Data-driven CSF biomarker profiling: imaging and clinical outcomes in a cohort at risk of Alzheimer's disease.
Cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction, neuroinflammation, and glial response, complementing Alzheimer's disease (AD) core biomarkers, have improved the pathophysiological characterization of the disease. Here, we tested the hypothesis that the co-expression of multiple CSF biomarkers will help the identification of AD-like phenotypes when biomarker positivity thresholds are not met yet.
Two hundred and seventy cognitively unimpaired adults with family history (FH) of sporadic AD (mean age = 60.6 ± 4.85 years, 64.8% women) underwent lumbar puncture, magnetic resonance imaging (n = 266) and positron emission tomography imaging (n = 239) protocols, and clinical evaluations. CSF Aβ42, Aβ40, p-tau181, p-tau217, p-tau231, NfL, neurogranin, sTREM2, YKL40, GFAP, S100, α-Synuclein, SYT1, and SNAP25 were measured. Participants were clustered based on CSF biomarker co-expression with an agglomerative algorithm. The predictive value of the classification against brain and cognitive outcomes was evaluated.
Three clusters (C) were identified. Higher Aβ burden and CSF p-tau was the hallmark of C1. The other two clusters showed lower Aβ burden but higher expression of glial (C2) or synaptic markers (C3). Participants in C1 showed an AD-like clinical phenotype, comprising participants with the overall highest percentage of two parent FH and APOE-ε4 carriers, in addition to comprising more females compared to C2. C3 displayed better vascular health compared to C1. C2 were older and comprised a lower percentage of females compared to C3. C1 showed an AD-like gray matter reduction in medial temporal (notably hippocampus) and frontal regions that were not observed in Aβ42/40 + compared with Aβ42/40 - . Furthermore, Aβ42/40 - participants in C1 showed GM reduction in inferior temporal areas compared with Aβ42/40 + participants overall. C1 membership also predicted cognitive decline in executive function, but not memory, beyond Aβ + status, overall suggesting a better prognosis in Aβ42/40 + participants without C1 membership. Additionally, C1 displayed a higher rate of conversion to Aβ + (25%) over time.
Our results suggest that examining multiple CSF biomarkers reflecting diverse pathological pathways may complement and/or outperform AD core biomarkers and thresholding approaches to identify individuals showing a clinical and cognitive AD-like phenotype, including higher conversion to Aβ + , GM reductions and cognitive decline. The clinical utility of this approach warrants further investigation and replication in other cohorts.
Argiris G
，Akinci M
，Peña-Gómez C
，Palpatzis E
，Garcia-Prat M
，Shekari M
，Blennow K
，Zetterberg H
，Kollmorgen G
，Quijano-Rubio C
，Ashton NJ
，Karikari TK
，Brinkmalm-Westman A
，Lantero-Rodriguez J
，Fauria K
，Sánchez-Benavides G
，Grau-Rivera O
，Suárez-Calvet M
，Arenaza-Urquijo EM
，Study FTA
... -
《Alzheimers Research & Therapy》
The impact of kidney function on Alzheimer's disease blood biomarkers: implications for predicting amyloid-β positivity.
Impaired kidney function has a potential confounding effect on blood biomarker levels, including biomarkers for Alzheimer's disease (AD). Given the imminent use of certain blood biomarkers in the routine diagnostic work-up of patients with suspected AD, knowledge on the potential impact of comorbidities on the utility of blood biomarkers is important. We aimed to evaluate the association between kidney function, assessed through estimated glomerular filtration rate (eGFR) calculated from plasma creatinine and AD blood biomarkers, as well as their influence over predicting Aβ-positivity.
We included 242 participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, comprising cognitively unimpaired individuals (CU; n = 124), mild cognitive impairment (MCI; n = 58), AD dementia (n = 34), and non-AD dementia (n = 26) patients all characterized by [18F] AZD-4694. Plasma samples were analyzed for Aβ42, Aβ40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), tau phosphorylated at threonine 181 (p-tau181), 217 (p-tau217), 231 (p-tau231) and N-terminal containing tau fragments (NTA-tau) using Simoa technology. Kidney function was assessed by eGFR in mL/min/1.73 m2, based on plasma creatinine levels, age, and sex. Participants were also stratified according to their eGFR-indexed stages of chronic kidney disease (CKD). We evaluated the association between eGFR and blood biomarker levels with linear models and assessed whether eGFR provided added predictive value to determine Aβ-positivity with logistic regression models.
Biomarker concentrations were highest in individuals with CKD stage 3, followed by stages 2 and 1, but differences were only significant for NfL, Aβ42, and Aβ40 (not Aβ42/Aβ40). All investigated biomarkers showed significant associations with eGFR except plasma NTA-tau, with stronger relationships observed for Aβ40 and NfL. However, after adjusting for either age, sex or Aβ-PET SUVr, the association with eGFR was no longer significant for all biomarkers except Aβ40, Aβ42, NfL, and GFAP. When evaluating whether accounting for kidney function could lead to improved prediction of Aβ-positivity, we observed no improvements in model fit (Akaike Information Criterion, AIC) or in discriminative performance (AUC) by adding eGFR to a base model including each plasma biomarker, age, and sex. While covariates like age and sex improved model fit, eGFR contributed minimally, and there were no significant differences in clinical discrimination based on AUC values.
We found that kidney function seems to be associated with AD blood biomarker concentrations. However, these associations did not remain significant after adjusting for age and sex, except for Aβ40, Aβ42, NfL, and GFAP. While covariates such as age and sex improved prediction of Aβ-positivity, including eGFR in the models did not lead to improved prediction for any biomarker. Our findings indicate that renal function, within the normal to mild impairment range, does not seem to have a clinically relevant impact when using highly accurate blood biomarkers, such as p-tau217, in a biomarker-supported diagnosis.
Arslan B
，Brum WS
，Pola I
，Therriault J
，Rahmouni N
，Stevenson J
，Servaes S
，Tan K
，Vitali P
，Montembeault M
，Klostranec J
，Macedo AC
，Tissot C
，Gauthier S
，Lantero-Rodriguez J
，Zimmer ER
，Blennow K
，Zetterberg H
，Rosa-Neto P
，Benedet AL
，Ashton NJ
... -
《Alzheimers Research & Therapy》
Evaluation of cerebrospinal fluid levels of VAMP-2 and SNAP-25 in a dementia with Lewy bodies clinical cohort stratified by Alzheimer's pathophysiological biomarkers.
Synaptic protein levels in cerebrospinal fluid (CSF) may represent much-needed objective biomarkers of cognitive impairment, disease progression and drug efficacy in patients with dementia with Lewy bodies (DLB). Soluble N-ethylmaleimide-sensitive factor attachment proteins receptors (SNARE) proteins, such as VAMP-2 and SNAP-25, are implicated in α-synuclein pathophysiology and CSF levels of these proteins are associated with pathophysiological biomarkers and cognitive decline in Alzheimer's disease (AD). The aim of the study was to compare CSF levels of VAMP-2 and SNAP-25 in patients with DLB to cognitively unimpaired controls and AD patients and study their association with cognitive performance and AD and neurodegeneration biomarkers.
VAMP-2 and SNAP-25 were quantified in CSF from cognitively normal controls (n = 62), DLB (n = 44) and AD (n = 114) patients from the Sant Pau Initiative for Neurodegeneration (SPIN) cohort using homebrew Single Molecule Array assays (Simoa). The DLB group was stratified into two groups with ("DLB + AD", n = 28) or without AD co-pathology ("pure DLB", n = 16) using our validated cut-off for the CSF phosphorylated tau (p-tau)/Aβ42 ratio. We used linear regression to test for group differences (adjusting for age) and association with AD biomarkers. We used standardized w-scores of the cognitive tests to analyze the association of the synaptic markers with cognitive performance.
CSF VAMP-2 and SNAP-25 levels correlated across all groups (r = 0.71-0.9, p < 0.001). Both proteins were decreased in pure DLB (p < 0.001, p = 0.01) but increased in DLB + AD (p = 0.01, p = 0.02) compared to controls and showed good accuracy to discriminate pure DLB from DLB + AD (AUC = 0.84, 0.85). Both proteins were associated with CSF p-tau and total tau (t-tau) across all groups (r2 = 0.49-0.88, p < 0.001), with the Aβ42/40 ratio in DLB + AD (r2 = 0.29-0.36, p < 0.001) and in AD (r2 = 0.12-0.23, p < 0.001) and with CSF neurofilament-light chain (NfL) in controls (r²=0.10-0.11, p < 0.001-0.01) and AD patients (r²=0.01-0.08, p = 0.01 - 0.001). SNAP-25 was associated with CSF NfL in the DLB + AD group (r²=0.15, p = 0.02). CSF VAMP-2 and SNAP-25 were associated with phonemic fluency in pure DLB (r2 = 0.39 - 0.28, p = 0.01-0.03) and SNAP-25 with the Clock drawing test and the MMSE in DLB + AD (adj.r2 = 0.15 - 0.14, p = 0.03-0.03) and DLB (adj.r2 = 0.12 - 0.08, p = 0.02-0.04) groups.
CSF VAMP-2 and SNAP-25 are promising surrogate markers of synapse degeneration in DLB. However, care should be taken when interpreting CSF levels of these synaptic markers in DLB in light of the confounding effect of AD pathophysiological markers.
González AC
，Goossens J
，Campuzano EV
，Sala I
，Sánchez-Saudinós MB
，Rodríguez-Baz Í
，Lidón L
，Perlaza D
，Bejanin A
，Haapasalo A
，Fortea J
，Alcolea D
，Lleó A
，Vanmechelen E
，Belbin O
... -
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