewed diagnostic criteria, all-cause dementia prevalence, and the AD/VaD ratio from 8 large population studies of dementia in Japan. Compared with the Okinawa 1992 study, studies conducted in 1994, 1998, 2005, and 2008 had a higher prevalence of all-cause dementia using Poisson regression models, after controlling for age and sex. In contrast to the US and some European countries, all-cause dementia prevalence is increasing in Japan. The prevalence of AD as opposed to VaD seems to be increasing over time, but large variability in diagnostic criteria, possible regional variability, and differences in prevalence of subtypes of dementia between men and women make it difficult to draw a conclusion about this trend at the national level. Further studies, for example, comparing the population attributable risk of vascular diseases to the prevalence and incidence of dementia could help to clarify the regional variations in etiological subtypes.
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Physical performance measures predict health and function in older populations. Walking speed in particular has consistently predicted morbidity and mortality. However, single brief walking measures may not reflect a person's typical ability. Using a system that unobtrusively and continuously measures walking activity in a person's home we examined walking speed metrics and their relation to function. In 76 persons living independently (mean age, 86) we measured every instance of walking past a line of passive infra-red motion sensors placed strategically in their home during a four-week period surrounding their annual clinical evaluation. Walking speeds and the variance in these measures were calculated and compared to conventional measures of gait, motor function and cognition. Median number of walks per day was 18±15. Overall mean walking speed was 61±17 cm/s. Characteristic fast walking speed was 96 cm/s. Men walked as frequently and fast as women. Those using a walking aid walked significantly slower and with greater variability. Morning speeds were significantly faster than afternoon/evening speeds. In-home walking speeds were significantly associated with several neuropsychological tests as well as tests of motor performance. Unobtrusive home walking assessments are ecologically valid measures of walking function. They provide previously unattainable metrics (periodicity, variability, range of minimum and maximum speeds) of everyday motor function.
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Marcha/fisiología , Monitoreo Ambulatorio/métodos , Resistencia Física/fisiología , Procesamiento de Señales Asistido por Computador , Caminata/fisiología , Factores de Edad , Anciano , Anciano de 80 o más Años , Ritmo Circadiano , Estudios de Cohortes , Intervalos de Confianza , Femenino , Evaluación Geriátrica , Humanos , Vida Independiente , Modelos Lineales , Masculino , Monitoreo Ambulatorio/instrumentación , Equilibrio Postural/fisiología , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores SexualesRESUMEN
BACKGROUND: Executive dysfunction has previously been found to be a risk factor for falls. The aim of this study is to investigate the association between executive dysfunction and risk of falling and to determine if this association is independent of balance. METHODS: Participants were 188 community-dwelling individuals aged 65 and older. All participants underwent baseline and annual evaluations with review of health history, standardized neurologic examination, neuropsychological testing, and qualitative and quantitative assessment of motor function. Falls were recorded prospectively using weekly online health forms. RESULTS: During 13 months of follow-up, there were 65 of 188 participants (34.6%) who reported at least one fall. Univariate analysis showed that fallers were more likely to have lower baseline scores in executive function than non-fallers (p = 0.03). Among participants without balance impairment we found that higher executive function z-scores were associated with lower fall counts (p = 0.03) after adjustment for age, sex, health status and prior history of falls using negative binomial regression models. This relationship was not present among participants with poor balance. CONCLUSIONS: Lower scores on executive function tests are a risk factor for falls in participants with minimal balance impairment. However, this effect is attenuated in individuals with poor balance where physical or more direct motor systems factors may play a greater role in fall risk.
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Accidentes por Caídas/prevención & control , Función Ejecutiva/fisiología , Equilibrio Postural/fisiología , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Proyectos Piloto , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de RiesgoRESUMEN
OBJECTIVES: To compare the trajectory of motor decline, as measured by gait speed and finger-tapping speed, between elderly people who developed mild cognitive impairment (MCI) and those who remained cognitively intact. We also sought to determine the approximate time at which the decline in motor function accelerated in persons who developed MCI. DESIGN: Longitudinal cohort study. PARTICIPANTS: Participants were 204 healthy seniors (57.8% women) from the Oregon Brain Aging Study evaluated for up to 20 years using annual neurologic, neuropsychological, and motor examinations. MAIN OUTCOME MEASURES: The pattern of motor decline with aging was compared using a mixed-effects model with an interaction term for age and a clinical diagnosis of MCI. The time before diagnosis of MCI, when the change in gait or finger-tapping speed accelerates, was assessed using a mixed-effects model with a change point for men and women, separately and combined, who developed MCI. RESULTS: The rates of change, with aging, in gait speed (P < .001) and finger-tapping speed in the dominant hand (P = .003) and nondominant hand (P < .001) were significantly different between participants who developed MCI (converters) and those who did not (nonconverters). Using a change point analysis for MCI converters, the decrease in gait speed accelerated by 0.023 m/s/y (P < .001), occurring 12.1 years before the onset of MCI. An acceleration in gait speed decline occurred earlier in men than women. For tapping speed, the change point occurred after the onset of MCI for both dominant and nondominant hands when men and women were combined. CONCLUSIONS: Motor decline as indexed by gait speed accelerates up to 12 years before MCI. Longitudinal changes in motor function may be useful in the early detection of dementia during preclinical stages, when the utility of disease-modifying therapies would be greatest.
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Trastornos del Conocimiento/complicaciones , Trastornos Neurológicos de la Marcha/etiología , Desempeño Psicomotor/fisiología , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Evaluación Geriátrica , Humanos , Masculino , Pruebas Neuropsicológicas , Factores SexualesRESUMEN
Ocular misalignment and ophthalmoparesis result in the symptom of binocular diplopia. In the evaluation of diplopia, localization of the ocular motility disorder is the main objective. This requires a systematic approach and knowledge of the ocular motor pathways and actions of the extraocular muscles. This article reviews the components of the ocular motor pathway and presents helpful tools for localization and common sources of error in the assessment of ophthalmoparesis.
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Oftalmoplejía/diagnóstico , Animales , Humanos , Trastornos de la Motilidad Ocular/diagnóstico , Trastornos de la Motilidad Ocular/fisiopatología , Oftalmoplejía/fisiopatología , Vías Visuales/fisiologíaRESUMEN
As life expectancy continues to increase over time, dementia is becoming an increasingly more common problem and a major cause of disability in older persons. It is now more important than ever to identify and manage common causes of dementia given variations in disease course, treatments and the possibility for modification of risk factors. Dementia with Lewy bodies (DLB) is a dementia syndrome characterized by progressive cognitive decline, with fluctuating cognition, recurrent detailed and well-formed hallucinations, and parkinsonism. This article aims to provide an overview of current concepts of DLB, including a description of the key clinical features and neuropathology, neurochemistry, and genetics of DLB, then a discussion of the relationship of DLB with Alzheimer's disease and Parkinson's disease, and, finally, a summary of current management strategies available for this disorder.