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OBJECTIVE: Along with the known effects of stress on brain structure and inflammatory processes, increasing evidence suggest a role of chronic stress in the pathogenesis of Alzheimer's disease (AD). We investigated the association of accumulated stressful life events (SLEs) with AD pathologies, neuroinflammation, and gray matter (GM) volume among cognitively unimpaired (CU) individuals at heightened risk of AD. METHODS: This cross-sectional cohort study included 1,290 CU participants (aged 48-77) from the ALFA cohort with SLE, lumbar puncture (n = 393), and/or structural magnetic resonance imaging (n = 1,234) assessments. Using multiple regression analyses, we examined the associations of total SLEs with cerebrospinal fluid (1) phosphorylated (p)-tau181 and Aß1-42/1-40 ratio, (2) interleukin 6 (IL-6), and (3) GM volumes voxel-wise. Further, we performed stratified and interaction analyses with sex, history of psychiatric disease, and evaluated SLEs during specific life periods. RESULTS: Within the whole sample, only childhood and midlife SLEs, but not total SLEs, were associated with AD pathophysiology and neuroinflammation. Among those with a history of psychiatric disease SLEs were associated with higher p-tau181 and IL-6. Participants with history of psychiatric disease and men, showed lower Aß1-42/1-40 with higher SLEs. Participants with history of psychiatric disease and women showed reduced GM volumes in somatic regions and prefrontal and limbic regions, respectively. INTERPRETATION: We did not find evidence supporting the association of total SLEs with AD, neuroinflammation, and atrophy pathways. Instead, the associations appear to be contingent on events occurring during early and midlife, sex and history of psychiatric disease. ANN NEUROL 2024;95:1058-1068.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Encéfalo , Enfermedades Neuroinflamatorias , Proteínas tau , Humanos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Femenino , Masculino , Anciano , Persona de Mediana Edad , Estudios Transversales , Estudios de Cohortes , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/diagnóstico por imagen , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Proteínas tau/líquido cefalorraquídeo , Imagen por Resonancia Magnética , Estrés Psicológico , Sustancia Gris/patología , Sustancia Gris/diagnóstico por imagen , Interleucina-6/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
INTRODUCTION: Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear. METHODS: We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269). RESULTS: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10-5) and higher CSF phosphorylated tau (p-tau) levels (P = 9.28 × 10-7). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10-6) and CSF p-tau levels (P = 4.38 × 10-9). DISCUSSION: These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels. HIGHLIGHTS: Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau. The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category. GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer's disease than controls. rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia.
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Enfermedad de Alzheimer , Estudio de Asociación del Genoma Completo , Glutatión Peroxidasa , Proteínas tau , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Proteínas de Unión al ADN/genética , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple/genética , Proteómica , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genéticaRESUMEN
Modifiable factors can influence the risk for Alzheimer's disease (AD) and serve as targets for intervention; however, the biological mechanisms linking these factors to AD are unknown. This study aims to identify plasma metabolites associated with modifiable factors for AD, including MIND diet, physical activity, smoking, and caffeine intake, and test their association with AD endophenotypes to identify their potential roles in pathophysiological mechanisms. The association between each of the 757 plasma metabolites and four modifiable factors was tested in the wisconsin registry for Alzheimer's prevention cohort of initially cognitively unimpaired, asymptomatic middle-aged adults. After Bonferroni correction, the significant plasma metabolites were tested for association with each of the AD endophenotypes, including twelve cerebrospinal fluid (CSF) biomarkers, reflecting key pathophysiologies for AD, and four cognitive composite scores. Finally, causal mediation analyses were conducted to evaluate possible mediation effects. Analyses were performed using linear mixed-effects regression. A total of 27, 3, 23, and 24 metabolites were associated with MIND diet, physical activity, smoking, and caffeine intake, respectively. Potential mediation effects include beta-cryptoxanthin in the association between MIND diet and preclinical Alzheimer cognitive composite score, hippurate between MIND diet and immediate learning, glutamate between physical activity and CSF neurofilament light, and beta-cryptoxanthin between smoking and immediate learning. Our study identified several plasma metabolites that are associated with modifiable factors. These metabolites can be employed as biomarkers for tracking these factors, and they provide a potential biological pathway of how modifiable factors influence the human body and AD risk.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Endofenotipos , Adulto , Humanos , Persona de Mediana Edad , Péptidos beta-Amiloides/metabolismo , beta-Criptoxantina , Biomarcadores , Cafeína/efectos adversos , Factores de Riesgo , Proteínas tauRESUMEN
INTRODUCTION: Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases. METHODS: We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of Aß42, Aß40, phosphorylated tau at threonine-181 (p-tau), neurofilament light (NfL), neurogranin, α-synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL-40, S100b, and interleukin 6 (IL-6) (Elecsys NeuroToolKit). RESULTS: Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/Aß42 alone (R2 ≥ 0.31) or together with NfL (R2 = 0.25), while p-tau/Aß42 (R2 ≥ 0.19) was sufficient to accurately predict change of the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P-tau/Aß42 (AUC ≥ 0.87) and p-tau/Aß42 together with NfL (AUC ≥ 0.75) were the best predictors of conversion to AD and all-cause dementia, respectively. DISCUSSION: P-tau/Aß42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all-cause dementia conversion and cognitive decline.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Estudios de Cohortes , Proteínas tau/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismoRESUMEN
INTRODUCTION: Apolipoprotein E (APOE) ε4-carrier status or ε4 allele count are included in analyses to account for the APOE genetic effect on Alzheimer's disease (AD); however, this does not account for protective effects of APOE ε2 or heterogeneous effect of ε2, ε3, and ε4 haplotypes. METHODS: We leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimer's Prevention (WRAP), Wisconsin Alzheimer's Disease Research Center (WADRC), and Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: The APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE ε4-carrier status and ε4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired (CU) participants. DISCUSSION: The APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Genotipo , Factores de Riesgo , Proteínas tau/genética , Proteínas tau/líquido cefalorraquídeoRESUMEN
PURPOSE: Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose ([18F]FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants. METHODS: We included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-ß (Aß) positive. Associations between GFAP markers and [18F]FDG uptake were studied. We also investigated whether these associations were modified by Aß and tau status (AT stages). RESULTS: Plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with [18F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aß pathology but became negative in Aß-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism. CONCLUSIONS: Higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Gliosis/diagnóstico por imagen , Gliosis/patología , Proteína Ácida Fibrilar de la Glía/metabolismo , Fluorodesoxiglucosa F18/metabolismo , Proteínas tau/metabolismo , Péptidos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Inflamación , Glucosa/metabolismoRESUMEN
INTRODUCTION: Neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion-weighted imaging (DWI) model, may be useful for detecting early cortical microstructural alterations in Alzheimer's disease prior to cognitive impairment. METHODS: Using neuroimaging (NODDI and T1-weighted magnetic resonance imaging [MRI]) and cerebrospinal fluid (CSF) biomarker data (measured using Elecsys® CSF immunoassays) from 219 cognitively unimpaired participants, we tested the main and interactive effects of CSF amyloid beta (Aß)42 /Aß40 and phosphorylated tau (p-tau) on cortical NODDI metrics and cortical thickness, controlling for age, sex, and apolipoprotein E ε4. RESULTS: We observed a significant CSF Aß42 /Aß40 × p-tau interaction on cortical neurite density index (NDI), but not orientation dispersion index or cortical thickness. The directionality of these interactive effects indicated: (1) among individuals with lower CSF p-tau, greater amyloid burden was associated with higher cortical NDI; and (2) individuals with greater amyloid and p-tau burden had lower cortical NDI, consistent with cortical neurodegenerative changes. DISCUSSION: NDI is a particularly sensitive marker for early cortical changes that occur prior to gross atrophy or development of cognitive impairment.
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Amiloide/líquido cefalorraquídeo , Corteza Cerebral , Voluntarios Sanos/estadística & datos numéricos , Neuritas/fisiología , Síntomas Prodrómicos , Proteínas tau/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquídeo , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
INTRODUCTION: This study examines the utility of a multipanel of cerebrospinal fluid (CSF) biomarkers complementing Alzheimer's disease (AD) biomarkers in a clinical research sample. We compared biomarkers across groups defined by clinical diagnosis and pTau181 /Aß42 status (+/-) and explored their value in predicting cognition. METHODS: CSF biomarkers amyloid beta (Aß)42 , pTau181 , tTau, Aß40 , neurogranin, neurofilament light (NfL), α-synuclein, glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), S100 calcium binding protein B (S100B), and interleukin 6 (IL6), were measured with the NeuroToolKit (NTK) for 720 adults ages 40 to 93 years (mean age = 63.9 years, standard deviation [SD] = 9.0; 50 with dementia; 54 with mild cognitive impairment [MCI], 616 unimpaired). RESULTS: Neurodegeneration and glial activation biomarkers were elevated in pTau181 /Aß42 + MCI/dementia participants relative to all pTau181 /Aß42 - participants. Neurodegeneration biomarkers increased with clinical severity among pTau181 /Aß42 + participants and predicted worse cognitive performance. Glial activation biomarkers were unrelated to cognitive performance. DISCUSSION: The NTK contains promising markers that improve the pathophysiological characterization of AD. Neurodegeneration biomarkers beyond tTau improved statistical prediction of cognition and disease stages.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Cognición/fisiología , Disfunción Cognitiva/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neurofilamentos , alfa-Sinucleína/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeoRESUMEN
Recency refers to the information learned at the end of a study list or task. Recency forgetting, as tracked by the ratio between recency recall in immediate and delayed conditions, i.e., the recency ratio (Rr), has been applied to list-learning tasks, demonstrating its efficacy in predicting cognitive decline, conversion to mild cognitive impairment (MCI), and cerebrospinal fluid (CSF) biomarkers of neurodegeneration. However, little is known as to whether Rr can be effectively applied to story recall tasks. To address this question, data were extracted from the database of the Alzheimer's Disease Research Center at the University of Wisconsin - Madison. A total of 212 participants were included in the study. CSF biomarkers were amyloid-beta (Aß) 40 and 42, phosphorylated (p) and total (t) tau, neurofilament light (NFL), neurogranin (Ng), and α-synuclein (a-syn). Story Recall was measured with the Logical Memory Test (LMT). We carried out Bayesian regression analyses with Rr, and other LMT scores as predictors; and CSF biomarkers (including the Aß42/40 and p-tau/Aß42 ratios) as outcomes. Results showed that models including Rr consistently provided best fits with the data, with few exceptions. These findings demonstrate the applicability of Rr to story recall and its sensitivity to CSF biomarkers of neurodegeneration, and encourage its inclusion when evaluating risk of neurodegeneration with story recall.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides , Teorema de Bayes , Biomarcadores , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Proteínas tau , NeuronasRESUMEN
Chronic systemic inflammation increases the risk of neurodegeneration, but the mechanisms remain unclear. Part of the challenge in reaching a nuanced understanding is the presence of multiple risk factors that interact to potentiate adverse consequences. To address modifiable risk factors and mitigate downstream effects, it is necessary, although difficult, to tease apart the contribution of an individual risk factor by accounting for concurrent factors such as advanced age, cardiovascular risk, and genetic predisposition. Using a case-control design, we investigated the influence of asthma, a highly prevalent chronic inflammatory disease of the airways, on brain health in participants recruited to the Wisconsin Alzheimer's Disease Research Center (31 asthma patients, 186 non-asthma controls, aged 45-90 years, 62.2% female, 92.2% cognitively unimpaired), a sample enriched for parental history of Alzheimer's disease. Asthma status was determined using detailed prescription information. We employed multi-shell diffusion weighted imaging scans and the three-compartment neurite orientation dispersion and density imaging model to assess white and gray matter microstructure. We used cerebrospinal fluid biomarkers to examine evidence of Alzheimer's disease pathology, glial activation, neuroinflammation and neurodegeneration. We evaluated cognitive changes over time using a preclinical Alzheimer cognitive composite. Using permutation analysis of linear models, we examined the moderating influence of asthma on relationships between diffusion imaging metrics, CSF biomarkers, and cognitive decline, controlling for age, sex, and cognitive status. We ran additional models controlling for cardiovascular risk and genetic risk of Alzheimer's disease, defined as a carrier of at least one apolipoprotein E (APOE) ε4 allele. Relative to controls, greater Alzheimer's disease pathology (lower amyloid-ß42/amyloid-ß40, higher phosphorylated-tau-181) and synaptic degeneration (neurogranin) biomarker concentrations were associated with more adverse white matter metrics (e.g. lower neurite density, higher mean diffusivity) in patients with asthma. Higher concentrations of the pleiotropic cytokine IL-6 and the glial marker S100B were associated with more salubrious white matter metrics in asthma, but not in controls. The adverse effects of age on white matter integrity were accelerated in asthma. Finally, we found evidence that in asthma, relative to controls, deterioration in white and gray matter microstructure was associated with accelerated cognitive decline. Taken together, our findings suggest that asthma accelerates white and gray matter microstructural changes associated with aging and increasing neuropathology, that in turn, are associated with more rapid cognitive decline. Effective asthma control, on the other hand, may be protective and slow progression of cognitive symptoms.
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Introduction: Metabolomics technology facilitates studying associations between small molecules and disease processes. Correlating metabolites in cerebrospinal fluid (CSF) with Alzheimer's disease (AD) CSF biomarkers may elucidate additional changes that are associated with early AD pathology and enhance our knowledge of the disease. Methods: The relative abundance of untargeted metabolites was assessed in 161 individuals from the Wisconsin Registry for Alzheimer's Prevention. A metabolome-wide association study (MWAS) was conducted between 269 CSF metabolites and protein biomarkers reflecting brain amyloidosis, tau pathology, neuronal and synaptic degeneration, and astrocyte or microglial activation and neuroinflammation. Linear mixed-effects regression analyses were performed with random intercepts for sample relatedness and repeated measurements and fixed effects for age, sex, and years of education. The metabolome-wide significance was determined by a false discovery rate threshold of 0.05. The significant metabolites were replicated in 154 independent individuals from then Wisconsin Alzheimer's Disease Research Center. Mendelian randomization was performed using genome-wide significant single nucleotide polymorphisms from a CSF metabolites genome-wide association study. Results: Metabolome-wide association study results showed several significantly associated metabolites for all the biomarkers except Aß42/40 and IL-6. Genetic variants associated with metabolites and Mendelian randomization analysis provided evidence for a causal association of metabolites for soluble triggering receptor expressed on myeloid cells 2 (sTREM2), amyloid ß (Aß40), α-synuclein, total tau, phosphorylated tau, and neurogranin, for example, palmitoyl sphingomyelin (d18:1/16:0) for sTREM2, and erythritol for Aß40 and α-synuclein. Discussion: This study provides evidence that CSF metabolites are associated with AD-related pathology, and many of these associations may be causal.
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Background: Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. Objective: In this study, we leveraged 10 years of longitudinal data from initially cognitively unimpaired individuals in the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. Methods: PRS and p-PRSs with and without apolipoprotein E ( APOE ) were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and global/domain-specific cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers for beta-amyloid 42 (Aß42), Aß42/40 ratio, total tau, and phosphorylated tau in a subset. Replication analyses were performed in an independent sample. Results: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of p-PRSs/PRS on rate of change in cognition, beta-amyloid, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. Conclusion: In addition to APOE , the p-PRSs can predict age-dependent changes in beta-amyloid, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating beta-amyloid and tau, long before the onset of clinical symptoms.
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BACKGROUND: Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. OBJECTIVE: In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. METHODS: PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample. RESULTS: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-ß, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. CONCLUSION: In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-ß, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-ß and tau, long before the onset of clinical symptoms.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Cognición , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Estudio de Asociación del Genoma Completo , Factores de Riesgo , Proteínas tau/genética , Proteínas tau/líquido cefalorraquídeoRESUMEN
BACKGROUND: Wordlist and story recall tests are routinely employed in clinical practice for dementia diagnosis. In this study, our aim was to establish how well-standard clinical metrics compared to process scores derived from wordlist and story recall tests in predicting biomarker determined Alzheimer's disease, as defined by CSF ptau/Aß42 ratio. METHODS: Data from 295 participants (mean age = 65 ± 9.) were drawn from the University of Wisconsin - Madison Alzheimer's Disease Research Center (ADRC) and Wisconsin Registry for Alzheimer's Prevention (WRAP). Rey's Auditory Verbal Learning Test (AVLT; wordlist) and Logical Memory Test (LMT; story) data were used. Bayesian linear regression analyses were carried out with CSF ptau/Aß42 ratio as outcome. Sensitivity analyses were carried out with logistic regressions to assess diagnosticity. RESULTS: LMT generally outperformed AVLT. Notably, the best predictors were primacy ratio, a process score indexing loss of information learned early during test administration, and recency ratio, which tracks loss of recently learned information. Sensitivity analyses confirmed this conclusion. CONCLUSIONS: Our study shows that story recall tests may be better than wordlist tests for detection of dementia, especially when employing process scores alongside conventional clinical scores.
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Enfermedad de Alzheimer , Humanos , Persona de Mediana Edad , Anciano , Enfermedad de Alzheimer/diagnóstico , Teorema de Bayes , Biomarcadores , Aprendizaje , Recuerdo MentalRESUMEN
Age-related disease may be mediated by low levels of chronic inflammation ("inflammaging"). Recent work suggests that gut microbes can contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer's disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation remains unclear. To investigate whether greater gut inflammation is associated with advanced age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity. Multiple regression with maximum likelihood estimation and Satorra-Bentler corrections were used to test relationships between fecal calprotectin and clinical diagnosis, participant age, cerebrospinal fluid biomarkers of AD pathology, amyloid burden measured using 11C-Pittsburgh compound B positron emission tomography (PiB PET) imaging, and performance on cognitive tests measuring executive function and verbal learning and recall. Calprotectin levels were elevated in advanced age and were higher in participants diagnosed with amyloid-confirmed AD dementia. Additionally, among individuals with AD dementia, higher calprotectin was associated with greater amyloid burden as measured with PiB PET. Exploratory analyses indicated that calprotectin levels were also associated with cerebrospinal fluid markers of AD, and with lower verbal memory function even among cognitively unimpaired participants. Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/metabolismo , Estudios de Cohortes , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Tomografía Computarizada por Rayos X , Tomografía de Emisión de Positrones/métodos , Amiloide/metabolismo , Complejo de Antígeno L1 de Leucocito/metabolismo , Biomarcadores/metabolismo , Proteínas tau/metabolismo , Disfunción Cognitiva/patologíaRESUMEN
Introduction: Evidence from epidemiology, neuroimaging, and animal models indicates that asthma adversely affects the brain, but the nature and extent of neuropathophysiological impact remain unclear. Methods: We tested the hypothesis that asthma is a risk factor for dementia by comparing cognitive performance and cerebrospinal fluid biomarkers of glial activation/neuroinflammation, neurodegeneration, and Alzheimer's disease (AD) pathology in 60 participants with asthma to 315 non-asthma age-matched control participants (45-93 years), in a sample enriched for AD risk. Results: Participants with severe asthma had higher neurogranin concentrations compared to controls and those with mild asthma. Positive relationships between cardiovascular risk and concentrations of neurogranin and α-synuclein were amplified in severe asthma. Severe asthma also amplified the deleterious associations that apolipoprotein E ε4 carrier status, cardiovascular risk, and phosphorylated tau181/amyloid beta42 have with rate of cognitive decline. Discussion: Our data suggest that severe asthma is associated with synaptic degeneration and may compound risk for dementia posed by cardiovascular disease and genetic predisposition. Highlights: Those with severe asthma showed evidence of higher dementia risk than controls evidenced by: higher levels of the synaptic degeneration biomarker neurogranin regardless of cognitive status, cardiovascular or genetic risk, and controlling for demographics.steeper increase in levels of synaptic degeneration biomarkers neurogranin and α-synuclein with increasing cardiovascular risk.accelerated cognitive decline with higher cardiovascular risk, genetic predisposition, or pathological tau.
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Introduction: White matter (WM) degeneration is a critical component of early Alzheimer's disease (AD) pathophysiology. Diffusion-weighted imaging (DWI) models, including diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI), and mean apparent propagator MRI (MAP-MRI), have the potential to identify early neurodegenerative WM changes associated with AD. Methods: We imaged 213 (198 cognitively unimpaired) aging adults with DWI and used tract-based spatial statistics to compare 15 DWI metrics of WM microstructure to 9 cerebrospinal fluid (CSF) markers of AD pathology and neurodegeneration treated as continuous variables. Results: We found widespread WM injury in AD, as indexed by robust associations between DWI metrics and CSF biomarkers. MAP-MRI had more spatially diffuse relationships with Aß42/40 and pTau, compared with NODDI and DTI. Discussion: Our results suggest that WM degeneration may be more pervasive in AD than is commonly appreciated and that innovative DWI models such as MAP-MRI may provide clinically viable biomarkers of AD-related neurodegeneration in the earliest stages of AD progression.
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Studying the correlation between cerebrospinal fluid (CSF) metabolites and the Alzheimer's Disease (AD) biomarkers may offer a window to the alterations of the brain metabolome and unveil potential biological mechanisms underlying AD. In this analysis, 308 CSF metabolites from 338 individuals of Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center were included in a principal component analysis (PCA). The resulted principal components (PCs) were tested for association with CSF total tau (t-tau), phosphorylated tau (p-tau), amyloid ß 42 (Aß42), and Aß42/40 ratio using linear regression models. Significant PCs were further tested with other CSF NeuroToolKit (NTK) and imaging biomarkers. Using a Bonferroni corrected p < 0.05, 5 PCs were significantly associated with CSF p-tau and t-tau and 3 PCs were significantly associated with CSF Aß42. Pathway analysis suggested that these PCS were enriched in 6 pathways, including metabolism of caffeine and nicotinate and nicotinamide. This study provides evidence that CSF metabolites are associated with AD pathology through core AD biomarkers and other NTK markers and suggests potential pathways to follow up in future studies.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Humanos , Metabolómica , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeoRESUMEN
Vanucizumab is a novel bispecific antibody inhibiting vascular endothelial growth factor (VEGF-A) and angiopoietin-2 (Ang-2) that demonstrated safety and anti-tumor activity in part I of a phase I study of 42 patients with advanced solid tumors. Part II evaluated the pharmacodynamic effects of vanucizumab 30 or 15â¯mg/kg every 2 weeks in 32 patients. Serial plasma samples, paired tumor, and skin-wound-healing biopsies were taken over 29 days to evaluate angiogenic markers. Vanucizumab was associated with marked post-infusion reductions in circulating unbound VEGF-A and Ang-2. By day 29, tumor samples revealed mean reductions in density of microvessels (-32.2%), proliferating vessels (-47.9%) and Ang-2 positive vessels (-62.5%). Skin biopsies showed a mean reduction in density of microvessels (-49.0%) and proliferating vessels (-25.7%). Gene expression profiling of tumor samples implied recruitment and potential activation of lymphocytes. Biopsies were safely conducted. Vanucizumab demonstrated a consistent biological effect on vascular-related biomarkers, confirming proof of concept. Skin-wound-healing biopsies were a valuable surrogate for studying angiogenesis-related mechanisms.
RESUMEN
BACKGROUND & AIMS: Annual testing for fecal occult blood is recommended as first-line screening for the detection of colorectal cancer (CRC), but is affected by limited sensitivity. We initiated a proteomics-based search for novel biomarkers to improve the sensitivity of detection of CRC in stool samples. METHODS: Six markers, including immunologic fecal occult blood test (iFOBT), were evaluated in a collective of 551 samples (186 CRC, 113 advanced adenoma, and 252 control patients) to establish the diagnostic performance of each marker and marker combinations. RESULTS: We tested the known stool markers hemoglobin (iFOBT), hemoglobin-haptoglobin, calprotectin, carcinoembryogenic antigen, and the novel fecal markers tissue inhibitor of metalloproteinase-1 (TIMP-1) and S100A12. The best diagnostic performance was found for S100A12 with an area under the curve of 0.95, followed by TIMP-1 (0.92), hemoglobin-haptoglobin (0.92), hemoglobin (0.91), calprotectin (0.90), and carcinoembryogenic antigen (0.66). By using Bayes logistic regression as a mathematic model, the highest sensitivity (88%) for the detection of CRC at 95% specificity was obtained with the marker pair S100A12 and hemoglobin-haptoglobin. Increasing the specificity to 98%, the combination of S100A12, hemoglobin-haptoglobin, and TIMP-1 resulted in a sensitivity of 82%, with the highest increase of sensitivity found in early tumor stages (international union against cancer stage I: 74% sensitivity vs 57% of the best single marker). CONCLUSIONS: Depending on the specificity selected, a marker pair, S100A12 and hemoglobin-haptoglobin, or a triple combination including TIMP-1, allowed the detection of CRC at significantly higher rates than can be obtained with iFOBT alone.