RESUMEN

OBJECTIVE: Preclinical Alzheimer disease (AD) has been associated with subtle changes in memory, attention, and spatial navigation abilities. The current study examined whether self- and informant-reported domain-specific cognitive changes are sensitive to AD-associated biomarkers. METHOD: Clinically normal adults aged 56-93 and their informants completed the memory, divided attention, and visuospatial abilities (which assesses spatial navigation) subsections of the Everyday Cognition Scale (ECog). Reliability and validity of these subsections were examined using Cronbach's alpha and confirmatory factor analysis. Logistic regression was used to examine the ability of ECog subsections to predict AD-related biomarkers (cerebrospinal fluid (CSF) ptau181/Aß42 ratio (N = 371) or hippocampal volume (N = 313)). Hierarchical logistic regression was used to examine whether the self-reported subsections continued to predict biomarkers when controlling for depressive symptomatology if available (N = 197). Additionally, logistic regression was used to examine the ability of neuropsychological composites assessing the same or similar cognitive domains as the subsections (memory, executive function, and visuospatial abilities) to predict biomarkers to allow for comparison of the predictive ability of subjective and objective measures. RESULTS: All subsections demonstrated appropriate reliability and validity. Self-reported memory (with outliers removed) was the only significant predictor of AD biomarker positivity (i.e., CSF ptau181/Aß42 ratio; p = .018) but was not significant when examined in the subsample with depressive symptomatology available (p = .517). Self-reported memory (with outliers removed) was a significant predictor of CSF ptau181/Aß42 ratio biomarker positivity when the objective memory composite was included in the model. CONCLUSIONS: ECog subsections were not robust predictors of AD biomarker positivity.

Asunto(s)

Enfermedad de Alzheimer , Disfunción Cognitiva , Navegación Espacial , Humanos , Enfermedad de Alzheimer/psicología , Reproducibilidad de los Resultados , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Pruebas Neuropsicológicas , Biomarcadores/líquido cefalorraquídeo , Atención , Fragmentos de Péptidos/líquido cefalorraquídeo , Disfunción Cognitiva/psicología

RESUMEN

OBJECTIVE: Subtle changes in memory, attention, and spatial navigation abilities have been associated with preclinical Alzheimer disease (AD). The current study examined whether baseline AD biomarkers are associated with self- and informant-reported decline in memory, attention, and spatial navigation. METHOD: Clinically normal (Clinical Dementia Rating Scale (CDR®) = 0) adults aged 56-93 (N = 320) and their informants completed the memory, divided attention, and visuospatial abilities (which assesses spatial navigation) subsections of the Everyday Cognition Scale (ECog) annually for an average of 4 years. Biomarker data was collected within (±) 2 years of baseline (i.e., cerebrospinal fluid (CSF) p-tau181/Aß42 ratio and hippocampal volume). Clinical progression was defined as CDR > 0 at time of final available ECog. RESULTS: Self- and informant-reported memory, attention, and spatial navigation significantly declined over time (ps < .001). Baseline AD biomarkers were significantly associated with self- and informant-reported decline in cognitive ability (ps < .030), with the exception of p-tau181/Aß42 ratio and self-reported attention (p = .364). Clinical progression did not significantly moderate the relationship between AD biomarkers and decline in self- or informant-reported cognitive ability (ps > .062). Post-hoc analyses indicated that biomarker burden was also associated with self- and informant-reported decline in total ECog (ps < .002), and again clinical progression did not significantly moderate these relationships (ps > .299). CONCLUSIONS: AD biomarkers at baseline may indicate risk of decline in self- and informant-reported change in memory, attention, and spatial navigation ability. As such, subjectively reported decline in these domains may have clinical utility in tracking the subtle cognitive changes associated with the earliest stages of AD.

Asunto(s)

Enfermedad de Alzheimer , Disfunción Cognitiva , Navegación Espacial , Humanos , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Progresión de la Enfermedad , Atención , Disfunción Cognitiva/etiología , Disfunción Cognitiva/líquido cefalorraquídeo

RESUMEN

While clinically significant cognitive impairment is the key feature of the symptomatic stages of the Alzheimer's disease (AD) continuum, subtle cognitive decline is now known to occur years before a clinical diagnosis of mild cognitive impairment (MCI) or dementia due to AD is made. The primary aim of this study was to examine criterion validity evidence for an operational definition of "cognitively unimpaired-declining" (CU-D) in the Wisconsin Registry for Alzheimer's Prevention (WRAP), a longitudinal cohort study following cognition and risk factors from mid-life and on. Cognitive status was determined for each visit using a consensus review process that incorporated internal norms and published norms; a multi-disciplinary panel reviewed cases first to determine whether MCI or dementia was present, and subsequently whether CU-D was present, The CU-D group differed from CU-stable (CU-S) and MCI on concurrent measures of cognition, demonstrating concurrent validity. Participants who changed from CU-S to CU-D at the next study visit demonstrated greater declines than those who stayed CU-S. In addition, those who were CU-D were more likely to progress to MCI or dementia than those who were CU-S (predictive validity). In a subsample with positron emission tomography (PET) imaging, the CU-D group also differed from the CU-S and MCI/Dementia groups on measures of amyloid and tau burden, indicating that biomarker evidence of AD was elevated in those showing sub-clinical (CU-D) decline. Together, the results corroborate other studies showing that cognitive decline begins long before a dementia diagnosis and indicate that operational criteria can detect subclinical decline that may signal AD or other dementia risk.

RESUMEN

This study examined the effect of neurodegeneration, and its interaction with Alzheimer's disease (AD) cerebrospinal fluid biomarkers, on longitudinal verbal learning and memory performance in cognitively unimpaired (CU) late middle-aged adults. Three hundred and forty-two CU adults (cognitive baseline mean age = 58.4), with cerebrospinal fluid and structural MRI, completed 2-10 (median = 5) cognitive assessments. Learning and memory were assessed using the Rey Auditory Verbal Learning Test (RAVLT). We used sequential comparison of nested linear mixed effects models to analyze the data. Model selection preserved a significant ptau181/Aß42 × global atrophy × age interaction; individuals with less global atrophy and lower ptau181/Aß42 levels had less learning and delayed recall decline than individuals with more global atrophy and/or higher levels of ptau181/Aß42. The hippocampal volume × age × ptau181/Aß42 interaction was not significant. Findings suggest that in a sample of CU late middle-aged adults, individuals with AD biomarkers, global atrophy, or both evidence greater verbal learning and memory decline than individuals without either risk factor.

Asunto(s)

Envejecimiento/psicología , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Memoria/fisiología , Degeneración Nerviosa/diagnóstico , Degeneración Nerviosa/psicología , Aprendizaje Verbal/fisiología , Anciano , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Atrofia , Biomarcadores/líquido cefalorraquídeo , Cognición/fisiología , Femenino , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo

RESUMEN

BACKGROUND: Studies have suggested associations between self-reported engagement in health behaviors and reduced risk of cognitive decline. Most studies explore these relationships using one health behavior, often cross-sectionally or with dementia as the outcome. In this study, we explored whether several individual self-reported health behaviors were associated with cognitive decline when considered simultaneously, using data from the Wisconsin Registry for Alzheimer's Prevention (WRAP), an Alzheimer's disease risk-enriched cohort who were non-demented and in late midlife at baseline. METHOD: We analyzed longitudinal cognitive data from 828 participants in WRAP, with a mean age at baseline cognitive assessment of 57 (range = 36-78, sd = 6.8) and an average of 6.3 years (standard deviation = 1.9, range = 2-10) of follow-up. The primary outcome was a multi-domain cognitive composite, and secondary outcomes were immediate/delayed memory and executive function composites. Predictors of interest were self-reported measures of physical activity, cognitive activity, adherence to a Mediterranean-style diet (MIND), and interactions with each other and age. We conducted linear mixed effects analyses within an Information-theoretic (IT) model averaging (MA) approach on a set of models including covariates and combinations of these 2- and 3-way interactions. The IT approach was selected due to the large number of interactions of interest and to avoid pitfalls of traditional model selection approaches. RESULTS: Model-averaged results identified no significant self-reported health behavior*age interactions in relationship to the primary composite outcome. In secondary outcomes, higher MIND diet scores associated with slower decline in executive function. Men showed faster decline than women on delayed memory, independent of health behaviors. There were no other significant interactions among any other health behaviors and cognitive trajectories. CONCLUSIONS: When multiple covariates and health behaviors were considered simultaneously, there were limited weak associations with cognitive decline in this age range. These results may be explained alone or in combination by three alternative explanations: 1) the range of cognitive decline is in middle age is too small to observe relationships with health behaviors, 2) the putative associations of these health behaviors on cognition may not be robust in this age range, or 3) the self-reported measures of the health behaviors may not be optimal for predicting cognitive decline. More study may be needed that incorporates sensitive measures of health behaviors, AD biomarker profiles, and/or other disease comorbidities.

Asunto(s)

Enfermedad de Alzheimer/epidemiología , Cognición , Adulto , Anciano , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/prevención & control , Función Ejecutiva , Ejercicio Físico , Femenino , Conductas Relacionadas con la Salud , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Autoinforme , Wisconsin/epidemiología

RESUMEN

INTRODUCTION: This study applies a novel algorithm to longitudinal amyloid positron emission tomography (PET) imaging to identify age-heterogeneous amyloid trajectory groups, estimate the age and duration (chronicity) of amyloid positivity, and investigate chronicity in relation to cognitive decline and tau burden. METHODS: Cognitively unimpaired participants (n = 257) underwent one to four amyloid PET scans (Pittsburgh Compound B, PiB). Group-based trajectory modeling was applied to participants with longitudinal scans (n = 171) to identify and model amyloid trajectory groups, which were combined with Bayes theorem to estimate age and chronicity of amyloid positivity. Relationships between chronicity, cognition, clinical progression, and tau PET (MK-6240) were investigated using regression models. RESULTS: Chronicity explained more heterogeneity in amyloid burden than age and binary amyloid status. Chronicity was associated with faster cognitive decline, increased risk of abnormal cognition, and higher entorhinal tau. DISCUSSION: Amyloid chronicity provides unique information about cognitive decline and neurofibrillary tangle development and may be useful to investigate preclinical Alzheimer's disease.

RESUMEN

INTRODUCTION: Spatial navigation deficits are observed in Alzheimer's disease cross-sectionally, but prediction of longitudinal clinical decline has been less examined. METHODS: Cognitive mapping (CM) was assessed in 95 participants and route learning (RL) was assessed in 65 participants at baseline. Clinical progression over an average of 4 to 5 years was assessed using the clinical dementia rating (CDR) scale. Relative predictive ability was compared to episodic memory, hippocampus, and cerebrospinal fluid biomarkers (phosphorylated tau/amyloid ß 42 (ptau181 /Aß42 ) ratio). RESULTS: CM and RL were predictors of clinical progression (P's < 0.032). All measures, except RL-Learning remained predictors with episodic memory in models (P's < 0.048). Only RL-Retrieval remained a predictor when ptau181 /Aß42 was included (P < 0.001). CM interacted with hippocampus and ptau181 /Aß42 in prediction (P's < 0.013). CM, RL, and episodic memory evidenced strong diagnostic accuracy (area under the curve (AUC) = 0.894, 0.794, and 0.735, respectively); CM tended to perform better than episodic memory (P = 0.056). DISCUSSION: Baseline spatial navigation performance may be appropriate for assessing risk of clinical progression.

Asunto(s)

Demencia , Progresión de la Enfermedad , Pruebas de Estado Mental y Demencia/estadística & datos numéricos , Desempeño Psicomotor/fisiología , Navegación Espacial/fisiología , Anciano , Biomarcadores/líquido cefalorraquídeo , Demencia/líquido cefalorraquídeo , Demencia/psicología , Femenino , Humanos , Memoria Episódica

RESUMEN

This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-ß and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.

Asunto(s)

Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Placa Amiloide/diagnóstico por imagen , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Compuestos de Anilina , Encéfalo/metabolismo , Radioisótopos de Carbono , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Femenino , Radioisótopos de Flúor , Humanos , Isoquinolinas , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Ovillos Neurofibrilares/metabolismo , Pruebas Neuropsicológicas , Placa Amiloide/metabolismo , Tomografía de Emisión de Positrones , Síntomas Prodrómicos , Tiazoles , Proteínas tau/metabolismo

RESUMEN

INTRODUCTION: Longitudinal cohort studies of cognitive aging must confront several sources of within-person variability in scores. In this article, we compare several neuropsychological measures in terms of longitudinal error variance and relationships with biomarker-assessed brain amyloidosis (Aß). METHODS: Analyses used data from the Wisconsin Registry for Alzheimer's Prevention. We quantified within-person longitudinal variability and age-related trajectories for several global and domain-specific composites and their constituent scores. For a subset with cerebrospinal fluid or amyloid positron emission tomography measures, we examined how Aß modified cognitive trajectories. RESULTS: Global and theoretically derived composites exhibited lower intraindividual variability and stronger age × Aß interactions than did empirically derived composites or raw scores from single tests. For example, the theoretical executive function outperformed other executive function scores on both metrics. DISCUSSION: These results reinforce the need for careful selection of cognitive outcomes in study design, and support the emerging consensus favoring composites over single-test measures.

RESUMEN

OBJECTIVE: There remains a need for a non-invasive and cost-effective screening measure that could be administered prior to the provision of a lumbar puncture or positron emission tomography scan for the detection of preclinical Alzheimer disease (AD). Previous findings suggest that a hippocampally-based spatial navigation task may be effective for screening individuals for the preclinical AD continuum (i.e., low cerebrospinal fluid (CSF) Aß42). Unfortunately, this task took 1.5-2 hours to administer, which would be time-prohibitive in a clinical setting. Therefore, the goal of this study was to compare psychometric properties of six spatial navigation-related tasks in order to take the next steps in developing a clinically appropriate screening measure. METHODS: Psychometric properties (i.e., reliability, diagnostic accuracy, validity) of a modified version of the cognitive mapping task, two binding tasks, a visual perspective taking task, and self- and informant report versions of a questionnaire were examined in a sample of 91 clinically normal (CN) individuals. CSF Aß42 and ptau181 were available for 30 individuals. RESULTS: The learning phase of the cognitive mapping task and the self-report questionnaire were sensitive to identifying individuals in the preclinical AD continuum (93% and 87% sensitivity, 60% and 67% specificity, respectively). These two measures also demonstrated good test-retest stability (intraclass correlation coefficients = .719 and .838, respectively) and internal consistency (Cronbach's αs = .825 and .965, respectively). CONCLUSIONS: These findings suggest that a self-report questionnaire and aspects of a cognitive mapping task may be particularly appropriate for development as screening tools for identifying individuals in the preclinical AD continuum.

Asunto(s)

Enfermedad de Alzheimer/diagnóstico , Pruebas Neuropsicológicas , Síntomas Prodrómicos , Navegación Espacial , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Femenino , Humanos , Aprendizaje , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas/normas , Fragmentos de Péptidos/líquido cefalorraquídeo , Psicometría , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Encuestas y Cuestionarios , Proteínas tau/líquido cefalorraquídeo

RESUMEN

BACKGROUND: Several neurodegeneration (N) metrics using structural MRI are used for the purpose of Alzheimer's disease (AD)-related staging, including hippocampal volume, global atrophy, and an "AD signature" composite consisting of thickness or volumetric estimates derived from regions impacted early in AD. This study sought to determine if less user-intensive estimates of global atrophy and hippocampal volume were equivalent to a thickness-based AD signature from FreeSurfer for defining N across the AD continuum (i.e., individuals who are amyloid-positive (A+)). METHODS: Cognitively unimpaired (CU) late middle-aged and older adults, as well as A+ mild cognitive impairment (MCI) and A+ AD dementia individuals, with available CSF and structural MRI scan <1.5 years apart, were selected for the study (n = 325, mean age = 62). First, in a subsample of A+ AD dementia and matched biomarker-negative (i.e., A- and tau tangle pathology (T)-) CU controls (n = 40), we examined ROC characteristics and identified N cut-offs using Youden's J for neurofilament light chain protein (NfL) and each of three MRI-based measures: a thickness-based AD signature from FreeSurfer, hippocampal volume (using FIRST), and a simple estimate of global atrophy (the ratio of intracranial CSF segmented volume to brain tissue volume, using SPM12). Based on the results from the ROC analyses, we then examined the concordance between NfL N positivity and N positivity for each MRI-based metric using Cohen's Kappa in the remaining subsample of 285 individuals. Finally, in the full sample (n = 325), we examined the relationship between the four measures of N and group membership across the AD continuum using Kruskal-Wallis tests and Cliff's deltas. RESULTS: The three MRI-based metrics and CSF NfL similarly discriminated between the A-T- CU (n = 20) and A+ AD (n = 20) groups (AUCs ≥0.885; ps < 0.001). Using the cut-off values derived from the ROCs to define N positivity, there was weak concordance between NfL and all three MRI-derived metrics of N in the subsample of 285 individuals (Cohen's Kappas ≤0.429). Finally, the three MRI-based measures of N and CSF NfL showed similar associations with AD continuum group (i.e., Kruskal-Wallis ps < 0.001), with relatively larger effect sizes noted when comparing the A-T- CU to the A+ MCI (Cliff's deltas ≥0.741) and A+ AD groups (Cliff's deltas ≥0.810) than to the A+T- CU (Cliff's deltas = 0.112-0.298) and A + T+ CU groups (Cliff's deltas = 0.212-0.731). CONCLUSIONS: These findings suggest that the three MRI-based morphometric estimates and CSF NfL similarly differentiate individuals across the AD continuum on N status. In many applications, a simple estimate of global atrophy may be preferred as an MRI marker of N across the AD continuum given its methodological robustness and ease of calculation when compared to hippocampal volume or a cortical thickness AD signature.

Asunto(s)

Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/patología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Imagen por Resonancia Magnética/métodos , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Neuroimagen/métodos , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Atrofia/patología , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

OBJECTIVES: Prior research has identified numerous genetic (including sex), education, health, and lifestyle factors that predict cognitive decline. Traditional model selection approaches (e.g., backward or stepwise selection) attempt to find one model that best fits the observed data, risking interpretations that only the selected predictors are important. In reality, several predictor combinations may fit similarly well but result in different conclusions (e.g., about size and significance of parameter estimates). In this study, we describe an alternative method, Information-Theoretic (IT) model averaging, and apply it to characterize a set of complex interactions in a longitudinal study on cognitive decline. METHODS: Here, we used longitudinal cognitive data from 1256 late-middle aged adults from the Wisconsin Registry for Alzheimer's Prevention study to examine the effects of sex, apolipoprotein E (APOE) ɛ4 allele (non-modifiable factors), and literacy achievement (modifiable) on cognitive decline. For each outcome, we applied IT model averaging to a set of models with different combinations of interactions among sex, APOE, literacy, and age. RESULTS: For a list-learning test, model-averaged results showed better performance for women versus men, with faster decline among men; increased literacy was associated with better performance, particularly among men. APOE had less of an association with cognitive performance in this age range (∼40-70 years). CONCLUSIONS: These results illustrate the utility of the IT approach and point to literacy as a potential modifier of cognitive decline. Whether the protective effect of literacy is due to educational attainment or intrinsic verbal intellectual ability is the topic of ongoing work. (JINS, 2019, 25, 119-133).

Asunto(s)

Disfunción Cognitiva/epidemiología , Alfabetización/estadística & datos numéricos , Modelos Teóricos , Sistema de Registros , Adulto , Anciano , Enfermedad de Alzheimer/prevención & control , Apolipoproteína E4/genética , Disfunción Cognitiva/genética , Escolaridad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores Protectores , Factores Sexuales , Wisconsin/epidemiología

RESUMEN

OBJECTIVES: A major challenge in cognitive aging is differentiating preclinical disease-related cognitive decline from changes associated with normal aging. Neuropsychological test authors typically publish single time-point norms, referred to here as unconditional reference values. However, detecting significant change requires longitudinal, or conditional reference values, created by modeling cognition as a function of prior performance. Our objectives were to create, depict, and examine preliminary validity of unconditional and conditional reference values for ages 40-75 years on neuropsychological tests. METHOD: We used quantile regression to create growth-curve-like models of performance on tests of memory and executive function using participants from the Wisconsin Registry for Alzheimer's Prevention. Unconditional and conditional models accounted for age, sex, education, and verbal ability/literacy; conditional models also included past performance on and number of prior exposures to the test. Models were then used to estimate individuals' unconditional and conditional percentile ranks for each test. We examined how low performance on each test (operationalized as <7th percentile) related to consensus-conference-determined cognitive statuses and subjective impairment. RESULTS: Participants with low performance were more likely to receive an abnormal cognitive diagnosis at the current visit (but not later visits). Low performance was also linked to subjective and informant reports of worsening memory function. CONCLUSIONS: The percentile-based methods and single-test results described here show potential for detecting troublesome within-person cognitive change. Development of reference values for additional cognitive measures, investigation of alternative thresholds for abnormality (including multi-test criteria), and validation in samples with more clinical endpoints are needed. (JINS, 2019, 25, 1-14).

Asunto(s)

Enfermedad de Alzheimer/prevención & control , Envejecimiento Cognitivo/fisiología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/fisiopatología , Pruebas Neuropsicológicas , Sistema de Registros , Adulto , Anciano , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valores de Referencia , Wisconsin

RESUMEN

BACKGROUND: This study tested if central obesity, hypertension, or depressive symptoms moderated the relationship between ß-amyloid (Aß) and longitudinal cognitive performance in late middle-aged adults enriched for Alzheimer's disease (AD) risk. METHODS: Participants (n = 207; ages = 40-70 years; 73% parental AD) in the Wisconsin Registry for Alzheimer's Prevention study completed 3+ neuropsychological evaluations and a [11C]PiB positron emission tomography scan or lumbar puncture. Linear mixed-effects regression models tested interactions of risk factor × Aß × visit age on longitudinal Verbal Learning & Memory and Speed & Flexibility factor scores. RESULTS: The relationship between Aß and Verbal Learning & Memory decline was moderated by hypertension (χ2(1) = 3.85, P = .04) and obesity (χ2(1) = 6.12, P = .01); those with both elevated Aß and the risk factor declined at faster rates than those with only elevated Aß or elevated risk factors. CONCLUSION: In this cohort, hypertension and obesity moderated the relationship between Aß and cognitive decline.

Asunto(s)

Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/metabolismo , Hipertensión/epidemiología , Obesidad Abdominal/epidemiología , Adulto , Anciano , Enfermedad de Alzheimer/epidemiología , Biomarcadores/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Depresión/diagnóstico por imagen , Depresión/epidemiología , Depresión/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Hipertensión/diagnóstico por imagen , Hipertensión/metabolismo , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Obesidad Abdominal/diagnóstico por imagen , Obesidad Abdominal/metabolismo , Tomografía de Emisión de Positrones , Factores de Riesgo , Wisconsin

RESUMEN

PURPOSE: Older adults experience impaired driving performance, and modify their driving habits, including limiting amount and spatial extent of travel. Alzheimer disease (AD)-related pathology, as well as spatial navigation difficulties, may influence driving performance and driving behaviors in clinically normal older adults. We examined whether AD biomarkers [cerebrospinal fluid (CSF) concentrations of Aß42, tau, and ptau181] were associated with lower self-reported spatial navigation abilities, and whether navigation abilities mediated the relationship of AD biomarkers with driving performance and extent. METHODS: Clinically normal older adults (n=112; aged 65+) completed an on-road driving test, the Santa Barbara Sense of Direction scale (self-report measure of spatial navigation ability), and the Driving Habits Questionnaire for an estimate of driving extent (composite of driving exposure and driving space). All participants had a lumbar puncture to obtain CSF. RESULTS: CSF Aß42, but not tau or ptau181, was associated with self-reported navigation ability. Lower self-reported navigation was associated with reduced driving extent, but not driving errors. Self-reported navigation mediated the relationship between CSF Aß42 and driving extent. CONCLUSIONS: Findings suggest that cerebral amyloid deposition is associated with lower perceived ability to navigate the environment, which may lead older adults with AD pathology to limit their driving extent.

Asunto(s)

Enfermedad de Alzheimer , Péptidos beta-Amiloides/líquido cefalorraquídeo , Conducción de Automóvil , Biomarcadores/líquido cefalorraquídeo , Navegación Espacial , Anciano , Enfermedad de Alzheimer/genética , Femenino , Humanos , Estudios Longitudinales , Masculino , Pruebas Neuropsicológicas , Proteínas tau/líquido cefalorraquídeo

RESUMEN

Previous research indicates age-related impairments in learning routes from a start location to a target destination. There is less research on age effects on the ability to reverse a learned path. The method used to learn routes may also influence performance. This study examined how encoding methods influence the ability of younger and older adults to recreate a route in a virtual reality environment in forward and reverse directions. Younger (n = 50) and older (n = 50) adults learned a route either by self-navigation through the virtual environment or through studying a map. At test, participants recreated the route in the forward and reverse directions. Older adults in the map study condition had greater difficulty learning the route in the forward direction compared to younger adults. Older adults who learned the route by self-navigation were less accurate in traversing the route in the reverse compared to forward direction after a delay. In contrast, for older adults who learned via map study there were no significant differences between forward and reverse directions. Results suggest that older adults may not as readily develop and retain a sufficiently flexible representation of the environment during self-navigation to support accurate route reversal. Thus, initially learning a route from a map may be more difficult for older adults, but may ultimately be beneficial in terms of better supporting the ability to return to a start location. (PsycINFO Database Record

Asunto(s)

Envejecimiento/fisiología , Aprendizaje por Laberinto/fisiología , Percepción Espacial/fisiología , Adulto , Factores de Edad , Anciano , Envejecimiento/psicología , Señales (Psicología) , Ambiente , Femenino , Humanos , Masculino , Recuerdo Mental/fisiología , Orientación , Conducta Espacial , Interfaz Usuario-Computador , Adulto Joven

RESUMEN

OBJECTIVE: The Adult Children Study (ACS) at the Knight Alzheimer's Disease Research Center is a longitudinal investigation designed to identify and validate potential biomarkers of preclinical Alzheimer's disease (AD) in cognitively normal individuals with and without a family history of AD. The purpose of the current study was to validate the proposed latent structure of the ACS psychometric battery. METHOD: Confirmatory factor analyses of baseline data in a sample of 229 (75 men) cognitively normal middle-aged to older adult individuals assessed a hypothesized 4-factor model of cognitive performance. Measurement invariance was investigated as a function of family history of AD and apolipoprotein E (APOE) status. RESULTS: This study confirmed a priori hypotheses of 4 latent cognitive domains in a unique longitudinal sample of cognitively normal adults. In addition, there was evidence of a similar factor structure for family history and APOE status groups. CONCLUSION: These robust indicators of a broad range of cognitive domains will be used in future investigations to track the influence of family history of AD on cognitive performance over time. In addition, associations with fluid, structural, and molecular biomarkers of preclinical AD will be further examined, both cross-sectionally and longitudinally in this sample.

Asunto(s)

Enfermedad de Alzheimer/diagnóstico , Biomarcadores , Pruebas Neuropsicológicas , Psicometría/instrumentación , Hijos Adultos , Anciano , Análisis Factorial , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad

RESUMEN

BACKGROUND: Diagnosis threat is a psychosocial factor proposed to contribute to poor cognitive outcomes following mild traumatic brain injury (mTBI). The current research explored diagnosis threat impact on objective and subjective cognitive performance in a "high risk" population of athletes. Two possible moderators of diagnosis threat - injury beliefs and suggestibility - were also investigated. METHOD: Seventy-six participants with a history of mTBI were recruited through sports clubs and randomized to a months threat group (instructions drew attention to mTBI history) or a control group (no mention of mTBI). They completed a battery of neuropsychological tests and questionnaires regarding day-to-day cognitive abilities. Measures of depression, anxiety, illness beliefs and suggestibility were also collected. RESULTS: No significant group differences were found on any neuropsychological tasks, nor on self-report of cognitive difficulties. Illness beliefs were not found to play a moderating role in general, although the majority of the study sample did not report negative mTBI beliefs and expectations: concern about the consequences of injury was associated with weaker performance on one test, WAIS-III Digit Span performance. Suggestibility was also found to have a significant affect on this test. CONCLUSIONS: Diagnosis threat did not appear to have a marked affect on objective or subjective cognitive performance after mTBI in athletes. Differing injury beliefs between the study's athlete population and the general population is a possible explanation for different findings in the area. This and other sources of potential variation in the affect of diagnosis threat are discussed.

RESUMEN

Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Aß42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD.

Asunto(s)

Enfermedad de Alzheimer/psicología , Navegación Espacial , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Escolaridad , Femenino , Humanos , Aprendizaje , Masculino , Pruebas Neuropsicológicas , Síntomas Prodrómicos , Desempeño Psicomotor , Curva ROC , Interfaz Usuario-Computador , Proteínas tau/líquido cefalorraquídeo

RESUMEN

IMPORTANCE: Measures of neuronal loss are likely good surrogates for clinical and radiological disease progression in Alzheimer disease (AD). Cerebrospinal fluid (CSF) markers of neuronal injury or neurodegeneration may offer usefulness in predicting disease progression and guiding outcome assessments and prognostic decisions in clinical trials of disease-modifying therapies. Visinin-like protein 1 (VILIP-1) has demonstrated potential usefulness as a marker of neuronal injury in AD. OBJECTIVE: To investigate the usefulness of CSF VILIP-1, tau, p-tau181, and Aß42 levels in predicting rates of whole-brain and regional atrophy in early AD and cognitively normal control subjects over time. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal observational study of brain atrophy in participants with early AD and cognitively normal controls. Study participants had baseline CSF biomarker measurements and longitudinal magnetic resonance imaging assessments for a mean follow-up period of 2 to 3 years. Mixed linear models assessed the ability of standardized baseline CSF biomarker measures to predict rates of whole-brain and regional atrophy over the follow-up period. The setting was The Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St Louis. Participants (mean age, 72.6 years) were individuals with a clinical diagnosis of very mild AD (n = 23) and cognitively normal controls (n = 64) who were enrolled in longitudinal studies of healthy aging and dementia. The study dates were 2000 to 2010. MAIN OUTCOMES AND MEASURES: Correlations between baseline CSF biomarker measures and rates of whole-brain or regional atrophy in the AD and control cohorts over the follow-up period. RESULTS: Baseline CSF VILIP-1, tau, and p-tau181 levels (but not Aß42 levels) predicted rates of whole-brain and regional atrophy in AD over the follow-up period. Baseline CSF VILIP-1 levels predicted whole-brain (P = .006), hippocampal (P = .01), and entorhinal (P = .001) atrophy rates at least as well as tau and p-tau181 in early AD. Cognitively normal controls whose CSF VILIP-1, tau, or p-tau181 levels were in the upper tercile had higher rates of whole-brain (P = .02, P = .003, and P = .02, respectively), hippocampal (P = .001, P = .01, and P = .02, respectively), and entorhinal (P = .007, P = .01, and P = .01, respectively) atrophy compared with those whose levels were in the lower 2 terciles. CONCLUSIONS AND RELEVANCE: Cerebrospinal fluid VILIP-1 levels predict rates of whole-brain and regional atrophy similarly to tau and p-tau181 and may provide a useful CSF biomarker surrogate for neurodegeneration in early symptomatic and preclinical AD.

Asunto(s)

Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Encéfalo/patología , Neurocalcina/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Atrofia/patología , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Estudios Longitudinales , Masculino , Fragmentos de Péptidos/líquido cefalorraquídeo , Índice de Severidad de la Enfermedad