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OBJECTIVE: We investigated how well a visual associative learning task discriminates Alzheimer's disease (AD) dementia from other types of dementia and how it relates to AD pathology. METHODS: 3,599 patients (63.9 ± 8.9 years old, 41% female) from the Amsterdam Dementia Cohort completed two sets of the Visual Association Test (VAT) in a single test session and underwent magnetic resonance imaging. We performed receiver operating curve analysis to investigate the VAT's discriminatory ability between AD dementia and other diagnoses and compared it to that of other episodic memory tests. We tested associations between VAT performance and medial temporal lobe atrophy (MTA), and amyloid status (n = 2,769, 77%). RESULTS: Patients with AD dementia performed worse on the VAT than all other patients. The VAT discriminated well between AD and other types of dementia (area under the curve range 0.70-0.86), better than other episodic memory tests. Six-hundred forty patients (17.8%) learned all associations on VAT-A, but not on VAT-B, and they were more likely to have higher MTA scores (odds ratios range 1.63 (MTA 0.5) through 5.13 for MTA ≥ 3, all p < .001) and to be amyloid positive (odds ratio = 3.38, 95%CI = [2.71, 4.22], p < .001) than patients who learned all associations on both sets. CONCLUSIONS: Performance on the VAT, especially on a second set administered immediately after the first, discriminates AD from other types of dementia and is associated with MTA and amyloid positivity. The VAT might be a useful, simple tool to assess early episodic memory deficits in the presence of AD pathology.
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INTRODUCTION: Inferring the timeline from mild cognitive impairment (MCI) to severe dementia is pivotal for patients, clinicians, and researchers. Literature is sparse and often contains few patients. We aim to determine the time spent in MCI, mild-, moderate-, severe dementia, and institutionalization until death. METHODS: Multistate modeling with Cox regression was used to obtain the sojourn time. Covariates were age at baseline, sex, amyloid status, and Alzheimer's disease (AD) or other dementia diagnosis. The sample included a register (SveDem) and memory clinics (Amsterdam Dementia Cohort and Memento). RESULTS: Using 80,543 patients, the sojourn time from clinically identified MCI to death across all patient groups ranged from 6.20 (95% confidence interval [CI]: 5.57-6.98) to 10.08 (8.94-12.18) years. DISCUSSION: Generally, sojourn time was inversely associated with older age at baseline, males, and AD diagnosis. The results provide key estimates for researchers and clinicians to estimate prognosis.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Demencia , Masculino , Humanos , Progresión de la Enfermedad , Enfermedad de Alzheimer/complicaciones , Demencia/diagnóstico , Demencia/complicaciones , Disfunción Cognitiva/psicología , InstitucionalizaciónRESUMEN
INTRODUCTION: We disclosed amyloid positron emission tomography (PET) results in individuals with subjective cognitive decline (SCD) and studied patient experiences and outcomes over a 6-month period. METHODS: Fifty-seven participants from the Subjective Cognitive Impairment Cohort (SCIENCe) (66 ± 8 years, 21 [37%] F, Mini-Mental State Examination 29 ± 1, 15 [26%] amyloid positive [A+]) completed questionnaires 1 week prior (T0), 1 day after (T1), and 6 months after amyloid PET disclosure (T2). Questionnaires addressed patient-reported experiences and outcomes. RESULTS: Independent of amyloid status, participants were satisfied with the consultation (scale 1-10; 7.9 ± 1.7) and information provided (scale 1-4; T1: 3.3 ± 0.9, T2: 3.2 ± 0.8). After 6 months, A+ participants reported more information needs (45% vs. 12%, p = 0.02). Independent of amyloid status, decision regret (scale 1-5; A+: 1.5 ± 0.9, A-: 1.4 ± 0.6, p = 0.53) and negative emotions (negative affect, uncertainty, anxiety) were low (all p > 0.15 and Pinteraction > 0.60). DISCUSSION: Participants with SCD valued amyloid PET disclosure positively, regardless of amyloid status. The need for information after 6 months, which was stronger in A+ individuals, underscores the importance of follow-up. HIGHLIGHTS: Participants with subjective cognitive decline (SCD) positively valued amyloid positron emission tomography (PET) disclosure. Participants with SCD experienced low levels of decision regret. We did not observe an increase in negative emotions. After 6 months, amyloid-positive individuals wanted more information.
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INTRODUCTION: We assessed whether co-morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease. METHODS: In 1090 non-demented participants (65.4 ± 10.7 years) SVD was assessed with magnetic resonance imaging and amyloid beta (Aß) with lumbar puncture and/or positron emission tomography scan (mean follow-up for cognitive function 3.1 ± 2.4 years). RESULTS: Thirty-nine percent had neither Aß nor SVD (A-V-), 21% had SVD only (A-V+), 23% Aß only (A+V-), and 17% had both (A+V+). Pooled cohort linear mixed model analyses demonstrated that compared to A-V- (reference), A+V- had a faster rate of cognitive decline. Co-morbid SVD (A+V+) did not further increase rate of decline. Cox regression showed that dementia risk was modestly increased in A-V+ (hazard ratio [95% confidence interval: 1.8 [1.0-3.2]) and most strongly in A+ groups. Also, mortality risk was increased in A+ groups. DISCUSSION: In non-demented persons Aß was predictive of cognitive decline, dementia, and mortality. SVD modestly predicts dementia in A-, but did not increase deleterious effects in A+. HIGHLIGHTS: Amyloid beta (Aß; A) was predictive for cognitive decline, dementia, and mortality. Small vessel disease (SVD) had no additional deleterious effects in A+. SVD modestly predicted dementia in A-. Aß should be assessed even when magnetic resonance imaging indicates vascular cognitive impairment.
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Enfermedad de Alzheimer , Enfermedades de los Pequeños Vasos Cerebrales , Trastornos del Conocimiento , Disfunción Cognitiva , Demencia Vascular , Humanos , Péptidos beta-Amiloides , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Imagen por Resonancia MagnéticaRESUMEN
INTRODUCTION: We developed a multimarker blood test result interpretation tool for the clinical dementia practice, including phosphorylated (P-)tau181, amyloid-beta (Abeta)42/40, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). METHODS: We measured the plasma biomarkers with Simoa (n = 1199), applied LASSO regression for biomarker selection and receiver operating characteristics (ROC) analyses to determine diagnostic accuracy. We validated our findings in two independent cohorts and constructed a visualization approach. RESULTS: P-tau181, GFAP, and NfL were selected. This combination had area under the curve (AUC) = 83% to identify amyloid positivity in pre-dementia stages, AUC = 87%-89% to differentiate Alzheimer's or controls from frontotemporal dementia, AUC = 74%-76% to differentiate Alzheimer's or controls from dementia with Lewy bodies. Highly reproducible AUCs were obtained in independent cohorts. The resulting visualization tool includes UpSet plots to visualize the stand-alone biomarker results and density plots to visualize the biomarker results combined. DISCUSSION: Our multimarker blood test interpretation tool is ready for testing in real-world clinical dementia settings. HIGHLIGHTS: We developed a multimarker blood test interpretation tool for clinical dementia practice. Our interpretation tool includes plasma biomarkers P-tau, GFAP, and NfL. Our tool is particularly useful for Alzheimer's and frontotemporal dementia diagnosis.
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BACKGROUND AND PURPOSE: Early diagnosis of behavioral variant frontotemporal dementia (bvFTD) is challenging due to symptomatic overlap with primary psychiatric disorders (PPD). As emotion recognition deficits are early and key features of bvFTD, the aim was to explore processes driving social cognition deficits that may aid in the differentiation between bvFTD and PPD. METHODS: The total sample (N = 51) included 18 patients with bvFTD, 11 patients with PPD (mood, autism spectrum and psychotic disorders) and 22 controls from the Alzheimer Center Amsterdam of the Amsterdam UMC. Emotion recognition was assessed with the Ekman 60 Faces test, during which eye tracking metrics were collected in the first 5 s a face was presented. Group differences in dwell time on the total image as well as the circumscribed eyes area and mouth area were analysed using ANOVA, with post hoc comparisons. RESULTS: Patients with bvFTD scored lowest, patients with PPD scored intermediate and controls scored highest on emotion recognition. During facial processing, patients with bvFTD spent less dwell time on the total image than controls (mean difference 11.3%, F(2, 48) = 6.095, p = 0.004; bvFTD-controls p = 0.001, 95% confidence interval [CI] -892.64, -239.70). Dwell time on the eyes area did not differ between diagnostic groups, whilst patients with bvFTD spent less dwell time on the mouth area than PPD patients (mean difference 10.7%; F(2, 48) = 3.423, p = 0.041; bvFTD-PPD p = 0.022, 95% CI -986.38, -79.47) and controls (mean difference 7.8%; bvFTD-controls p = 0.043, 95% CI -765.91, -12.76). CONCLUSIONS: In bvFTD, decreased emotion recognition may be related to reduced focus on facial hallmarks. These findings suggest a valuable role for biometrics in social cognition assessment and the differentiation between bvFTD and PPD.
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Enfermedad de Alzheimer , Demencia Frontotemporal , Humanos , Demencia Frontotemporal/psicología , Pruebas Neuropsicológicas , Reconocimiento en Psicología , Emociones , Cognición , Enfermedad de Alzheimer/diagnósticoRESUMEN
INTRODUCTION: We investigated changes in self- and study partner-reported self-perceived cognitive decline in relation to amyloid pathology and clinical progression, in a sample of cognitively normal individuals. METHODS: A total of 404 participants (63 ± 9 years, 44% female) and their study partners completed the Cognitive Change Index (CCI) yearly (0.7-6.8 follow-up years; n visits = 1436). Baseline and longitudinal associations between (change in) CCI scores, amyloid, and clinical progression were modeled in linear mixed models and Cox regressions. RESULTS: CCI-study partner scores of amyloid-positive individuals increased over time (B = 1.79, 95% confidence interval [CI] = [0.51, 3.06]), while CCI-self scores remained stable (B = -0.45, 95% CI = [-1.77, 0.87]). Ten-point higher baseline CCI-study partner (hazard ratio [HR] = 1.75, 95% CI = [1.30, 2.36]) and CCI-self scores (HR = 1.90, 95% CI = [1.40, 2.58]) were associated with an approximately 2-fold increased risk of progression to mild cognitive impairment or dementia. DISCUSSION: Study partner-reported but not self-perceived complaints increase over time in amyloid-positive individuals, supporting the value of longitudinal study partner report, even in initially cognitively normal individuals.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Femenino , Masculino , Enfermedad de Alzheimer/patología , Estudios Longitudinales , Progresión de la Enfermedad , Cognición , Disfunción Cognitiva/psicología , Amiloide , Proteínas Amiloidogénicas , Péptidos beta-AmiloidesRESUMEN
INTRODUCTION: We examined the association between cerebrospinal fluid (CSF)-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms (NPS) in older non-demented adults. METHODS: We included 784 persons (699 cognitively unimpaired, 85 with mild cognitive impairment) aged ≥ 50 years who underwent CSF amyloid beta (Aß42), hyperphosphorylated tau 181 (p-tau), and total tau (t-tau) as well as NPS assessment using Beck Depression and Anxiety Inventories (BDI-II, BAI), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Lower CSF Aß42, and higher t-tau/Aß42 and p-tau/Aß42 ratios were associated with BDI-II and BAI total scores, clinical depression (BDI-II ≥ 13), and clinical anxiety (BAI ≥ 10), as well as NPI-Q-assessed anxiety, apathy, and nighttime behavior. DISCUSSION: CSF Aß42, t-tau/Aß42, and p-tau/Aß42 ratios were associated with NPS in community-dwelling individuals free of dementia. If confirmed by a longitudinal cohort study, the findings have clinical relevance of taking into account the NPS status of individuals with abnormal CSF biomarkers.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Estudios Longitudinales , Proteínas tau/líquido cefalorraquídeo , Envejecimiento , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
INTRODUCTION: We aimed to provide cut points for the automated Elecsys Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers. METHODS: Cut points for Elecsys amyloid beta 42 (Aß42), total tau (t-tau), hyperphosphorylated tau (p-tau), and t-tau/Aß42 and p-tau/Aß42 ratios were evaluated in Mayo Clinic Study of Aging (n = 804) and Mayo Clinic Alzheimer's Disease Research Center (n = 70) participants. RESULTS: The t-tau/Aß42 and p-tau/Aß42 ratios had a higher percent agreement with normal/abnormal amyloid positron emission tomography (PET) than the individual CSF markers. Reciever Operating Characteristic (ROC)-based cut points were 0.26 (0.24-0.27) for t-tau/Aß42 and 0.023 (0.020-0.025) for p-tau/Aß42. Ratio cut points derived from other cohorts performed as well in our cohort as our own did. Individual biomarkers had worse diagnostic properties and more variable results in terms of positive and negative percent agreement (PPA and NPA). CONCLUSION: CSF t-tau/Aß42 and p-tau/Aß42 ratios are very robust indicators of AD. For individual biomarkers, the intended use should determine which cut point is chosen.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Amiloide , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Humanos , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeoRESUMEN
The Alzheimer's Association's Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimer's Association Research Framework. This review will summarize the "A, T, N System" (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/terapia , Ensayos Clínicos como Asunto , Enfermedad de Alzheimer/fisiopatología , Biomarcadores/metabolismo , Desarrollo de Medicamentos , Humanos , National Institute on Aging (U.S.) , Estados UnidosRESUMEN
In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-ß1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-ß1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-ß amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-ß1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-ß1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-ß1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-ß1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Cognición/fisiología , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Análisis de Varianza , Apolipoproteínas E/genética , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/etiología , Pruebas Neuropsicológicas , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND AND PURPOSE: In patients with subjective cognitive decline, we assessed whether small vessel disease was associated with clinical progression and cognitive decline. METHODS: We included 334 patients with subjective cognitive decline. Follow-up was 3±2 years. RESULTS: Fifty-three (16%) patients progressed clinically to mild cognitive impairment or dementia. White matter hyperintensities were associated with clinical progression and with annual decline on memory, attention, executive functioning, and global cognition. Microbleeds and lacunes were not associated with clinical progression or cognitive decline. CONCLUSIONS: In patients with subjective cognitive decline, patients with white matter hyperintensities are at increased risk of clinical progression and cognitive decline.
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Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Demencia/patología , Demencia/fisiopatología , Progresión de la Enfermedad , Sustancia Blanca/patología , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , MasculinoRESUMEN
There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.
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Enfermedad de Alzheimer/fisiopatología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/fisiopatología , Progresión de la Enfermedad , Síntomas Prodrómicos , Edad de Inicio , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Terminología como AsuntoRESUMEN
BACKGROUND: Apolipoprotein-E (APOE) genetic testing for Alzheimer's disease is becoming more important as clinical trials are increasingly targeting individuals carrying APOE-ε4 alleles. Little is known about the interest in finding out one's genetic risk for Alzheimer's disease in the general population. Our objective was to examine this in a sample of cognitively normal (CN) adults within a population-based online research registry with the goal to implement APOE-ε4 status for trial recruitment. METHODS: An online survey was completed by 442 CN participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia and knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOE-ε4/ε4 genotypes). Cochran's Q and post hoc McNemar tests were used to analyse differences in frequencies across scenarios. RESULTS: Most participants were interested in participating in research into and disclosure of their genetic risk (81%). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, whilst lower-educated participants were more often undecided. When provided with different risk scenarios, interest in knowing their risk was somewhat higher in the scenarios with higher risk, i.e. in the 50% (79%) compared to the 10% scenario (73%;χ2(2) = 7.98; p = .005). Most individuals expected they would share their genetic risk with close relatives (77-89%), would participate in medication trials (79-88%), and would make long-term arrangements, e.g. retirement, health care, will (69-82%), with larger proportions for scenarios with higher hypothetical genetic risk. CONCLUSIONS: Our findings indicate that the vast majority of CN adults participating in a research registry expresses interest in AD genetic risk research and disclosure. Interest in genetic risk disclosure is higher in scenarios corresponding to the APOE-ε4 genotype. This suggests APOE-ε4 screening within an online research registry is potentially a well-received method to accelerate inclusion for trials.
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Enfermedad de Alzheimer , Masculino , Adulto , Humanos , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/epidemiología , Revelación , Genotipo , Apolipoproteínas E/genética , Predisposición Genética a la Enfermedad/genética , Apolipoproteína E4/genéticaRESUMEN
BACKGROUND AND OBJECTIVES: Cognitive decline rates in Alzheimer disease (AD) vary greatly. Disease-modifying treatments may alter cognitive decline trajectories, rendering their prediction increasingly relevant. We aimed to construct clinically applicable prediction models of cognitive decline in amyloid-positive patients with mild cognitive impairment (MCI) or mild dementia. METHODS: From the Amsterdam Dementia Cohort, we selected amyloid-positive participants with MCI or mild dementia and at least 2 longitudinal Mini-Mental State Examination (MMSE) measurements. Amyloid positivity was based on CSF AD biomarker concentrations or amyloid PET. We used linear mixed modeling to predict MMSE over time, describing trajectories using a cubic time curve and interactions between linear time and the baseline predictors age, sex, baseline MMSE, APOE ε4 dose, CSF ß-amyloid (Aß) 1-42 and pTau, and MRI total brain and hippocampal volume. Backward selection was used to reduce model complexity. These models can predict MMSE over follow-up or the time to an MMSE value. MCI and mild dementia were modeled separately. Internal 5-fold cross-validation was performed to calculate the explained variance (R2). RESULTS: In total, 961 participants were included (age 65 ± 7 years, 49% female), 310 had MCI (MMSE 26 ± 2) and 651 had mild dementia (MMSE 22 ± 4), with 4 ± 2 measurements over 2 (interquartile range 1-4) years. Cognitive decline rates increased over time for both MCI and mild dementia (model comparisons linear vs squared vs cubic time fit; p < 0.05 favoring a cubic fit). For MCI, backward selection retained age, sex, and CSF Aß1-42 and pTau concentrations as time-varying effects altering the MMSE trajectory. For mild dementia, retained time-varying effects were Aß1-42, age, APOE ε4, and baseline MMSE. R2 was 0.15 for the MCI model and 0.26 for mild dementia in internal cross-validation. A hypothetical patient with MCI, baseline MMSE 28, and CSF Aß1-42 of 925 pg/mL was predicted to reach an MMSE of 20 after 6.0 years (95% CI 5.4-6.7) and after 8.6 years with a hypothetical treatment reducing decline by 30%. DISCUSSION: We constructed models for MCI and mild dementia that predict MMSE over time. These models could inform patients about their potential cognitive trajectory and the remaining uncertainty and aid in conversations about individualized potential treatment effects.
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Péptidos beta-Amiloides , Disfunción Cognitiva , Demencia , Fragmentos de Péptidos , Humanos , Femenino , Masculino , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico por imagen , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Demencia/diagnóstico por imagen , Demencia/líquido cefalorraquídeo , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Imagen por Resonancia Magnética , Biomarcadores/líquido cefalorraquídeo , Pruebas de Estado Mental y Demencia , Estudios de Cohortes , Progresión de la Enfermedad , Encéfalo/diagnóstico por imagen , Encéfalo/patologíaRESUMEN
Background: We hypothesize that Alzheimer's disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases. Objective: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline. Methods: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-ß42/40 (Aß42/40), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models with terms for biomarker, time and biomarker*time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline. Results: Among patients, Aß42/40 was not associated with cognitive performance at baseline. However, lower Aß42/40 was associated with steeper decline in global cognition (ß±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (-0.14±0.04) and memory (-0.31±0.09) and with steeper decline in global cognition (-0.07±0.02), memory (-0.09±0.04), attention (-0.05±0.02), and language (-0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (-0.22±0.05), memory (-0.43±0.10), attention (-0.14±0.06), language (-0.15±0.05), and executive functioning (-0.15±0.05) and steeper decline in global cognition (-0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (-0.16±0.04), memory (-0.28±0.09), attention (-0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found. Conclusions: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases.
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Enfermedad de Alzheimer , Enfermedades Cardiovasculares , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/patología , Enfermedades Cardiovasculares/complicaciones , Péptidos beta-Amiloides , Encéfalo/patología , Disfunción Cognitiva/psicología , Biomarcadores , Proteínas tauRESUMEN
OBJECTIVE: To evaluate the performance of Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers in a tertiary neurology clinic setting with high frequency of non-AD cases, including normal pressure hydrocephalus (NPH). METHODS: There were 534 patients who underwent AD CSF biomarkers (Roche Elecsys Aß42, p-Tau181, total-Tau) from April 1, 2020, through April 23, 2021. A behavioral neurologist blinded to CSF results assigned a clinical diagnosis retrospectively on the basis of consensus criteria, and a neuroradiologist blinded to the diagnosis and CSF studies graded brain magnetic resonance images for indicators of CSF dynamics disorders. Associations between biomarkers, diagnoses, and imaging were assessed by χ2, analysis of covariance, and linear regression methods. RESULTS: Median age at time of testing was 67 years (range, 19 to 96 years), median symptom duration was 2 years (range, 0.4 to 28 years), and median Short Test of Mental Status score was 30 (range, 0 to 38). Clinical diagnoses significantly correlated with different CSF biomarker values (χ2=208.3; P=10e-4). p-Tau181/Aß42 ratios above 0.023 positively correlated with Alzheimer dementia (more than individual measures). This ratio also had the best performance for differentiating Alzheimer dementia from NPH (area under the curve, 0.869). Imaging markers supportive of CSF dynamics disorders correlated with low Aß42, p-Tau181, and total-Tau. CONCLUSION: In a heterogeneous clinical population, abnormal p-Tau181/Aß42 ratios (>0.023) have the strongest association with Alzheimer dementia and probably represent a comorbid AD pathologic component in persons clearly matching non-AD neurodegenerative syndromes. Altered CSF dynamics were associated with lower concentrations of AD CSF biomarkers regardless of clinical diagnosis, but the ratio compensates for these changes. In the appropriate clinical setting, an isolated abnormal Aß42 should prompt consideration of NPH.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Proteínas tau , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Anciano , Masculino , Femenino , Persona de Mediana Edad , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano de 80 o más Años , Adulto , Estudios Retrospectivos , Fragmentos de Péptidos/líquido cefalorraquídeo , Hidrocéfalo Normotenso/líquido cefalorraquídeo , Hidrocéfalo Normotenso/diagnóstico , Centros de Atención Terciaria , Adulto Joven , Imagen por Resonancia Magnética/métodosRESUMEN
BACKGROUND AND OBJECTIVES: It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups. METHODS: Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (ßtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years. RESULTS: We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (ßtime range -0.30 to -0.71), followed by delayed word list recognition (ßtime range -0.18 to -0.50). Functional decline (ßtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (ßtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction. DISCUSSION: In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.
Asunto(s)
Enfermedad de Alzheimer , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/diagnóstico por imagen , Apolipoproteína E4/genética , Proteínas Amiloidogénicas , Biomarcadores , CogniciónRESUMEN
BACKGROUND: Digital speech assessment has potential relevance in the earliest, preclinical stages of Alzheimer's disease (AD). We evaluated the feasibility, test-retest reliability, and association with AD-related amyloid-beta (Aß) pathology of speech acoustics measured over multiple assessments in a remote setting. METHODS: Fifty cognitively unimpaired adults (Age 68 ± 6.2 years, 58% female, 46% Aß-positive) completed remote, tablet-based speech assessments (i.e., picture description, journal-prompt storytelling, verbal fluency tasks) for five days. The testing paradigm was repeated after 2-3 weeks. Acoustic speech features were automatically extracted from the voice recordings, and mean scores were calculated over the 5-day period. We assessed feasibility by adherence rates and usability ratings on the System Usability Scale (SUS) questionnaire. Test-retest reliability was examined with intraclass correlation coefficients (ICCs). We investigated the associations between acoustic features and Aß-pathology, using linear regression models, adjusted for age, sex and education. RESULTS: The speech assessment was feasible, indicated by 91.6% adherence and usability scores of 86.0 ± 9.9. High reliability (ICC ≥ 0.75) was found across averaged speech samples. Aß-positive individuals displayed a higher pause-to-word ratio in picture description (B = -0.05, p = 0.040) and journal-prompt storytelling (B = -0.07, p = 0.032) than Aß-negative individuals, although this effect lost significance after correction for multiple testing. CONCLUSION: Our findings support the feasibility and reliability of multi-day remote assessment of speech acoustics in cognitively unimpaired individuals with and without Aß-pathology, which lays the foundation for the use of speech biomarkers in the context of early AD.
Asunto(s)
Estudios de Factibilidad , Acústica del Lenguaje , Humanos , Femenino , Masculino , Anciano , Reproducibilidad de los Resultados , Persona de Mediana Edad , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides , Habla/fisiologíaRESUMEN
BACKGROUND: The need to recognize Alzheimer's disease (AD) as early as possible led us to evaluate the predictive value of amyloid ß(1-42) (Aß42), total tau (tau), and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) for clinical progression in patients with subjective complaints. METHODS: We recruited nondemented patients with subjective complaints (i.e., criteria for mild cognitive impairment [MCI] not fulfilled) from our memory clinic. We assessed the predictive value of CSF Aß42, tau, and ptau for clinical progression using Cox proportional hazards models adjusted for age, gender, and baseline findings on the Mini-Mental State Examination (MMSE). Clinical progression was defined as progression to MCI or AD. RESULTS: We included 127 patients with subjective complaints (age 60 ± 10 years, 61 [48%] females, MMSE 29 ± 1). At baseline, Aß42 and tau were abnormal in 20 patients (both 16%), and ptau in 32 patients (25%). Thirteen patients (10%) progressed to MCI (n = 11) or AD (n = 2). Aß42 was the strongest predictor of progression to MCI or AD with an adjusted hazard ratio (HR) of 16.0 (3.8-66.4). The adjusted HR associated with tau was 2.8 (0.9-9.2) and with ptau 2.6 (0.8-8.2). Combinations of biomarkers had a lower predictive value than Aß42 alone. CONCLUSION: Low Aß42 was the strongest predictor of clinical progression in patients with subjective complaints. These results are in line with the hypothesis that the cascade of pathologic events starts with deposition of Aß42, whereas neuronal degeneration and hyperphosphorylation of tau are more downstream events, closer to clinical manifestation of AD.