Cerebrospinal Fluid Tau Biomarkers Research Articles

Novel CSF tau biomarkers can be used for disease staging of sporadic Alzheimer’s

AbstractBackgroundStaging Alzheimer’s disease (AD) allows for the identification of key milestones and inflection points in the disease course. However, most current in vivo disease staging methods rely on costly and low‐accessible measures such as PET. Our objective was to generate and evaluate a staging model based on multiple cerebrospinal fluid (CSF) biomarkers.MethodWe created a staging model using the Subtype and Stage Inference (SuStaIn) algorithm in 426 participants covering the whole AD spectrum (Table 1) by evaluating CSF Ab42/40 and 5 CSF tau markers: the proportion of tau phosphorylated at three threonine residues (pT205/T205, pT217/T217, and pT231/T231), and the concentrations of microtubule‐binding region of tau at residue 243 [MTBR‐tau243] and total‐tau [mid‐domain containing T212‐221]). We investigated associations between CSF stages and cross‐sectional and longitudinal changes in amyloid and tau pathologies, neurodegeneration and cognition using linear regression models. ROC curves were used to identify the optimal stage for predicting positivity in imaging biomarkers and to separate AD vs non‐AD cognitive symptoms. We also tested the relative risk of progression from cognitively unimpaired or MCI to AD‐type dementia using Kaplan‐Meier curves and Cox‐proportional Hazard models. Creation of the model and cross‐sectional analyses were replicated in an independent cohort (n = 222, Table 1).ResultSuStaIn revealed that only one subtype was present and that five CSF biomarkers (ordered: Ab42/40, pT217/T217, pT205/T205, MTBR‐tau243, T212‐221) were sufficient to create an accurate disease staging model (Fig.1A‐B). Increasing stages (0‐5) were associated with increased abnormality in other AD‐related biomarkers (Fig.1C). In both cohorts, stage ≥2 accurately predicted amyloid‐PET positivity (AUC≥0.89), stage ≥4 predicted tau‐PET (AUC≥0.94) and neurodegeneration positivity (AUC≥0.81). In the main cohort, stage≥2 separated non‐AD from AD‐related cognitive impairment (AUC = 0.96). Longitudinal changes for several AD‐biomarkers by stages are presented in (Fig.2A). Higher stages (4‐5) at baseline were associated with higher hazard ratios (HR) of progressing to AD‐type dementia (CU&MCI: HR = 4.6[2.0,10.9], MCI: HR = 3.5[1.5,8.1], Fig.2B‐C).ConclusionOur results suggest that the AD continuum can be accurately staged with a single CSF sample, which may be useful in the clinical setting for patient management but also as a tool in clinical trials for selection and monitoring of study participants.

The relationship between plasma matrix metalloproteinase‐9 and cerebrospinal fluid biomarkers of tau is sex‐dependent

AbstractBackgroundMatrix metalloproteinase‐9 (MMP‐9) is a proinflammatory, proteolytic enzyme that is dysregulated in Apolipoprotein (APOE) ε4 carriers, patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and has been shown to accelerate tau oligomerization, blood‐brain barrier breakdown and amyloid‐β (Aβ) accumulation. Evidence suggests that MMP‐9 activity may be regulated by sex hormones, yet it is unknown whether the association between plasma MMP‐9 and cerebrospinal fluid (CSF) AD biomarker levels varies by sex.MethodIn 335 ADNI participants (128 women, mean age 74.8±7.4), including 56 cognitively normal adults, 183 MCI patients and 96 AD dementia patients, we examined whether sex modulates total and free plasma MMP‐9 associations with CSF total tau (t‐tau), tau phosphorylated at threonine 181 (p‐tau181) and Aβ42.ResultFree and total plasma MMP‐9 levels were not associated with sex, age, APOE ε4 status or cardiovascular disease risk (CVDR). Total plasma MMP‐9 levels were higher in AD dementia patients versus MCI patients but did not differ between normal controls and MCI or AD patients. Free and total MMP‐9 levels were not associated with CSF Aβ42 regardless of sex. There was a sex × total plasma MMP‐9 interaction on CSF t‐tau (β=24.7; 95% CI, 82.5 to 355.2; P=0.002) and p‐tau181 (β=24.7; 95% CI, 8.9 to 40.4; P=0.002). Higher total MMP‐9 correlated with higher t‐tau and p‐tau181 levels in women, but with lower levels in men. There was a sex × free plasma MMP‐9 interaction on CSF p‐tau181 (β=19.5; 95% CI, 6.0 to 33.1; P=0.005) and t‐tau (β=147.8; 95% CI, 30.2 to 265.3; P=0.01). Higher free plasma MMP‐9 correlated with lower CSF p‐tau181 and t‐tau in men, but not women. These relationships were independent of age, education, diagnosis, CVDR, and CSF Aβ42 levels, and were likely driven by APOE ε4‐carriers as free or total MMP‐9 levels were not significantly associated with CSF biomarkers among non‐carriers regardless of sex.ConclusionOur findings provide preliminary evidence of sex differences in associations between MMP‐9 and CSF tau biomarkers, particularly among APOE ε4‐carriers. Compared to male ε4‐carriers, female ε4‐carriers might be more vulnerable to MMP‐9 activity, possibly promoting higher levels of AD‐related tau pathology.

Cerebrospinal fluid tau biomarkers in the prediction and concordance of neurofibrillary tangle and amyloid pathology

AbstractBackgroundCerebrospinal fluid (CSF) measures of tau (p‐tau181 and t‐tau) are central to the research diagnostic criteria for Alzheimer’s disease (AD). Nevertheless, alternative tau phosphorylation sites or tau fragments merit further evaluation to better index neurofibrillary tangle (NFT) and amyloid‐β (Aβ) pathology.MethodWe evaluated 168 participants from the TRIAD cohort (young controls, cognitively normal controls (CN), mild cognitive impairment, frontotemporal dementia and AD patients). LUMIPULSE® G1200 (Fujirebio) was used to measure CSF p‐tau181 and t‐tau. CSF p‐tau231 was quantified using a prototype ELISA assay (ADx NeuroSciences). CSF p‐tau217 and tau368 was measured using an in‐house Simoa assay (University of Gothenburg). For PET ([18F]MK6240 and [18F]AZD4694), standard uptake value ratios (SUVR) were determined using the cerebellar and cerebellar cortex as reference tissue, respectively. Finally, ROC curves were generated to investigate the predictive power of the CSF biomarkers.ResultAll CSF p‐tau biomarkers equally associated with [18F]MK6240 (r>0.51), while CSF p‐tau231 correlated more to [18F]AZD4694 (r=0.815) than other tau biomarkers. ROC curves revealed p‐tau biomarkers accurately detected Braak I‐II (AUC>0.905) and III‐IV positivity (AUC>0.940), with p‐tau217 significantly out performing p‐tau231 and p‐tau181 at both stages. Tau368/t‐tau ratio was the superior biomarker in the prediction of Braak V‐VI positivity. P‐tau217 and p‐tau231 demonstrated high accuracy in predicting Aβ positivity (ROC>0.950). This was significantly better than p‐tau181 (p‐tau217, P<0.01; p‐tau231, P<0.001). Prediction of Aβ positivity was also high at the pre‐symptomatic stage for p‐tau231 (ROC>0.9) and again was significantly superior to p‐tau181 (P<0.01). All p‐tau biomarkers demonstrated full concordance (CSF‐/PET‐) with [18F]MK6240 and [18F]AZD4694 for young controls and FTD subjects. P‐tau217 and p‐tau231 demonstrated high concordance with [18F]MK6240 and discordant cases were restricted to the CSF+/PET‐ quadrant (Figure 1). In the same manner, CSF p‐tau217 and p‐tau231 demonstrated the highest concordance with [18F]AZD4694, although subjects were observed in both discordant quadrants (Figure 2).ConclusionAll CSF p‐tau biomarkers relate to NFT pathology to the same degree, however, tau368/t‐tau seemingly characterises NFT pathology at an advanced stage. CSF p‐tau217 and p‐tau231 are better predictors of Aβ pathology, with p‐tau231 a stronger predictor of Aβ pathology at the pre‐symptomatic stage.

18F]FLORTAUCIPIR BINDING STRONGLY CORRELATES TO COGNITION ACROSS THE CLINICAL ALZHEIMER’S DISEASE CONTINUUM, INDEPENDENTLY OF CSF TAU

Tau pathology can be measured in cerebrospinal fluid (CSF) and by [18F]flortaucipir PET in vivo. The aim of this study was twofold. First we examined associations between CSF total tau (t-tau) and phosphorylated tau(p-tau) with [18F]flortaucipir PET across the clinical Alzheimer's disease (AD) continuum, and second we investigated associations of CSF-tau and [18F]flortaucipir PET with cognitive performance. We included 51 MCI/ AD patients (all amyloid-positive, age: 65±6 years, MMSE: 24±4) and 24 subjective cognitive decline(SCD) subjects (28% amyloid-positive, age: 65±6 years, MMSE: 28±1, Table-1). Dynamic 130 minute [18F]flortaucipir PET scans were performed to generate global binding potential (BPND) images using receptor parametric mapping. Cognitive assessment consisted of MMSE and composite scores of four cognitive domains. Linear regressions and voxel-wise linear regressions were used to investigate associations between CSF-tau and tau-PET; adjusted for age, sex and time lag between lumbar puncture(LP) and tau-PET. Linear regression models were used to assess the relationships between CSF-tau and tau-PET with cognition(model 1; separate models for CSF and PET) and assessed the independent effects of CSF t-tau and tau-PET on cognition(model 2, with both CSF t-tau and [18F]flortaucipir BPND as predictor). Models were adjusted for age, sex, education and time lag between assessments. Overall, global [18F]flortaucipir BPND was positively correlated with CSF p-tau (r=0.55) and t-tau (r=0.59). Within groups, correlations were stronger for SCD subjects than MCI/AD patients (r=0.76 for p-tau; r=0.81 for t-tau vs. r=0.38 for p-tau; r=0.42 for t-tau, Figure-1). Voxel-wise analyses across all subjects showed significant associations between widespread cortical [18F]flortaucipir binding (right>left) and CSF-tau, whereas in SCD a temporoparietal pattern was seen(Figure-2). When entered simultaneously (model 2), global [18F]flortaucipir BPND, but not CSF tau biomarkers, was associated with MMSE and all four cognitive domains across all subjects. In MCI/AD, worse MMSE, attention and executive functions were only associated with global [18F]flortaucipir BPND(Table-2).

Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers.

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.