| 1. |
- Ashton, Nicholas J., et al.
(author)
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Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology
- 2024
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In: JAMA NEUROLOGY. - 2168-6149 .- 2168-6157.
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Journal article (peer-reviewed)abstract
- ImportancePhosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. ObjectiveTo determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid beta (A beta) and longitudinal change across 3 selected cohorts. Design, Setting, and ParticipantsThis cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023. ExposuresMagnetic resonance imaging, A beta positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (A beta 42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay). Main Outcomes and MeasuresAccuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status. ResultsThe study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated A beta (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal A beta pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in A beta-positive individuals, with the highest increase observed in those with tau positivity. Conclusions and RelevanceThis study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.
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| 2. |
- Ashton, Nicholas J., et al.
(author)
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Plasma concentrations of glial fibrillary acidic protein, neurofilament light, and tau in Alexander disease
- 2024
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In: Neurological Sciences. - 1590-1874 .- 1590-3478.
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Journal article (peer-reviewed)abstract
- Introduction: Alexander disease (AxD) is a rare leukodystrophy caused by dominant gain-of-function mutations in the gene encoding the astrocyte intermediate filament, glial fibrillary acidic protein (GFAP). However, there is an urgent need for biomarkers to assist in monitoring not only the progression of disease but also the response to treatment. GFAP is the obvious candidate for such a biomarker, as it is measurable in body fluids that are readily accessible for biopsy, namely cerebrospinal fluid and blood. However, in the case of ASOs, the treatment that is furthest in development, GFAP is the target of therapy and presumably would go down independent of disease status. Hence, there is a critical need for biomarkers that are not directly affected by the treatment strategy. Methods: We explored the potential utility of biomarkers currently being studied in other neurodegenerative diseases and injuries, specifically neurofilament light protein (NfL), phosphorylated forms of tau, and amyloid-β peptides (Aβ42/40). Results and Conclusions: Here, we report that GFAP is elevated in plasma of all age groups afflicted by AxD, including those with adult onset. NfL and p-tau are also elevated, but to a much lesser extent than GFAP. In contrast, the levels of Aß40 and Aß42 are not altered in AxD.
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| 3. |
- Baril, Andree-Ann, et al.
(author)
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Day-to-day sleep variability with Alzheimer's biomarkers in at-risk elderly
- 2024
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In: ALZHEIMER'S & DEMENTIA: DIAGNOSIS, ASSESSMENT & DISEASE MONITORING. - 2352-8729. ; 16:1
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Journal article (peer-reviewed)abstract
- INTRODUCTION Measuring day-to-day sleep variability might reveal unstable sleep-wake cycles reflecting neurodegenerative processes. We evaluated the association between Alzheimer's disease (AD) fluid biomarkers with day-to-day sleep variability. METHODS In the PREVENT-AD cohort, 203 dementia-free participants (age: 68.3 +/- 5.4; 78 males) with a parental history of sporadic AD were tested with actigraphy and fluid biomarkers. Day-to-day variability (standard deviations over a week) was assessed for sleep midpoint, duration, efficiency, and nighttime activity count. RESULTS Lower cerebrospinal fluid (CSF) ApoE, higher CSF p-tau181/amyloid-beta (A beta)(42), and higher plasma p-tau231/A beta(42) were associated with higher variability of sleep midpoint, sleep duration, and/or activity count. The associations between fluid biomarkers with greater sleep duration variability were especially observed in those that carried the APOE4 allele, mild cognitive impairment converters, or those with gray matter atrophy. DISCUSSION Day-to-day sleep variability were associated with biomarkers of AD in at-risk individuals, suggesting that unstable sleep promotes neurodegeneration or, conversely, that AD neuropathology disrupts sleep-wake cycles.
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| 4. |
- Bastgen, Theres, et al.
(author)
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Repetitive head injuries in German American football players do not change blood-based biomarker candidates for CTE during a single season
- 2024
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In: NEUROLOGICAL RESEARCH AND PRACTICE. - 2524-3489. ; 6:1
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Journal article (peer-reviewed)abstract
- BackgroundRepetitive traumatic brain injuries in American football players (AFPs) can lead to the neurodegenerative disease chronic traumatic encephalopathy (CTE). Clinical symptoms of CTE range from mood and behavioral changes to cognitive impairment, depression, and suicidality. So far, CTE cannot be diagnosed in vivo and thus specific diagnostic parameters for CTE need to be found, to observe and treat exposed athletes as early as possible. Promising blood-based biomarkers for CTE include total tau (tTau), hyperphosphorylated tau (pTau), neurofilament light protein (NF-L), glial fibrillary acidic protein (GFAP), amyloid-beta 40 (A beta 40), amyloid-beta 42 (A beta 42) and calcium-binding protein B (S100-B). Previous studies have found elevated levels of these biomarkers in subjects exposed to TBIs, whereas cerebrospinal fluid (CSF) levels of A beta 40 and A beta 42 were decreased in CTE subjects. Here, we investigated whether young AFPs already exhibit changes of these biomarker candidates during the course of a single active season.MethodsBlood samples were drawn from n = 18 American Football Players before and after a full season and n = 18 male age-matched control subjects. The plasma titers of tTau, pTau, NF-L, GFAP, A beta 40, A beta 42 and S100-B were determined. Additionally, Apathy, Depression, and Health status as well as the concussion history and medical care were assessed and analyzed for correlations.ResultsHere we show, that the selected biomarker candidates for CTE do not change significantly during the seven-month period of a single active season of American Football in blood samples of AFPs compared to healthy controls. But interestingly, they exhibit generally elevated pTau titers. Furthermore, we found correlations of depression, quality-of-life, career length, training participation and training continuation with headache after concussion with various titers.ConclusionOur data indicates, that changes of CTE marker candidates either occur slowly over several active seasons of American Football or are exclusively found in CSF. Nevertheless, our results underline the importance of a long-term assessment of these biomarker candidates, which might be possible through repeated blood biomarker monitoring in exposed athletes in the future.
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| 5. |
- Brum, Wagner S., et al.
(author)
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Biological variation estimates of Alzheimer's disease plasma biomarkers in healthy individuals
- 2024
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In: Alzheimer's and Dementia. - 1552-5260 .- 1552-5279. ; 20:2, s. 1284-1297
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Blood biomarkers have proven useful in Alzheimer's disease (AD) research. However, little is known about their biological variation (BV), which improves the interpretation of individual-level data. METHODS: We measured plasma amyloid beta (Aβ42, Aβ40), phosphorylated tau (p-tau181, p-tau217, p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) in plasma samples collected weekly over 10 weeks from 20 participants aged 40 to 60 years from the European Biological Variation Study. We estimated within- (CVI) and between-subject (CVG) BV, analytical variation, and reference change values (RCV). RESULTS: Biomarkers presented considerable variability in CVI and CVG. Aβ42/Aβ40 had the lowest CVI (≈ 3%) and p-tau181 the highest (≈ 16%), while others ranged from 6% to 10%. Most RCVs ranged from 20% to 30% (decrease) and 25% to 40% (increase). DISCUSSION: BV estimates for AD plasma biomarkers can potentially refine their clinical and research interpretation. RCVs might be useful for detecting significant changes between serial measurements when monitoring early disease progression or interventions. Highlights Plasma amyloid beta (Aβ42/Aβ40) presents the lowest between- and within-subject biological variation, but also changes the least in Alzheimer's disease (AD) patients versus controls. Plasma phosphorylated tau variants significantly vary in their within-subject biological variation, but their substantial fold-changes in AD likely limits the impact of their variability. Plasma neurofilament light chain and glial fibrillary acidic protein demonstrate high between-subject variation, the impact of which will depend on clinical context. Reference change values can potentially be useful in monitoring early disease progression and the safety/efficacy of interventions on an individual level. Serial sampling revealed that unexpectedly high values in heathy individuals can be observed, which urges caution when interpreting AD plasma biomarkers based on a single test result.
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| 6. |
- Coley, Nicola, et al.
(author)
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Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trial
- 2024
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In: The Lancet Healthy Longevity. - 2666-7568. ; 5:2, s. e120-e130
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Journal article (peer-reviewed)abstract
- Background: It is unknown whether multidomain interventions, which might preserve late-life cognition, affect Alzheimer's disease pathology. Previous studies measured cerebrospinal fluid and imaging Alzheimer's disease biomarkers in small subsamples of multidomain trial participants. Newly developed assays enable the measurement of blood-based Alzheimer's disease biomarkers in larger samples. We aimed to assess whether plasma tau phosphorylated at threonine 181 (p-tau181) was able to detect or predict 3-year multidomain intervention effects. Methods: This is a secondary analysis of the randomised, controlled, Multidomain Alzheimer Prevention Trial (MAPT) testing a 3-year multidomain intervention, omega-3 fatty acid supplementation, or both versus placebo, in individuals aged 70 years and older in 13 memory centres in France and Monaco. Plasma p-tau181 was measured in stored blood samples in a subsample of 527 participants on an intention-to-treat basis. Changes in cognitive score were calculated as a composite measure using the average of Z scores for the following tests: Mini Mental State Examination orientation items, Free and Cued Selective Reminding Test (sum of free and total recall scores), category fluency, and Digit Symbol Substitution Test. Intervention effects on 3-year change in p-tau181 concentration were estimated by use of a linear mixed model with centre-specific random intercepts. Findings: Recruitment took place between May 30, 2008, and Feb 24, 2011. Median baseline plasma p-tau181 was 8·8 pg/mL (IQR 6·7–11·9) in the total sample, and significantly higher in older individuals, men, APOE ε4 carriers, and participants with renal dysfunction or a positive PET amyloid scan. During 3-year follow-up, individuals with raised baseline p-tau181 underwent greater cognitive decline (eg, mean difference in 3-year change on the composite cognitive score between control group participants with normal and abnormal baseline levels of p-tau was −0·34 [effect size −0·52; 95% CI −0·61 to 0·07] in the fully adjusted model using a 12·4 pg/mL cutoff for abnormal baseline p-tau181), but there were no intervention effects on change in p-tau181 either in this subgroup or the total population, and no effect on cognitive change in individuals with raised baseline p-tau181 (eg, in the fully adjusted model using the 12·4 pg/mL cutoff for p-tau181 abnormality, the mean difference [95% CI] in this subgroup in 3-year decline on the composite cognitive score between the control group and the multidomain + omega-3 group, the omega-3 group, and the multidomain intervention group, was, respectively: 0·13 [−0·21 to 0·47], 0·03 [−0·30 to 0·36], and 0·10 [−0·26 to 0·46]). Surprisingly, individuals with raised baseline p-tau181 showed a decrease in p-tau181 during follow-up (eg, unadjusted mean [95% CI] 3-year change was −3·01 pg/mL (−4·45 to −1·56) in control group subjects with abnormal baseline p-tau181 [using the 12·4 pg/mL abnormal p-tau cutoff]). Interpretation: Our results support the utility of p-tau181 as a prognostic biomarker, but it did not predict or detect intervention effects in this study. Further investigation of its usefulness as a prevention trial outcome measure is required.
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| 7. |
- Ferrari-Souza, Joao Pedro, et al.
(author)
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Vascular risk burden is a key player in the early progression of Alzheimer's disease
- 2024
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In: NEUROBIOLOGY OF AGING. - 0197-4580 .- 1558-1497. ; 136, s. 88-98
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Journal article (peer-reviewed)abstract
- Understanding whether vascular risk factors (VRFs) synergistically potentiate Alzheimer's disease (AD) progression is important in the context of emerging treatments for preclinical AD. In a group of 503 cognitively unimpaired individuals, we tested whether VRF burden interacts with AD pathophysiology to accelerate neurodegeneration and cognitive decline. Baseline VRF burden was calculated considering medical data and AD pathophysiology was assessed based on cerebrospinal fluid (CSF) amyloid-beta 1-42 (A beta 1-42) and tau phosphorylated at threonine 181 (p-tau181). Neurodegeneration was assessed with plasma neurofilament light (NfL) and global cognition with the modified version of the Preclinical Alzheimer's Cognitive Composite. The mean (SD) age of participants was 72.9 (6.1) years, and 220 (43.7%) were men. Linear mixed-effects models revealed that an elevated VRF burden synergistically interacted with AD pathophysiology to drive longitudinal plasma NfL increase and cognitive decline. Additionally, VRF burden was not associated with CSF A beta 1-42or p-tau181 changes over time. Our results suggest that VRF burden and AD pathophysiology are independent processes; however, they synergistically lead to neurodegeneration and cognitive deterioration. In preclinical stages, the combination of therapies targeting VRFs and AD pathophysiology might potentiate treatment outcomes.
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| 8. |
- Franzmeier, Nicolai, et al.
(author)
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Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer's disease.
- 2024
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In: Nature communications. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- In Alzheimer's disease, amyloid-beta (Aβ) triggers the trans-synaptic spread of tau pathology, and aberrant synaptic activity has been shown to promote tau spreading. Aβ induces aberrant synaptic activity, manifesting in increases in the presynaptic growth-associated protein 43 (GAP-43), which is closely involved in synaptic activity and plasticity. We therefore tested whether Aβ-related GAP-43 increases, as a marker of synaptic changes, drive tau spreading in 93 patients across the aging and Alzheimer's spectrum with available CSF GAP-43, amyloid-PET and longitudinal tau-PET assessments. We found that (1) higher GAP-43 was associated with faster Aβ-related tau accumulation, specifically in brain regions connected closest to subject-specific tau epicenters and (2) that higher GAP-43 strengthened the association between Aβ and connectivity-associated tau spread. This suggests that GAP-43-related synaptic changes are linked to faster Aβ-related tau spread across connected regions and that synapses could be key targets for preventing tau spreading in Alzheimer's disease.
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| 9. |
- Gaetani, Lorenzo, et al.
(author)
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The Immune Signature of CSF in Multiple Sclerosis with and without Oligoclonal Bands: A Machine Learning Approach to Proximity Extension Assay Analysis
- 2024
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In: International Journal of Molecular Sciences. - 1661-6596 .- 1422-0067. ; 25:1
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Journal article (peer-reviewed)abstract
- Early diagnosis of multiple sclerosis (MS) relies on clinical evaluation, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. Reliable biomarkers are needed to differentiate MS from other neurological conditions and to define the underlying pathogenesis. This study aimed to comprehensively profile immune activation biomarkers in the CSF of individuals with MS and explore distinct signatures between MS with and without oligoclonal bands (OCB). A total of 118 subjects, including relapsing–remitting MS with OCB (MS OCB+) (n = 58), without OCB (MS OCB−) (n = 24), and controls with other neurological diseases (OND) (n = 36), were included. CSF samples were analyzed by means of proximity extension assay (PEA) for quantifying 92 immune-related proteins. Neurofilament light chain (NfL), a marker of axonal damage, was also measured. Machine learning techniques were employed to identify biomarker panels differentiating MS with and without OCB from controls. Analyses were performed by splitting the cohort into a training and a validation set. CSF CD5 and IL-12B exhibited the highest discriminatory power in differentiating MS from controls. CSF MIP-1-alpha, CD5, CXCL10, CCL23 and CXCL9 were positively correlated with NfL. Multivariate models were developed to distinguish MS OCB+ and MS OCB− from controls. The model for MS OCB+ included IL-12B, CD5, CX3CL1, FGF-19, CST5, MCP-1 (91% sensitivity and 94% specificity in the training set, 81% sensitivity, and 94% specificity in the validation set). The model for MS OCB− included CX3CL1, CD5, NfL, CCL4 and OPG (87% sensitivity and 80% specificity in the training set, 56% sensitivity and 48% specificity in the validation set). Comprehensive immune profiling of CSF biomarkers in MS revealed distinct pathophysiological signatures associated with OCB status. The identified biomarker panels, enriched in T cell activation markers and immune mediators, hold promise for improved diagnostic accuracy and insights into MS pathogenesis.
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| 10. |
- Garcia-Cordero, Indira, et al.
(author)
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Functional connectivity changes in neurodegenerative biomarker-positive athletes with repeated concussions
- 2024
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In: JOURNAL OF NEUROLOGY. - 0340-5354 .- 1432-1459.
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Journal article (peer-reviewed)abstract
- Multimodal biomarkers may identify former contact sports athletes with repeated concussions and at risk for dementia. Our study aims to investigate whether biomarker evidence of neurodegeneration in former professional athletes with repetitive concussions (ExPro) is associated with worse cognition and mood/behavior, brain atrophy, and altered functional connectivity. Forty-one contact sports athletes with repeated concussions were divided into neurodegenerative biomarker-positive (n = 16) and biomarker-negative (n = 25) groups based on positivity of serum neurofilament light-chain. Six healthy controls (negative for biomarkers) with no history of concussions were also analyzed. We calculated cognitive and mood/behavior composite scores from neuropsychological assessments. Gray matter volume maps and functional connectivity of the default mode, salience, and frontoparietal networks were compared between groups using ANCOVAs, controlling for age, and total intracranial volume. The association between the connectivity networks and sports characteristics was analyzed by multiple regression analysis in all ExPro. Participants presented normal-range mean performance in executive function, memory, and mood/behavior tests. The ExPro groups did not differ in professional years played, age at first participation in contact sports, and number of concussions. There were no differences in gray matter volume between groups. The neurodegenerative biomarker-positive group had lower connectivity in the default mode network (DMN) compared to the healthy controls and the neurodegenerative biomarker-negative group. DMN disconnection was associated with increased number of concussions in all ExPro. Biomarkers of neurodegeneration may be useful to detect athletes that are still cognitively normal, but with functional connectivity alterations after concussions and at risk of dementia.
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