RESUMO
BACKGROUND: In Alzheimer's disease (AD) diagnosis, a cerebrospinal fluid (CSF) biomarker panel is commonly interpreted with binary cutoff values. However, these values are not generic and do not reflect the disease continuum. We explored the use of interval-specific likelihood ratios (LRs) and probability-based models for AD using a CSF biomarker panel. METHODS: CSF biomarker (Aß1-42, tTau and pTau181) data for both a clinical discovery cohort of 241 patients (measured with INNOTEST) and a clinical validation cohort of 129 patients (measured with EUROIMMUN), both including AD and non-AD dementia/cognitive complaints were retrospectively retrieved in a single-center study. Interval-specific LRs for AD were calculated and validated for univariate and combined (Aß1-42/tTau and pTau181) biomarkers, and a continuous bivariate probability-based model for AD, plotting Aß1-42/tTau versus pTau181 was constructed and validated. RESULTS: LR for AD increased as individual CSF biomarker values deviated from normal. Interval-specific LRs of a combined biomarker model showed that once one biomarker became abnormal, LRs increased even further when another biomarker largely deviated from normal, as replicated in the validation cohort. A bivariate probability-based model predicted AD with a validated accuracy of 88% on a continuous scale. CONCLUSIONS: Interval-specific LRs in a combined biomarker model and prediction of AD using a continuous bivariate biomarker probability-based model, offer a more meaningful interpretation of CSF AD biomarkers on a (semi-)continuous scale with respect to the post-test probability of AD across different assays and cohorts.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Probabilidade , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Humanos , Biomarcadores/líquido cefalorraquidiano , Feminino , Masculino , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Funções Verossimilhança , Pessoa de Meia-Idade , Proteínas tau/líquido cefalorraquidiano , Estudos Retrospectivos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Estudos de CoortesRESUMO
BACKGROUND: Cholinesterase inhibitors (ChEIs) are prescribed for Alzheimer's disease (AD) and sometimes for mild cognitive impairment (MCI) without knowing underlying pathologies and its effect on cognition. We investigated the frequency of ChEI prescriptions in amyloid-negative MCI and their association with cognitive changes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. METHODS: We included participants with amyloid positron emission tomography (PET)-negative MCI from the ADNI. We analyzed the associations of ChEI use with cognitive changes, brain volume, and cerebrospinal fluid (CSF) total tau (t-tau), hyperphosphorylated tau181 (p-tau181), and p-tau181/t-tau ratio. RESULTS: ChEIs were prescribed in 27.4% of amyloid PET-negative MCI and were associated with faster cognitive decline, reduced baseline hippocampal volume and entorhinal cortical thickness, and a longitudinal decrease in the frontal lobe cortical thickness. CONCLUSIONS: The association between ChEI use and accelerated cognitive decline may stem from underlying pathologies involving reduced hippocampal volume, entorhinal cortical thickness and faster frontal lobe atrophy. We suggest that ChEI use in amyloid PET-negative MCI patients might need further consideration, and studies investigating the causality between ChEI use and cognitive decline are warranted in the future.
Assuntos
Inibidores da Colinesterase , Disfunção Cognitiva , Tomografia por Emissão de Pósitrons , Humanos , Disfunção Cognitiva/diagnóstico por imagem , Masculino , Tomografia por Emissão de Pósitrons/métodos , Feminino , Idoso , Inibidores da Colinesterase/uso terapêutico , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismo , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Amiloide/metabolismoRESUMO
It has been suggested that the diagnostic landscape of Alzheimer disease (AD) is undergoing a profound transformation, marked by a shift toward a biomarker-based approach, as proposed by the Revised Criteria for Diagnosis and Staging of Alzheimer's Disease. These criteria advocate for diagnosing AD solely on biomarkers, without requiring clinical symptoms. This article explores the drivers behind this transition, primarily influenced by the Food and Drug Administration's approval of amyloid-lowering treatments. We evaluate the proposed criteria, which allow for an AD diagnosis based on amyloid "A" or phosphorylated tau "T1" positivity through surrogate amyloid PET imaging, CSF, or plasma biomarkers, and consider the arguments for and against their use. The merits of the new criteria include a clearer definition of AD, which is currently used interchangeably to refer to both the presence of neuropathology and the clinical syndrome. We argue that a purely biological definition risks a category error and emphasize the need for longitudinal data to establish the lifetime risk of dementia in amyloid-positive and tau-positive individuals. We also caution against limiting the scope of biomarker-based AD diagnosis to amyloid and tau alone. In conclusion, we recommend that the criteria remain within the research domain for the present while advocating for the considered adoption of plasma biomarkers in clinical practice.
Assuntos
Doença de Alzheimer , Biomarcadores , Proteínas tau , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/sangue , Humanos , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: Both blood (plasma and serum) and CSF tau phosphorylated at Threonine 217 (pTau217) have been shown to be able to discriminate early to mild Alzheimer's disease (AD) from non-AD neurodegenerative disorders and healthy controls with high sensitivity and specificity. OBJECTIVES: We report the full validation of the ALZpath ultra-sensitive pTau217 research-use only (RUO) assays for human EDTA plasma, serum, and CSF using the Quanterix Simoa HD-X platform, in support of clinical trials and early diagnosis of Alzheimer's disease. METHODS: The ALZpath pTau217 Simoa Advantage v2 kit from ALZpath/Quanterix was used for method development and validation of pTau217 in human plasma, serum, and CSF. All three method validations have followed the 2018 FDA BMV and 2022 ICH M10 guidelines. RESULTS: Validation of pTau217 quantitation in human plasma, serum, and CSF demonstrated that the validated pTau217 assay has an analytical LLOQ of 0.00977 pg/mL. It is one of the most sensitive assays with a minimal required sample volume of 33.3 µl for plasma and serum, and 5 µl for CSF, and is relatively cost-effective, compared to the currently published data. The minimum required dilution (MRD) for plasma, serum, and CSF were determined. The analyte passed short-term stability tests. It was also tolerant of moderate hemolytic, and lipemic interferences in plasma and serum. pTau217 was detected in 100% of tested healthy control plasma, 90.0% of healthy control serum, 92.3% of healthy control CSF samples, and 100% of AD plasma and CSF samples. The validated assay was successfully applied in the analysis of AD samples, with data showing dramatic differences in the pTau217 levels between healthy control subjects and AD patients in both plasma and CSF. CONCLUSION: Validation of the ALZpath pTau217 Simoa assay in human plasma, serum, and CSF demonstrates ultra sensitivity, high accuracy, and assay robustness. Together with other established and sensitive assays for pTau181, GFAP, and NfL, these assays have immediate utility for application in clinical trials and can play a role in the early diagnosis of neurodegenerative diseases.
Assuntos
Doença de Alzheimer , Proteínas tau , Humanos , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Fosforilação , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Sensibilidade e Especificidade , Reprodutibilidade dos TestesRESUMO
Background: Bridging integrator 1 (BIN1) gene polymorphism has been reported to play a role in the pathological processes of Alzheimer's disease (AD). Objective: To explore the association of BIN1 loci with neuroinflammation and AD pathology. Methods: Alzheimer's Disease Neuroimaging Initiative (ADNI, Nâ=â495) was the discovery cohort, and Chinese Alzheimer's Biomarker and LifestylE (CABLE, Nâ=â619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model and causal mediation analysis conducted through 10,000 bootstrapped iterations were used to examine the BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia-soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Results: In ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and levels of CSF phosphorylated-tau (P-tau) (pcâ=â0.017; 0.010, respectively) and total-tau (T-tau) (pcâ=â0.011; 0.013, respectively). The BIN1 loci were also correlated with CSF sTREM2 levels (pcâ=â0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of BIN1 loci with P-tau (Proportion of rs7561528â:â20.8%; Proportion of rs744373â:â24.8%) and T-tau (Proportion of rs7561528â:â36.5%; Proportion of rs744373â:â43.9%). The analysis in CABLE study replicated the mediation role of rs7561528. Conclusions: This study demonstrated the correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarkers. Additionally, the link between BIN1 loci and tau pathology was partially mediated by CSF sTREM2.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Doença de Alzheimer , Biomarcadores , Glicoproteínas de Membrana , Receptores Imunológicos , Proteínas Supressoras de Tumor , Proteínas tau , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Feminino , Proteínas Supressoras de Tumor/genética , Masculino , Idoso , Receptores Imunológicos/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Polimorfismo de Nucleotídeo Único/genética , Idoso de 80 Anos ou mais , Proteínas NuclearesRESUMO
AIMS: The early stages of Alzheimer's disease (AD) are no longer insurmountable. Therefore, identifying at-risk individuals is of great importance for precise treatment. We developed a model to predict cognitive deterioration in patients with mild cognitive impairment (MCI). METHODS: Based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, we constructed models in a derivation cohort of 761 participants with MCI (138 of whom developed dementia at the 36th month) and verified them in a validation cohort of 353 cognitively normal controls (54 developed MCI and 19 developed dementia at the 36th month). In addition, 1303 participants with available AD cerebrospinal fluid core biomarkers were selected to clarify the ability of the model to predict AD core features. We assessed 32 parameters as candidate predictors, including clinical information, blood biomarkers, and structural imaging features, and used multivariable logistic regression analysis to develop our prediction model. RESULTS: Six independent variables of MCI deterioration were identified: apolipoprotein E ε4 allele status, lower Mini-Mental State Examination scores, higher levels of plasma pTau181, smaller volumes of the left hippocampus and right amygdala, and a thinner right inferior temporal cortex. We established an easy-to-use risk heat map and risk score based on these risk factors. The area under the curve (AUC) for both internal and external validations was close to 0.850. Furthermore, the AUC was above 0.800 in identifying participants with high brain amyloid-ß loads. Calibration plots demonstrated good agreement between the predicted probability and actual observations in the internal and external validations. CONCLUSION: We developed and validated an accurate prediction model for dementia conversion in patients with MCI. Simultaneously, the model predicts AD-specific pathological changes. We hope that this model will contribute to more precise clinical treatment and better healthcare resource allocation.
Assuntos
Disfunção Cognitiva , Demência , Progressão da Doença , Proteínas tau , Humanos , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Masculino , Idoso , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Demência/sangue , Demência/diagnóstico por imagem , Idoso de 80 Anos ou mais , Imageamento por Ressonância Magnética/métodos , Biomarcadores/sangue , Estudos de Coortes , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neuroimagem/métodosRESUMO
AIM: To examine whether changes in biomarker concentrations in patients with idiopathic normal-pressure hydrocephalus (iNPH) during 72 h of external lumbar drainage (ELD) can differentiate between responders and non-responders. METHODS: Twenty patients with clinical and neuroradiological signs of iNPH underwent ELD over a period of 72 h. During this period, changes in cerebrospinal fluid (CSF) concentrations of biomarkers (amyloid-ß, total and phosphorylated tau proteins) and intracranial pressure were monitored, and the volume of drained CSF was measured. Changes in the concentrations of selected biomarkers at three time points (0, 36, and 72 h) during ELD were tested for association with changes in clinical condition. RESULTS: Ten patients showed significant clinical improvement after ELD, quantified as a difference of two or more points on the Mini-Mental State Examination and/or Japanese iNPH grading scale. The concentration of all tested biomarkers increased during the first 36 h. Respondents had higher Aß 1-42 at all time points, with a significant difference seen after 72 h. They also had a significantly higher Aß1-42/Aß1-40 ratio at all time points. CONCLUSION: A gradual increase in Aß 1-42 concentration during three-day ELD represents a possible positive prognostic factor for the placement of permanent CSF drainage in patients with iNPH.
Assuntos
Peptídeos beta-Amiloides , Biomarcadores , Drenagem , Hidrocefalia de Pressão Normal , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/cirurgia , Masculino , Feminino , Projetos Piloto , Biomarcadores/líquido cefalorraquidiano , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Idoso de 80 Anos ou mais , Proteínas tau/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Pessoa de Meia-Idade , Pressão Intracraniana , Punção EspinalRESUMO
METHODS: This study conducted a genome-wide association study (GWAS) on longitudinal CSF t-tau and genotype data from 319 non-Hispanic Caucasians within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. The aim was to identify genetic determinants influencing the rate of change in CSF t-tau, a key biomarker in AD. RESULTS: The GWAS identified a significant single nucleotide polymorphism (SNP), rs17149074, within the C9orf171 (CFAP77) gene region that showed significant association with changes in CSF t-tau over time. Additionally, five other SNPs-rs10916844, rs10916846, rs9425869, rs3744474, and rs8078303-were found to potentially influence CSF t-tau variability. CONCLUSIONS: These findings not only enhance our understanding of t-tau's progression in AD but also suggest that these identified SNPs could serve as novel genetic biomarkers, potentially providing novel insights in the prognostic landscape of AD by refining the predictive value of CSF-tau measurements (Tab. 2, Fig. 2, Ref. 31). Text in PDF www.elis.sk Keywords: cerebrospinal fluid, t-tau, genome-wide association study, single nucleotide polymorphism, genetic factors.
Assuntos
Doença de Alzheimer , Biomarcadores , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Proteínas tau , Humanos , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genética , Idoso , Feminino , Masculino , Estudos Longitudinais , Doença de Alzheimer/genética , Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Idoso de 80 Anos ou mais , GenótipoRESUMO
BACKGROUND: Alzheimer's disease (AD) heritability is estimated to be around 70-80%. Yet, much of it remains to be explained. Studying transmission patterns may help in understanding other factors contributing to the development of AD. OBJECTIVE: In this study, we aimed to search for evidence of autosomal recessive or X- and Y-linked inheritance of risk factors in a large cohort of Portuguese AD patients. METHODS: We collected family history from patients with AD and cognitively healthy controls over 75 years of age. We compared the proportions of maternal and paternal history in male and female patients and controls (to search for evidence of X-linked and Y-linked inherited risk factors). We compared the risk of developing AD depending on parents' birthplace (same vs. different), as a proxy of remote consanguinity. We performed linear regressions to study the association of these variables with different endophenotypes. RESULTS: We included 3090 participants, 2183 cognitively healthy controls and 907 patients with AD. Men whose mother had dementia have increased odds of developing AD comparing to women whose mother had dementia. In female patients with a CSF biomarker-supported diagnosis of AD, paternal history of dementia is associated with increased CSF phosphorylated Tau levels. People whose parents are from the same town have higher risk of dementia. In multivariate analysis, this proxy is associated with a lower age of onset and higher CSF phosphorylated tau. CONCLUSIONS: Our study gives evidence supporting an increased risk of developing AD associated with an X-linked inheritance pattern and remote consanguinity.
Assuntos
Doença de Alzheimer , Humanos , Masculino , Feminino , Doença de Alzheimer/genética , Doença de Alzheimer/epidemiologia , Portugal/epidemiologia , Idoso , Fatores de Risco , Idoso de 80 Anos ou mais , Estudos de Coortes , Predisposição Genética para Doença , Genes Ligados ao Cromossomo X , Genes Recessivos , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genética , Cromossomos Humanos X/genéticaRESUMO
BACKGROUND: Impulse control disorders (ICDs) are an increasingly recognized complication in Parkinson disease (PD). The pathogenesis of ICDs is currently unclear. Few genetic studies have been conducted in this area. OBJECTIVE: We aimed to ascertain the correlation between APOE and ICDs, and identify clinical predictors of ICDs in PD. METHODS: This study included 287 PD patients from the Parkinson's Progression Markers Initiative. They were followed up to investigate the progression of ICDs over a period of 5 years. The cumulative incidence of ICDs and potential risk factors were evaluated using Kaplan-Meier and Cox regression analyses. RESULTS: 44.3% (31/70) patients with APOE É4 and 32.3% (70/217) patients without APOE É4 developed ICDs during the five-year follow up period. There were significant differences between the PD with and without ICDs development group in age, MSEADLG score, ESS score, GDS score, and STAI score at baseline. In multivariable Cox regression analysis, APOE ε4 (HR = 1.450, p = 0.048) and STAI score (HR = 1.017, p = 0.001) were predictors of the development of ICDs. Patients with APOE É4 group showed significantly lower CSF Aß42 and CSF α-syn level than patients without APOE É4 group at baseline. In patients with APOE É4 group, the "low α-syn level" group and the "low ptau/tau ratio" group had a significantly higher incidence of ICDs, respectively. CONCLUSIONS: This study provides important insights into the potential role of the APOE gene in the development of ICDs in PD. Further studies are needed to confirm our findings and to investigate the underlying mechanisms in more detail.
Assuntos
Progressão da Doença , Transtornos Disruptivos, de Controle do Impulso e da Conduta , Doença de Parkinson , Humanos , Doença de Parkinson/genética , Doença de Parkinson/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Transtornos Disruptivos, de Controle do Impulso e da Conduta/genética , Fatores de Risco , Apolipoproteína E4/genética , Estudos Longitudinais , Incidência , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genética , Apolipoproteínas E/genéticaRESUMO
BACKGROUND AND OBJECTIVES: There is a clear need to characterize and validate molecular biomarkers of cerebral amyloid angiopathy (CAA), in an effort to improve diagnostics, especially in the context of patients with Alzheimer disease (AD) receiving immunotherapies (for whom underlying CAA is the driver of amyloid-related imaging abnormalities). We performed an updated meta-analysis of 5 core CSF biomarkers (Aß42, Aß40, Aß438, total tau [T-tau], and phosphorylated tau [P-tau]) to assess which of these are most altered in sporadic CAA. METHODS: We systematically searched PubMed for eligible studies reporting data on CSF biomarkers reflecting APP metabolism (Aß42, Aß40, Aß38), neurodegeneration (T-tau), and tangle pathology (P-tau), in symptomatic sporadic CAA cohorts (based on the Boston criteria) vs control groups and/or vs patients with AD. Biomarker performance was assessed in random-effects meta-analysis based on ratio of mean (RoM) biomarker concentrations in (1) patients with CAA to controls and (2) CAA to patients with AD. RoM >1 indicates higher biomarker concentration in CAA vs comparison population, and RoM <1 indicates higher concentration in comparison groups. RESULTS: 8 studies met inclusion criteria: a total of 11 CAA cohorts (n = 289), 9 control cohorts (n = 310), and 8 AD cohorts (n = 339). Overall included studies were of medium quality based on our assessment tools. CAA to controls had lower mean level of all amyloid markers with CSF Aß42, Aß40, and Aß38 RoMs of 0.46 (95% CI 0.38-0.55, p < 0.0001), 0.70 (95% CI 0.63-0.78, p < 0.0001), and 0.71 (95% CI 0.56-0.89, p = 0.003), respectively. CSF T-tau and P-tau RoMs of patients with CAA to controls were both greater than 1: 1.56 (95% CI 1.32-1.84, p < 0.0001) and 1.31 (95% CI 1.13-1.51, p < 0.0001), respectively. Differentiation between CAA and AD was strong for CSF Aß40 (RoM 0.76, 95% CI 0.69-0.83, p < 0.0001) and Aß38 (RoM 0.55, 95% CI 0.38-0.81, p < 0.0001), but not Aß42 (RoM 1.00; 95% CI 0.81-1.23, p = 0.970). For T-tau and P-tau, average CSF ratios in patients with CAA vs AD were 0.64 (95% CI 0.58-0.71, p < 0.0001) and 0.64 (95% CI 0.58-0.71, p < 0.0001), respectively. DISCUSSION: Specific CSF patterns of Aß42, Aß40, Aß38, T-tau, and P-tau might serve as molecular biomarkers of CAA, in research and clinical settings, offering the potential to improve the clinical diagnostic approach pathway in specific scenarios.
Assuntos
Peptídeos beta-Amiloides , Biomarcadores , Angiopatia Amiloide Cerebral , Proteínas tau , Humanos , Angiopatia Amiloide Cerebral/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnósticoRESUMO
OBJECTIVES: Recently, a subset of patients affected by cerebral amyloid angiopathy (CAA) distinguished by atypical juvenile onset and a hypothesized iatrogenic origin (iatrogenic CAA, iCAA) has emerged. ß-Amyloid (Aß) accumulation evidenced by amyloid PET positivity or CSF Aß decrease was included in the iCAA diagnostic criteria. Conversely, diagnostic criteria for sporadic CAA (sCAA) do not involve biomarker analysis. The aim of this study was to assess CSF and plasma levels of Aß and tau in iCAA and sCAA cohorts. METHODS: Patients affected by probable or possible CAA according to established criteria (Boston 2.0) were prospectively recruited at Fondazione IRCCS Carlo Besta and San Gerardo dei Tintori from May 2021 to January 2024. Patients with probable and possible iCAA or sCAA with available plasma and/or CSF samples were included. Clinical and neurologic data were collected, and levels of Aß40, Aß42, total tau, and phospho-tau (p-tau) were assessed in CSF and plasma by SiMoA and Lumipulse. RESULTS: 21 patients with iCAA (72% male, mean age at symptom onset 50 years [36-74]) and 32 patients with sCAA (44% male, mean age at symptom onset 68 years [52-80]) were identified. Cognitive impairment and cardiovascular risk factors in the sCAA cohort were more common compared with the iCAA cohort. Patients with sCAA and iCAA showed similar CSF levels for Aß40 (p = 0.5 [sCAA, 95% CI 2,604-4,228; iCAA, 95% CI 1,958-3,736]), Aß42 (p = 0.7 [sCAA, 95% CI 88-157; iCAA, 95% CI 83-155]), and total tau (p = 0.08 [sCAA, 95% CI 80-134; iCAA, 95% CI 37-99]). Plasma levels of Aß40 (p = 0.08, 95% CI 181-222), Aß42 (p = 0.3, 95% CI 6-8), and total tau (p = 0.4, 95% CI 3-6) were not statistically different in patients with sCAA compared with iCAA ones (Aß40, 95% CI 153-193; Aß42, 95% CI 6-7 and total tau, 95% CI 2-4). DISCUSSION: Despite presenting with a younger age at onset, fewer cardiovascular risk factors, and lower cognitive impairment, patients with iCAA demonstrated Aß and tau levels comparable with elderly patients with sCAA, supporting a common molecular paradigm between the 2 CAA forms.
Assuntos
Peptídeos beta-Amiloides , Biomarcadores , Angiopatia Amiloide Cerebral , Doença Iatrogênica , Fragmentos de Peptídeos , Proteínas tau , Humanos , Masculino , Feminino , Angiopatia Amiloide Cerebral/sangue , Angiopatia Amiloide Cerebral/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Idoso , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Estudos Prospectivos , Idoso de 80 Anos ou maisRESUMO
BACKGROUND AND OBJECTIVES: Vascular risk factors (VRFs) and cerebral small vessel disease (cSVD) are common in patients with Alzheimer disease (AD). It remains unclear whether this coexistence reflects shared risk factors or a mechanistic relationship and whether vascular and amyloid pathologies have independent or synergistic influence on subsequent AD pathophysiology in preclinical stages. We investigated links between VRFs, cSVD, and amyloid levels (Aß1-42) and their combined effect on downstream AD biomarkers, that is, CSF hyperphosphorylated tau (P-tau181), atrophy, and cognition. METHODS: This retrospective study included nondemented participants (Clinical Dementia Rating < 1) from the European Prevention of Alzheimer's Dementia (EPAD) cohort and assessed VRFs with the Framingham risk score (FRS) and cSVD features on MRI using visual scales and white matter hyperintensity volumes. After preliminary linear analysis, we used structural equation modeling (SEM) to create a "cSVD severity" latent variable and assess the direct and indirect effects of FRS and cSVD severity on Aß1-42, P-tau181, gray matter volume (baseline and longitudinal), and cognitive performance (baseline and longitudinal). RESULTS: A total cohort of 1,592 participants were evaluated (mean age = 65.5 ± 7.4 years; 56.16% F). We observed positive associations between FRS and all cSVD features (all p < 0.05) and a negative association between FRS and Aß1-42 (ß = -0.04 ± 0.01). All cSVD features were negatively associated with CSF Aß1-42 (all p < 0.05). Using SEM, the cSVD severity fully mediated the association between FRS and CSF Aß1-42 (indirect effect: ß = -0.03 ± 0.01), also when omitting vascular amyloid-related markers. We observed a significant indirect effect of cSVD severity on P-tau181 (indirect effect: ß = 0.12 ± 0.03), baseline and longitudinal gray matter volume (indirect effect: ß = -0.10 ± 0.03; ß = -0.12 ± 0.05), and baseline cognitive performance (indirect effect: ß = -0.16 ± 0.03) through CSF Aß1-42. DISCUSSION: In a large nondemented population, our findings suggest that cSVD is a mediator of the relationship between VRFs and CSF Aß1-42 and affects downstream neurodegeneration and cognitive impairment. We provide evidence of VRFs indirectly affecting the pathogenesis of AD, highlighting the importance of considering cSVD burden in memory clinics for AD risk evaluation and as an early window for intervention. These results stress the role of VRFs and cerebrovascular pathology as key biomarkers for accurate design of anti-amyloid clinical trials and offer new perspectives for patient stratification.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Doenças de Pequenos Vasos Cerebrais , Fragmentos de Peptídeos , Proteínas tau , Humanos , Doença de Alzheimer/patologia , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Masculino , Feminino , Idoso , Fatores de Risco , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Estudos Retrospectivos , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/patologia , Proteínas tau/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética , Biomarcadores/líquido cefalorraquidiano , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Atrofia/patologiaRESUMO
Background: The N-glycan structure bisecting N-acetylglucosamine (bisecting GlcNAc) is present on several N-glycans that are elevated in Alzheimer's disease (AD), and previous studies have shown that bisecting GlcNAc levels correlate with total tau and phospho-tau181 in cerebrospinal fluid at early stages of AD. A recent population-based study showed that bisecting GlcNAc correlates with total tau also in blood and that this correlation could predict conversion to dementia. Objective: In this study, we have further investigated how bisecting GlcNAc relates to total tau and phospho-tau 181 in cerebrospinal fluid samples from controls and cases with early cognitive deficits, stratified by amyloid/tau status and gender. Methods: Relative levels of bisecting GlcNAc in cerebrospinal fluid were measured by an enzyme-linked lectin assay in individuals with subjective cognitive decline, mild cognitive impairment and controls from the Norwegian Dementia Disease Initiation cohort. Results: As in our previous study, the correlation between bisecting GlcNAc and total tau or phospho-tau181 was particularly strong in the subjective cognitive decline group. The correlation was observed in amyloid negative and tau negative as well as amyloid positive and tau positive individuals, both in females and in males. Interestingly, among the amyloid negative and tau negative individuals, the correlation was observed in individuals with subjective cognitive decline but not in the controls. Conclusions: Thus, bisecting GlcNAc could be a biomarker for early cognitive decline.
Assuntos
Acetilglucosamina , Disfunção Cognitiva , Proteínas tau , Humanos , Masculino , Feminino , Acetilglucosamina/metabolismo , Proteínas tau/líquido cefalorraquidiano , Idoso , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/sangue , Pessoa de Meia-Idade , Fosforilação , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidianoRESUMO
BACKGROUND: Mechanisms underlying neurodegeneration in multiple sclerosis (MS) remain poorly understood but mostly implicate molecular pathways that are not unique to MS. Recently detected tau seeding activity in MS brain tissues corroborates previous neuropathological reports of hyperphosphorylated tau (p-tau) accumulation in secondary and primary progressive MS (PPMS). We aimed to investigate whether aberrant tau phosphorylation can be detected in the cerebrospinal fluid (CSF) of MS patients by using novel ultrasensitive immunoassays for different p-tau biomarkers. METHODS: CSF samples of patients with MS (n = 55) and non-inflammatory neurological disorders (NIND, n = 31) were analysed with in-house Single molecule array (Simoa) assays targeting different tau phosphorylation sites (p-tau181, p-tau212, p-tau217 and p-tau231). Additionally, neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were measured with a multiplexed Simoa assay. Patients were diagnosed with clinically isolated syndrome (CIS, n = 10), relapsing-remitting MS (RRMS, n = 21) and PPMS (n = 24) according to the 2017 McDonald criteria and had MRI, EDSS and basic CSF analysis performed at the time of diagnosis. RESULTS: Patients with progressive disease course had between 1.4-fold (p-tau217) and 2.2-fold (p-tau212) higher p-tau levels than relapsing MS patients (PPMS compared with CIS + RRMS, p < 0.001 for p-tau181, p-tau212, p-tau231 and p = 0.042 for p-tau217). P-tau biomarkers were associated with disease duration (ρ=0.466-0.622, p < 0.0001), age (ρ=0.318-0.485, p < 0.02, all but p-tau217) and EDSS at diagnosis and follow-up (ρ=0.309-0.440, p < 0.02). In addition, p-tau biomarkers correlated with GFAP (ρ=0.517-0.719, p ≤ 0.0001) but not with the albumin quotient, CSF cell count or NFL. Patients with higher MRI lesion load also had higher p-tau levels p ≤ 0.01 (<10 vs. ≥ 10 lesions, all p ≤ 0.01). CONCLUSION: CSF concentrations of novel p-tau biomarkers point to a higher degree of tau phosphorylation in PPMS than in RRMS. Associations with age, disease duration and EDSS suggest this process increases with disease severity; however, replication of these results in larger cohorts is needed to further clarify the relevance of altered tau phosphorylation throughout the disease course in MS.
Assuntos
Biomarcadores , Progressão da Doença , Proteínas tau , Humanos , Proteínas tau/líquido cefalorraquidiano , Feminino , Masculino , Pessoa de Meia-Idade , Fosforilação , Adulto , Biomarcadores/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/diagnóstico , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/metabolismo , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/metabolismoRESUMO
BACKGROUND: Cerebrospinal fluid (CSF) leaks can lead to serious complications if left untreated, making rapid and accurate diagnosis essential. Biomarkers such as ß2-transferrin (B2TRF) and ß-trace protein are used to detect CSF leaks, but their limitations warrant the exploration of alternative markers. This study investigates the potential of phosphorylated tau at threonine 181 (p-tau181) as a biomarker for CSF leaks. METHODS: Samples from 56 subjects were analyzed for B2TRF and p-tau181 using immunoaffinity blotting and chemiluminescent enzyme immunoassay, respectively. Data analysis included Mann-Whitney test to assess the overall difference in median p-tau181 concentrations between B2TRF positive and negative patients and a receiver operating characteristic (ROC) curve analysis to determine optimal p-tau181 cutoff values for predicting B2TRF positivity. RESULTS: p-tau181 levels were significantly higher in B2TRF positive samples compared to negative samples (p < 0.001). ROC analysis showed high diagnostic performance for p-tau181, with an optimal cutoff of 13.22 pg/mL providing 92.0% sensitivity and 93.1% specificity. Excluding hemolyzed samples improved further the diagnostic performances, maintaining high sensitivity (90.9%) and achieving perfect specificity (100.0%). CONCLUSIONS: This study highlights the potential of p-tau181 as a valuable biomarker for the detection of CSF leaks due to its high diagnostic accuracy and practical advantages over the current biomarkers. The characteristics of p-tau181 assay being both quantitative and rapid, with high diagnostic accuracy, suggest that it could be a valuable tool for the detection of CSF leaks. Further research are now needed to validate these findings.
Assuntos
Biomarcadores , Vazamento de Líquido Cefalorraquidiano , Proteínas tau , Humanos , Proteínas tau/líquido cefalorraquidiano , Feminino , Biomarcadores/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Idoso , Fosforilação , Adulto , Vazamento de Líquido Cefalorraquidiano/diagnóstico , Vazamento de Líquido Cefalorraquidiano/líquido cefalorraquidiano , Curva ROC , Transferrina/líquido cefalorraquidiano , Transferrina/análise , Sensibilidade e EspecificidadeRESUMO
BACKGROUND AND OBJECTIVES: This study evaluates the discriminative performance of the automated Lumipulse plasma pTau-217 compared to plasma pTau-181 and the Aß42/Aß40 ratio across cerebrospinal fluid (CSF) A/T classes and diagnostic groups within a memory-center-based population of cognitively impaired patients. METHODS: This cross-sectional study in a Memory Center enrolled 98 patients along the AD continuum or affected by other neurodegenerative disorders, stratified by CSF A/T status and clinical syndrome. Plasma pTau-217, pTau-181, and Aß42/Aß40 were measured using Lumipulse. Relationships with CSF and glomerular filtration rate (GFR) were explored. ROC analysis was conducted to assess diagnostic performance. RESULTS: The CSF A/T profiles included 49 A+/T+, 8 A+/T-, and 41 A-/T-. Clinical diagnoses at discharge were AD-dementia (AD-DEM), AD-MCI, NonAD-MCI, and NonAD-dementia (NonAD-DEM). Plasma pTau-217 and the pTau-217/Aß42 ratio strongly correlated with CSF pTau-181 and total Tau (R = 0.80). GFR had minimal influence on plasma biomarker ratios. Plasma pTau-217 exhibited excellent AUC values (0.94-0.97) for distinguishing CSF A+/T+ and A+ status, showing higher discriminative accuracy than pTau-181 and Aß42/Aß40 (AUCs: 0.66-0.83). Optimal cutoff for plasma pTau-217 indicated excellent accuracy (93.3%), sensitivity (91.8%), and specificity (95.1%). AD-DEM patients displayed the highest pTau-217 levels, with significant differences across clinical groups. DISCUSSION: The findings confirm that Lumipulse plasma pTau-217 offers superior diagnostic accuracy for reflecting CSF A/T status. Plasma pTau-217 emerged as an accurate standalone biomarker of AD neuropathology across MCI and dementia stages. The study underscores the utility of automated Lumipulse assays, promoting their integration into routine diagnostic workflows to facilitate early and accurate AD detection.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Fragmentos de Peptídeos , Proteínas tau , Humanos , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Feminino , Masculino , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Idoso , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Estudos Transversais , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/sangue , Disfunção Cognitiva/líquido cefalorraquidianoRESUMO
Background: While drainage/removal of fluid and toxins from the brain by cerebrospinal fluid (CSF) directly into venous blood is well-known, a second drainage route has recently been (re)discovered-meningeal lymphatic vessels (mLVs)-which are responsible for up to half of total brain fluid/toxin drainage. The cytokine vascular endothelial growth factor (VEGF) increases mLV diameter and numbers to increase mLV drainage, resulting in increased mLV drainage. Alzheimer's disease (AD) is characterized by low plasma and CSF levels of VEGF. Objective: To determine if non-invasive transcranial radiofrequency wave treatment (TRFT), through modulation of VEGF levels in blood and CSF, can affect removal of toxins tau and amyloid-ß (Aß) from the brain. Methods: Eight mild/moderate AD subjects were given twice-daily 1-hour TRFT sessions at home by their caregivers. Blood and CSF samples were taken at baseline and following completion of 2 months of TRFT. Results: In plasma and/or CSF, strong baseline correlations between VEGF levels and AD markers (t-tau, p-tau, Aß1-40, Aß1-42) were eliminated by TRFT. This effect was primarily due to TRFT-induced increases in VEGF levels in AD subjects with low or unmeasurable "baseline" VEGF levels. These increased VEGF levels were associated with increased clearance/drainage of tau and Aß from the brain, likely through VEGF's actions on mLVs. Conclusions: A new mechanism of TRFT is identified (facilitation of brain tau and Aß clearance via VEGF) that is likely contributory to TRFT's reversal of cognitive impairment in AD subjects. TRFT may be particularly effective for cognitive benefit in AD subjects who have low VEGF levels.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Encéfalo , Fator A de Crescimento do Endotélio Vascular , Proteínas tau , Humanos , Doença de Alzheimer/terapia , Doença de Alzheimer/metabolismo , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/líquido cefalorraquidiano , Masculino , Feminino , Idoso , Encéfalo/metabolismo , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Ondas de RádioRESUMO
BACKGROUND: Precisely defining the delay in onset of dementia is a particular challenge for early diagnosis. Brain [18F] fluoro-2-deoxy-2-D-glucose (18F-FDG) Positron Emission Tomography (PET) is a particularly interesting tool for the early diagnosis of neurodegenerative diseases, through the measurement of the cerebral glucose metabolic rate. There is currently a lack of longitudinal studies under real-life conditions, with sufficient patients, to accurately evaluate the predictive values of brain 18F-FDG PET scans. Here, we aimed to estimate the value of brain 18F-FDG PET for predicting the risk of dementia conversion and the risk of occurrence of a neurodegenerative pathology. METHODS: Longitudinal data for a cohort of patients with no diagnosis of dementia at the time of recruitment referred by a tertiary memory clinic for brain 18F-FDG PET were matched with (Prince M, Wimo A, Guerchet Maëlenn, Ali G-C, Wu Y-T et al. World Alzheimer Report 2015. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. [Research Report] Alzheimer's Disease International. 2015. 2015.) data from the French National Health Data System (NHDS), (Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-62.) data from the National Alzheimer Bank (NAB), and (Davis M, O`Connell T, Johnson S, Cline S, Merikle E, Martenyi F, et al. Estimating Alzheimer's Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia. CAR. 2018;15(8):777-88.) lumbar puncture (LP) biomarker data. The criteria for dementia conversion were the designation, within the three years after the brain 18F-FDG PET scan, of a long-term condition for dementia in the NHDS and a dementia stage of cognitive impairment in the NAB. The criterion for the identification of a neurodegenerative disease in the medical records was the determination of LP biomarker levels. RESULTS: Among the 403 patients (69.9 ± 11.4 years old, 177 women) from the initial cohort with data matched with the NHDS data, 137 were matched with the NAB data, and 61 were matched with LP biomarker data. Within three years of the scan, a 18F-FDG PET had negative predictive values of 85% for dementia conversion (according to the NHDS and NAB datasets) and 95% for the presence of LP neurodegeneration biomarkers. CONCLUSION: A normal brain 18F-FDG PET scan can help rule out the risk of dementia conversion and the presence of cerebrospinal fluid (CSF) biomarker of neurodegeneration early with high certainty, allowing modifications to patient management regimens in the short term. TRIAL REGISTRATION: Clinical Trials database (NCT04804722). March 18, 2021. Retrospectively registered.
Assuntos
Biomarcadores , Demência , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Humanos , Tomografia por Emissão de Pósitrons/métodos , Feminino , Masculino , Idoso , Demência/diagnóstico por imagem , Demência/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Estudos Longitudinais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Pessoa de Meia-Idade , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Progressão da Doença , Idoso de 80 Anos ou mais , Diagnóstico Precoce , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Estudos de CoortesRESUMO
Alterations in functional connectivity (FC) have been observed in individuals with Alzheimer's disease (AD) with elevated amyloid (Aß) and tau. However, it is not yet known whether directed FC is already influenced by Aß and tau load in cognitively healthy (CH) individuals. A 21-channel electroencephalogram (EEG) was used from 46 CHs classified based on cerebrospinal fluid (CSF) Aß tau ratio: pathological (CH-PAT) or normal (CH-NAT). Directed FC was estimated with Partial Directed Coherence in frontal, temporal, parietal, central, and occipital regions. We also examined the correlations between directed FC and various functional metrics, including neuropsychology, cognitive reserve, MRI volumetrics, and heart rate variability between both groups. Compared to CH-NATs, the CH-PATs showed decreased FC from the temporal regions, indicating a loss of relative functional importance of the temporal regions. In addition, frontal regions showed enhanced FC in the CH-PATs compared to CH-NATs, suggesting neural compensation for the damage caused by the pathology. Moreover, CH-PATs showed greater FC in the frontal and occipital regions than CH-NATs. Our findings provide a useful and non-invasive method for EEG-based analysis to identify alterations in brain connectivity in CHs with a pathological versus normal CSF Aß/tau.