Cerebrospinal Fluid Alzheimer's Disease Biomarkers Research Articles

Longitudinal trajectories of Alzheimer's disease CSF biomarkers and blood pressure in cognitively healthy subjects.

We examined whether hypertension (HTN) was associated with Alzheimer's disease-related biomarkers in cerebrospinal fluid (CSF) and how changes in blood pressure (BP) related to changes in CSF biomarkers over time. A longitudinal observation of cognitively healthy normotensive subjects (n=134, BP<140/90, withno antihypertensive medication), controlled HTN(n=36, BP<140/90, taking antihypertensive medication), and 35 subjects with uncontrolled HTN (BP ≥ 140/90). The follow-up range was 0.5to15.6 years. Total tau (T-tau) and phospho-tau181 (P-tau 181) increased in allbut controlled HTN subjects (group×timeinteraction: p<0.05 for both), but no significant Aβ42 changes were seen. SignificantBP reduction wasobserved in uncontrolled HTN, andit was related to increase in T-tau (p=0.001) and P-tau 181 (p<0.001). Longitudinal increases in T-tau and P-tau 181 were observed in most subjects; however, onlyuncontrolled HTN had both markers increase alongside BPreductions. We speculatecumulative vascular injury renders thebrain susceptible to relative hypoperfusion with BP reduction. Over the course of the study, participants with uncontrolled HTN at baseline showed greater accumulation of CSF total tau and phospho-tau181 (P-tau 181) than subjects with normal BP or with controlled HTN. In the group with uncontrolled HTN, increases in total tau and P-tau 181 coincided with reduction in BP. We believe this highlights the role of HTN in vascular injury and suggests decline in cerebral perfusion resulting in increased biomarker concentrations in CSF. Medication use was the main factor differentiating controlled from uncontrolled HTN, indicating that earlier treatment was beneficial for preventing accumulations of pathology.

CAIDE Score, Alzheimer's Disease Pathology, and Cognition in Cognitively Normal Adults: The CABLE Study.

Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score serves as a credible predictor of an individual's risk of dementia. However, studies on the link of the CAIDE score to Alzheimer's disease (AD) pathology are scarce. To explore the links of CAIDE score to cerebrospinal fluid (CSF) biomarkers of AD as well as to cognitive performance. In the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, we recruited 600 cognitively normal participants. Correlations between the CAIDE score and CSF biomarkers of AD as well as cognitive performance were probed through multiple linear regression models. Whether the correlation between CAIDE score and cognitive performance was mediated by AD pathology was researched by means of mediation analyses. Linear regression analyses illustrated that CAIDE score was positively associated with tau-related biomarkers, including pTau (p < 0.001), tTau (p < 0.001), as well as tTau/Aβ42 (p = 0.008), while it was in negative association with cognitive scores, consisting of MMSE score (p < 0.001) as well as MoCA score (p < 0.001). The correlation from CAIDE score to cognitive scores was in part mediated by tau pathology, with a mediation rate varying from 3.2% to 13.2% . A higher CAIDE score, as demonstrated in our study, was linked to more severe tau pathology and poorer cognitive performance, and tau pathology mediated the link of CAIDE score to cognitive performance. Increased dementia risk will lead to cognitive decline through aggravating neurodegeneration.

Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases.

Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well as in clinical practice for diagnosis of neurological diseases, e.g., Alzheimer's disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related inter-individual variability. Here we use a data-driven approach to demonstrate the existence of inter-individual variability in mean standardized CSF protein levels. We show that these non-disease related differences cause many commonly reported CSF biomarkers to be highly correlated, thereby producing misleading results if not accounted for. To adjust for this inter-individual variability, we identified and evaluated high-performing reference proteins which improved the diagnostic accuracy of key CSF AD biomarkers. Our reference protein method attenuates the risk for false positive findings, and improves the sensitivity and specificity of CSF biomarkers, with broad implications for both research and clinical practice.

Echocardiographic measures of the left heart and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: The CABLE study.

This study delineated the interrelationships between subclinical alterations in the left heart, cerebrospinal fluid (CSF), Alzheimer's disease (AD) biomarkers, and cognition. Multiple linear regressions were conducted in 1244 cognitively normal participants (mean age=65.5; 43% female) who underwent echocardiography (left atrial [LA] and left ventricular [LV] morphologic or functional parameters) and CSF AD biomarkers measurements. Mediating effects of AD pathologies were examined. Differences in cardiac parameters across ATN categories were tested using analysis of variance (ANOVA) and logistic regressions. LA or LV enlargement (characterized by increased diameters and volumes) and LV hypertrophy (increased interventricular septal or posterior wall thickness and ventricular mass) were associated with higher CSF phosphorylated (p)-tau and total (t)-tau levels, and poorer cognition. Tau pathologies mediated the heart-cognition relationships. Cardiac parameters were higher in stage 2 and suspected non-Alzheimer's pathology groups than controls. These findings suggested close associations of subclinical cardiac changes with tau pathologies and cognition. Various subclinical alterations in the left heart related to poorer cognition. Subclinical cardiac changes related to tau pathologies in cognitively normal adults. Tau pathologies mediated the heart-cognition relationships. Subclinical cardiac changes related to the AD continuum, especially to stage 2. The accumulation of cardiac alterations magnified their damage to the brain.

CSF biomarkers of immune activation and Alzheimer's disease for predicting cognitive impairment risk in the elderly.

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aβ42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aβ42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aβ42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

Alzheimer's disease cerebrospinal fluid biomarkers and kidney function in normal and cognitively impaired older adults.

Recent Alzheimer's disease (AD) clinical trials have used cerebrospinal fluid (CSF) biomarker levels for screening and enrollment. Preliminary evidence suggests that AD risk is related to impaired renal function. The impact of kidney function on commonly used AD biomarkers remains unknown. Participants in studies conducted at the Goizueta Alzheimer's Disease Research Center (N=973) had measurements of serum creatinine and CSF AD biomarkers. General linear models and individual data were used to assess the relationships between biomarkers and eGFR. Lower estimated glomerular filtration rate (eGFR) was associated with lower amyloid beta (Aβ)42/tau ratio (p<0.0001) and Aβ42 (p=0.002) and higher tau (p<0.0001) and p-tau (p=0.0002). The impact of eGFR on AD biomarker levels was more robust in individuals with cognitive impairment (all p-values were<0.005). The association between eGFR and CSF AD biomarkers has a significant impact that varies by cognitive status. Future studies exploring this impact on the pathogenesis of AD and related biomarkers are needed. There is a significant association between Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers and both estimated glomerular filtration rate (eGFR) and mild cognitive impairment (MCI).Kidney function influences CSF biomarker levels in individuals with normal cognitive function and those with MCI.The impact of kidney function on AD biomarker levels is more pronounced in individuals with cognitive impairment.The variation in CSF tau levels is independent of cardiovascular factors and is likely directly related to kidney function.Tau may have a possible role in both kidney and cognitive function.

Personal value of Alzheimer's disease biomarker testing and result disclosure from the patient and care partner perspective.

We described patients' and care partners' experiences with Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing and result disclosure in routine care. IMPACT-AD BC is an observational study of clinic patients who underwent AD CSF biomarker testing as part of their routine medical care (n = 142). In the personal utility arm of the study, semi-structured phone interviews were conducted with a subset of patients (n = 34), and separately with their care partners (n = 31). Post-disclosure interviews were conducted ∼1 month and ∼6 months after biomarker result disclosure and investigated the patients' decision-making process around testing, impact of receiving results, wellness and lifestyle changes, and future planning. A majority of patients (90%) rated their decision to undergo testing as "easy." Post-disclosure, the majority (82%) reported overall positive feelings from having greater certainty and the ability to plan ahead, and results spurred them to adopt/continue healthy behaviors such as exercise (84%) and cognitive activities (54%). Care partners expressed relief from having more diagnostic certainty, increased appreciation of future caregiving responsibilities, and a desire to connect with support resources. Perspectives of persons with lived experience in dementia provide new insight into the value of biomarker testing and should be included as part of evidence-guided considerations for pre-test counseling and result disclosure. Moreover, study findings identify an interval when patients and care partners are highly receptive to positive lifestyle and medical interventions.

Clinical value of Alzheimer's disease biomarker testing.

In the Investigating the Impact of Alzheimer's Disease Diagnostics in British Columbia (IMPACT-AD BC) study, we aimed to understand how Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing-used in medical care-impacted medical decision-making (medical utility), personal decision-making (personal utility), and health system economics. The study was designed as an observational, longitudinal cohort study. A total of 149 patients were enrolled between February 2019 and July 2021. Patients referred to memory clinics were approached to participate if their dementia specialist ordered AD CSF biomarker testing as part of their routine medical care, and the clinical scenario met the appropriate use criteria for lumbar puncture and AD CSF biomarker testing. For the medical utility pillar, detailed clinical management plans were collected via physician questionnaires pre- and post-biomarker disclosure. Patients with completed management questionnaires (n = 142) had a median age of 64 (interquartile range: 59-69) years, 48% were female, and 60% had CSF biomarker profiles on the AD continuum. Clinical management changed in 89.4% of cases. AD biomarker testing was associated with decreased need for other diagnostic procedures, including brain imaging (-52.0%) and detailed neuropsychological assessments (-63.2%), increased referrals and counseling (57.0%), and guided AD-related drug prescriptions (+88.4% and -50.0% in biomarker-positive and -negative cases, respectively). AD biomarker testing was associated with significant and positive changes in clinical management, including decreased health care resource use, therapy optimization, and increased patient and family member counseling. While certain changes in management were linked to the AD biomarker profile (e.g., referral to clinical trials), the majority of changes were independent of baseline clinical presentation and level of cognitive impairment, demonstrating a broad value for AD biomarker testing in individuals meeting the appropriate use criteria for testing.

Constitutive NOS Production Is Modulated by Alzheimer's Disease Pathology Depending on APOE Genotype.

Both the endothelial (eNOS) and the neuronal (nNOS) isoforms of constitutive Nitric Oxide Synthase have been implicated in vascular dysfunctions in Alzheimer's disease (AD). We aimed to explore the relationship between amyloid pathology and NO dynamics by comparing the cerebrospinal fluid (CSF) levels of nNOS and eNOS of 8 healthy controls (HC) and 27 patients with a clinical diagnosis of Alzheimer's disease and isolated CSF amyloid changes, stratified according to APOE ε genotype (APOE ε3 = 13, APOE ε4 = 14). Moreover, we explored the associations between NOS isoforms, CSF AD biomarkers, age, sex, cognitive decline, and blood-brain barrier permeability. In our cohort, both eNOS and nNOS levels were increased in APOE ε3 with respect to HC and APOE ε4. CSF eNOS inversely correlated with CSF Amyloid-β42 selectively in carriers of APOE ε3; CSF nNOS was negatively associated with age and CSF p-tau only in the APOE ε4 subgroup. Increased eNOS could represent compensative vasodilation to face progressive Aβ-induced vasoconstriction in APOE ε3, while nNOS could represent the activation of NO-mediated plasticity strategies in the same group. Our results confirm previous findings that the APOE genotype is linked with different vascular responses to AD pathology.

Lumbar puncture increases Alzheimer’s disease biomarker levels in cerebrospinal fluid of rhesus monkeys

Cerebrospinal fluid (CSF) samples are commonly collected via lumbar puncture (LP) in both clinical and research settings for measurement of biomarkers of Alzheimer's disease (AD). To determine the effects of LP on CSF AD biomarkers, we collected CSF samples at seven different time points after an LP in rhesus monkeys. We find that amyloid-beta (Aβ) and Tau levels increased significantly on day 1, peaked on day 3, and returned to baseline on day 10 after LP. The NFL levels increased significantly on day 5, peaked on day 10, and returned to baseline after day 30. The increased AD biomarker levels were mainly due to CSF outflow and deep intrathecal invasion during LP. Therefore, if LPs are repeated within a short period of time, prior LP can affect Aβ and Tau levels within 10days and NFL levels within 30days, which may lead to clinical misdiagnosis or incorrect scientific conclusions.

Cerebrospinal fluid biomarker profiling of diverse pathophysiological domains in Alzheimer's disease.

While Alzheimer's disease (AD) is defined by amyloid-β plaques and tau tangles in the brain, it is evident that many other pathophysiological processes such as inflammation, neurovascular dysfunction, oxidative stress, and metabolic derangements also contribute to the disease process and that varying contributions of these pathways may reflect the heterogeneity of AD. Here, we used a previously validated panel of cerebrospinal fluid (CSF) biomarkers to explore the degree to which different pathophysiological domains are dysregulated in AD and how they relate to each other. Twenty-five CSF biomarkers were analyzed in individuals with a clinical diagnosis of AD verified by positive CSF AD biomarkers (AD, n = 54) and cognitively unimpaired controls negative for CSF AD biomarkers (CU-N, n = 26) using commercial single- and multi-plex immunoassays. We noted that while AD was associated with increased levels of only three biomarkers (MMP-10, FABP3, and 8OHdG) on a group level, half of all AD participants had increased levels of biomarkers belonging to at least two pathophysiological domains reflecting the diversity in AD. LASSO modeling showed that a panel of FABP3, 24OHC, MMP-10, MMP-2, and 8OHdG constituted the most relevant and minimally correlated set of variables differentiating AD from CU-N. Interestingly, factor analysis showed that two markers of metabolism and oxidative stress (24OHC and 8OHdG) contributed independent information separate from MMP-10 and FABP3 suggestive of two independent pathophysiological pathways in AD, one reflecting neurodegeneration and vascular pathology, and the other associated with metabolism and oxidative stress. Better understanding of the heterogeneity among individuals with AD and the different contributions of pathophysiological processes besides amyloid-β and tau will be crucial for optimizing personalized treatment strategies. A panel of 25 highly validated biomarker assays were measured in CSF.MMP10, FABP3, and 8OHdG were increased in AD in univariate analysis.Many individuals with AD had increased levels of more than one biomarker.Markers of metabolism and oxidative stress contributed to an AD multianalyte profile.Assessing multiple biomarker domains is important to understand disease heterogeneity.

Cardiovascular Risk Scales Association with Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cardiovascular Low Cardiovascular Risk Regions.

Cardiovascular risk factors are associated with Alzheimer's Disease (AD) development. However, few studies compare the overall cardiovascular risk with AD biomarkers, and when done, they are mainly performed in moderate cardiovascular risk regions. To determine whether cardiovascular risk in older adults is associated with pathological cerebrospinal fluid (CSF) biomarkers of AD in a low cardiovascular risk population. This is a cross-sectional study performed between 2017 and 2020. The present work included patients between 50 and 75 years old who were negative for CSF AD biomarkers and had minimum cognitive alterations (controls) and patients with positive CSF AD biomarkers and in early stages of AD (cases). CSF biomarkers included total tau, phosphorylated tau 181 and amyloid ß42 (Aß42). Analytical variables were obtained. ERICE, SCORE2 and Framingham scales were used to calculate the overall patient's cardiovascular risk. The Aß42/Aß40 ratio and neurofilaments were explored when available. Two hundred and thirty-three patients were included. Nearly 76% of the sample had AD. AD patients had higher cardiovascular risk than controls (p-value < 0.05). ERICE and SCORE2 were associated with AD presence. Framingham was not. A correlation between elevated cardiovascular risk and higher total tau and NfL levels was observed when adjusted by age. Cardiovascular risk assessment may be helpful in neurodegenerative disorders detection, as it is associated with CSF total tau and NfL. ERICE and SCORE2 may be useful scales in low cardiovascular risk regions to improve cardiovascular control and prevent neurodegenerative pathologies.

Associations between liver function and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in non-demented adults: The CABLE study.

Liver function has been suggested as a possible factor in the progression of Alzheimer's disease (AD) development. However, the association between liver function and cerebrospinal fluid (CSF) levels of AD biomarkers remains unclear. In this study, we analyzed the data from 1687 adults without dementia from the Chinese Alzheimer's Biomarker and LifestylE study to investigate differences in liver function between pathological and clinical AD groups, as defined by the 2018 National Institute on Aging-Alzheimer's Association Research Framework. We also examined the linear relationship between liver function, CSF AD biomarkers, and cognition using linear regression models. Furthermore, mediation analyses were applied to explore the potential mediation effects of AD pathological biomarkers on cognition. Our findings indicated that, with AD pathological and clinical progression, the concentrations of total protein (TP), globulin (GLO), and aspartate aminotransferase/alanine transaminase (ALT) increased, while albumin/globulin (A/G), adenosine deaminase, alpha-L-fucosidase, albumin, prealbumin, ALT, and glutamate dehydrogenase (GLDH) concentrations decreased. Furthermore, we also identified significant relationships between TP (β = -0.115, pFDR < 0.001), GLO (β = -0.184, pFDR < 0.001), and A/G (β = 0.182, pFDR < 0.001) and CSF β-amyloid1-42 (Aβ1-42 ) (and its related CSF AD biomarkers). Moreover, after 10 000 bootstrapped iterations, we identified a potential mechanism by which TP and GLDH may affect cognition by mediating CSF AD biomarkers, with mediation effect sizes ranging from 3.91% to 16.44%. Overall, our results suggested that abnormal liver function might be involved in the clinical and pathological progression of AD. Amyloid and tau pathologies also might partially mediate the relationship between liver function and cognition. Future research is needed to fully understand the underlying mechanisms and causality to develop an approach to AD prevention and treatment approach.

Blood‐based biomarkers of Alzheimer disease as measured by a mass spectrometry assay are as accurate as CSF tests

AbstractBackgroundEspecially because disease‐modifying treatments (DMTs) for Alzheimer disease (AD) are likely to become more available soon, highly accurate AD blood tests for use in clinical diagnosis are critically needed. Although amyloid PET scans and cerebrospinal fluid (CSF) tests are highly accurate in the identification of individuals with brain amyloidosis, blood tests are likely the only test modality that will enable an adequate scale of AD biomarker testing. Mass spectrometry‐based AD blood tests have consistently demonstrated very high performance.MethodsResearch participants enrolled in studies at the Knight Alzheimer Disease Research Center who underwent amyloid PET and measurement of established CSF biomarkers of AD with Lumipulse automated assays were included. The presence and severity of dementia was evaluated with the Clinical Dementia Rating® (CDR®) and Clinical Dementia Rating Sum of Boxes (CDR‐SB). Plasma samples collected at the same session as CSF underwent analysis for specific phosphorylated and non‐phosphorylated tau species with an immunoprecipitation‐mass spectrometry assay. Plasma T217 occupancy was calculated as the percent of phosphorylated to non‐phosphorylated tau at threonine 217.ResultsThe study cohort included 337 individuals with an average age of 69.8 ± 8.3 years (mean ± standard deviation); 175 (52%) were female, 128 (38%) were APOE ε4 carriers, 112 (33%) were amyloid PET positive, and 50 (15%) were cognitively impaired. Classification accuracy of amyloid PET status was equivalent for plasma T217 occupancy (AUC 0.973) and CSF Aβ42/Aβ40 (AUC 0.970), (p = 0.72 for the difference). Interestingly, plasma T217 occupancy more accurately classified individuals as cognitively impaired (CDR&gt;0) or cognitively unimpaired (CDR 0), with an AUC of 0.876 versus 0.814 for CSF Aβ42/Aβ40 (p = 0.006 for the difference). Further, plasma T217 occupancy was better correlated with dementia severity as measured by the CDR‐SB (Spearman ρ = 0.455 versus ‐0.338 for CSF Aβ42/Aβ40, p = 0.02).ConclusionPlasma T217 occupancy as measured by mass spectrometry had equivalent classification accuracy of amyloid PET status compared to Lumipulse CSF Aβ42/Aβ40. Notably, plasma T217 occupancy was more strongly associated with cognitive impairment and dementia severity than CSF Aβ42/Aβ40. Overall, these data suggest that some AD blood tests have equivalent or better performance characteristics than clinically used CSF tests.

Memory performance mediates subjective sleep quality associations with cerebrospinal fluid Alzheimer's disease biomarker levels and hippocampal volume among individuals with mild cognitive symptoms.

Sleep disturbances are prevalent in Alzheimer's disease (AD), affecting individuals during its early stages. We investigated associations between subjective sleep measures and cerebrospinal fluid (CSF) biomarkers of AD in adults with mild cognitive symptoms from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study, considering the influence of memory performance. A total of 442 participants aged >50 years with a Clinical Dementia Rating (CDR) score of 0.5 completed the Pittsburgh Sleep Quality Index questionnaire and underwent neuropsychological assessment, magnetic resonance imaging acquisition, and CSF sampling. We analysed the relationship of sleep quality with CSF AD biomarkers and cognitive performance in separated multivariate linear regression models, adjusting for covariates. Poorer cross-sectional sleep quality was associated with lower CSF levels of phosphorylated tau and total tau alongside better immediate and delayed memory performance. After adjustment for delayed memory scores, associations between CSF biomarkers and sleep quality became non-significant, and further analysis revealed that memory performance mediated this relationship. In post hoc analyses, poorer subjective sleep quality was associated with lesser hippocampal atrophy, with memory performance also mediating this association. In conclusion, worse subjective sleep quality is associated with less altered AD biomarkers in adults with mild cognitive symptoms (CDR score 0.5). These results could be explained by a systematic recall bias affecting subjective sleep assessment in individuals with incipient memory impairment. Caution should therefore be exercised when interpreting subjective sleep quality measures in memory-impaired populations, emphasising the importance of complementing subjective measures with objective assessments.

Montreal Cognitive Assessment in Mild Cognitive Impairment: Relationship with Cerebrospinal Fluid Biomarkers and Conversion to Dementia.

Mild cognitive impairment (MCI) is considered a prodromal state of dementia. Abnormal values of cerebrospinal fluid Alzheimer's disease biomarkers (CSF-AD-b) have been associated with a higher risk of conversion to dementia (due to Alzheimer's disease), but studies evaluating the ability of Montreal Cognitive Assessment (MoCA) in this task are lacking. This study aims to investigate the relationship between MoCA and CSF-AD-b, as well as the ability of those tools to predict conversion to dementia. Taking advantage of our MCI cohort with biological characterization on longitudinal follow-up (180 patients followed for 62.6 months during which 41.3% converted), we computed MoCA and MMSE z-scores, using Portuguese normative data. The performance in MoCA z-score was correlated with CSF-AD-b and the relative time to conversion and risk according to baseline characteristics were analyzed using Kaplan-Meier analysis and Cox regression models. MoCA z-scores were correlated with Aβ42 (p = 0.026), t-tau (p = 0.033), and p-tau (p = 0.01). Impaired MMSE (p < 0.001) and MoCA z-scores (p = 0.019), decreased Aβ42 (p < 0.001) and increased t-tau (p < 0.001) and p-tau (p < 0.001) were associated with shorter estimated time of conversion. Aβ42 (p < 0.001) and MMSE z-scores (p = 0.029) were independent predictors of conversion. For those with at least 9 years of education, MoCA z-score (p = 0.004) (but not MMSE) was an independent predictor of conversion as well as Aβ42. This study confirms the role of CSF-AD-b, namely Aβ42, in predicting conversion from MCI to dementia and suggests the utility of MoCA in predicting conversion in highly educated subjects, supporting its use in the evaluation of MCI patients.

Agreement of cerebrospinal fluid biomarkers and amyloid-PET in a multicenter study.

Core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers have shown incomplete agreement with amyloid-positron emission tomography (PET). Our goal was to analyze the agreement between AD CSF biomarkers and amyloid-PET in a multicenter study. Retrospective multicenter study (5 centers). Participants who underwent both CSF biomarkers and amyloid-PET scan within 18months were included. Clinical diagnoses were made according to latest diagnostic criteria by the attending clinicians. CSF Amyloid Beta1-42 (Aβ1-42, A), phosphorliated tau 181 (pTau181, T) and total tau (tTau, N) biomarkers were considered normal (-) or abnormal ( +) according to cutoffs of each center. Amyloid-PET was visually classified as positive/negative. Agreement between CSF biomarkers and amyloid-PET was analyzed by overall percent agreement (OPA). 236 participants were included (mean age 67.9years (SD 9.1), MMSE score 24.5 (SD 4.1)). Diagnoses were mild cognitive impairment or dementia due to AD (49%), Lewy body dementia (22%), frontotemporal dementia (10%) and others (19%). Mean time between tests was 5.1months (SD 4.1). OPA between single CSF biomarkers and amyloid-PET was 74% for Aβ1-42, 75% for pTau181, 73% for tTau. The use of biomarker ratios improved OPA: 87% for Aβ1-42/Aβ1-40 (n = 155), 88% for pTau181/Aβ1-42 (n = 94) and 82% for tTau/Aβ1-42 (n = 160). A + T + N + cases showed the highest agreement between CSF biomarkers and amyloid-PET (96%), followed by A-T-N- cases (89%). Aβ1-42/Aβ1-40 was a better marker of cerebral amyloid deposition, as identified by amyloid tracers, than Aβ1-42 alone. Combined biomarkers in CSF predicted amyloid-PET result better than single biomarkers.

Alzheimer Disease Biomarkers: Moving from CSF to Plasma for Reliable Detection of Amyloid and tau Pathology.

Development of validated biomarkers to detect early Alzheimer disease (AD) neuropathology is needed for therapeutic AD trials. Abnormal concentrations of "core" AD biomarkers, cerebrospinal fluid (CSF) amyloid beta1-42, total tau, and phosphorylated tau correlate well with neuroimaging biomarkers and autopsy findings. Nevertheless, given the limitations of established CSF and neuroimaging biomarkers, accelerated development of blood-based AD biomarkers is underway. Here we describe the clinical significance of CSF and plasma AD biomarkers to detect disease pathology throughout the Alzheimer continuum and correlate with imaging biomarkers. Use of the AT(N) classification by CSF and imaging biomarkers provides a more objective biologically based diagnosis of AD than clinical diagnosis alone. Significant progress in measuring CSF AD biomarkers using extensively validated highly automated assay systems has facilitated their transition from research use only to approved in vitro diagnostics tests for clinical use. We summarize development of plasma AD biomarkers as screening tools for enrollment and monitoring participants in therapeutic trials and ultimately in clinical care. Finally, we discuss the challenges for AD biomarkers use in clinical trials and precision medicine, emphasizing the possible ethnocultural differences in the levels of AD biomarkers. CSF AD biomarker measurements using fully automated analytical platforms is possible. Building on this experience, validated blood-based biomarker tests are being implemented on highly automated immunoassay and mass spectrometry platforms. The progress made developing analytically and clinically validated plasma AD biomarkers within the AT(N) classification scheme can accelerate use of AD biomarkers in therapeutic trials and routine clinical practice.

A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with heterogenous pathophysiological changes that develop years before the onset of clinical symptoms. These preclinical changes have generated considerable interest in identifying markers for the pathophysiological mechanisms linked to AD and AD-related disorders (ADRD). On the basis of our prior work integrating cerebrospinal fluid (CSF) and brain proteome networks, we developed a reliable and high-throughput mass spectrometry-selected reaction monitoring assay that targets 48 key proteins altered in CSF. To test the diagnostic utility of these proteins and compare them with existing AD biomarkers, CSF collected at baseline visits was assayed from 706 participants recruited from the Alzheimer's Disease Neuroimaging Initiative. We found that the targeted CSF panel of 48 proteins (CSF 48 panel) performed at least as well as existing AD CSF biomarkers (Aβ42, tTau, and pTau181) for predicting clinical diagnosis, FDG PET, hippocampal volume, and measures of cognitive and dementia severity. In addition, for each of those outcomes, the CSF 48 panel plus the existing AD CSF biomarkers significantly improved diagnostic performance. Furthermore, the CSF 48 panel plus existing AD CSF biomarkers significantly improved predictions for changes in FDG PET, hippocampal volume, and measures of cognitive decline and dementia severity compared with either measure alone. A potential reason for these improvements is that the CSF 48 panel reflects a range of altered biology observed in AD/ADRD. In conclusion, we show that the CSF 48 panel complements existing AD CSF biomarkers to improve diagnosis and predict future cognitive decline and dementia severity.

Mapping sleep's oscillatory events as a biomarker of Alzheimer's disease.

Memory-associated neural circuits produce oscillatory events including theta bursts (TBs), sleep spindles (SPs), and slow waves (SWs) in sleep electroencephalography (EEG). Changes in the"coupling" of these events may indicate early Alzheimer's disease (AD) pathogenesis. We analyzed 205 aging adults using single-channel sleep EEG, cerebrospinal fluid (CSF) AD biomarkers, and Clinical Dementia Rating® (CDR®) scale. We mapped SW-TB and SW-SP neural circuit coupling precision to amyloid positivity, cognitive impairment, and CSF AD biomarkers. Cognitive impairment correlated with lower TB spectral power in SW-TB coupling. Cognitively unimpaired, amyloid positive individuals demonstrated lower precision in SW-TB and SW-SP coupling compared to amyloid negative individuals. Significant biomarker correlations were found in oscillatory event coupling with CSF Aβ42 /Aβ40 , phosphorylated- tau181 , and total-tau. Sleep-dependent memory processing integrityin neural circuits can be measured for both SW-TB and SW-SP coupling. This breakdownassociateswith amyloid positivity, increased AD pathology, and cognitive impairment. At-home sleep EEG is a potential biomarker of neural circuits linked to memory. Circuit precision is associated with amyloid positivity in asymptomatic aging adults. Levels of CSF amyloid and tau also correlate with circuit precision in sleep EEG. Theta burst EEG power is decreased in very early mild cognitive impairment. This technique may enable inexpensive wearable EEGs for monitoring brain health.