A blood-based biomarker workflow for optimal tau-PET referral in memory clinic settings.

Blood-based biomarkers for screening may guide tau positrion emissition tomography (PET) scan referrals to optimize prognostic evaluation in Alzheimer's disease. Plasma Aß42/Aß40, pTau181, pTau217, pTau231, NfL, and GFAP were measured along with tau-PET in memory clinic patients with subjective cognitive decline, mild cognitive impairment or dementia, in the Swedish BioFINDER-2 study (n = 548) and in the TRIAD study (n = 179). For each plasma biomarker, cutoffs were determined for 90%, 95%, or 97.5% sensitivity to detect tau-PET-positivity. We calculated the percentage of patients below the cutoffs (who would not undergo tau-PET; "saved scans") and the tau-PET-positivity rate among participants above the cutoffs (who would undergo tau-PET; "positive predictive value"). Generally, plasma pTau217 performed best. At the 95% sensitivity cutoff in both cohorts, pTau217 resulted in avoiding nearly half tau-PET scans, with a tau-PET-positivity rate among those who would be referred for a scan around 70%. And although tau-PET was strongly associated with subsequent cognitive decline, in BioFINDER-2 it predicted cognitive decline only among individuals above the referral cutoff on plasma pTau217, supporting that this workflow could reduce prognostically uninformative tau-PET scans. In conclusion, plasma pTau217 may guide selection of patients for tau-PET, when accurate prognostic information is of clinical value.

Efficacy assessment of an active tau immunotherapy in Alzheimer's disease patients with amyloid and tau pathology: a post hoc analysis of the "ADAMANT" randomised, placebo-controlled, double-blind, multi-centre, phase 2 clinical trial.

BACKGROUND: Tau pathology correlates with and predicts clinical decline in Alzheimer's disease. Approved tau-targeted therapies are not available. METHODS: ADAMANT, a 24-month randomised, placebo-controlled, parallel-group, double-blinded, multicenter, Phase 2 clinical trial (EudraCT2015-000630-30, NCT02579252) enrolled 196 participants with Alzheimer's disease; 119 are included in this post-hoc subgroup analysis. AADvac1, active immunotherapy against pathological tau protein. A machine learning model predicted likely Amyloid+Tau+ participants from baseline MRI. STATISTICAL METHODS: MMRM for change from baseline in cognition, function, and neurodegeneration; linear regression for associations between antibody response and endpoints. RESULTS: The prediction model achieved PPV of 97.7% for amyloid, 96.2% for tau. 119 participants in the full analysis set (70 treatment and 49 placebo) were classified as A+T+. A trend for CDR-SB 104-week change (estimated marginal means [emm] = -0.99 points, 95% CI [-2.13, 0.13], p = 0.0825]) and ADCS-MCI-ADL (emm = 3.82 points, CI [-0.29, 7.92], p = 0.0679) in favour of the treatment group was seen. Reduction was seen in plasma NF-L (emm = -0.15 log pg/mL, CI [-0.27, -0.03], p = 0.0139). Higher antibody response to AADvac1 was related to slowing of decline on CDR-SB (rho = -0.10, CI [-0.21, 0.01], p = 0.0376) and ADL (rho = 0.15, CI [0.03, 0.27], p = 0.0201), and related to slower brain atrophy (rho = 0.18-0.35, p < 0.05 for temporal volume, whole cortex, and right and left hippocampus). CONCLUSIONS: In the subgroup of ML imputed or CSF identified A+T+, AADvac1 slowed AD-related decline in an antibody-dependent manner. Larger anti-tau trials are warranted. FUNDING: AXON Neuroscience SE.

A two-step workflow based on plasma p-tau217 to screen for amyloid ß positivity with further confirmatory testing only in uncertain cases.

Cost-effective strategies for identifying amyloid-ß (Aß) positivity in patients with cognitive impairment are urgently needed with recent approvals of anti-Aß immunotherapies for Alzheimer's disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow can reduce the number of confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests needed while accurately classifying patients. We evaluated a two-step workflow for determining Aß-PET status in patients with mild cognitive impairment (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE ε4 status was developed in BioFINDER-1 (area under the curve (AUC) = 89.3%) and validated in BioFINDER-2 (AUC = 94.3%). In step 1, the blood-based model was used to stratify the patients into low, intermediate or high risk of Aß-PET positivity. In step 2, we assumed referral only of intermediate-risk patients to CSF Aß42/Aß40 testing, whereas step 1 alone determined Aß-status for low- and high-risk groups. Depending on whether lenient, moderate or stringent thresholds were used in step 1, the two-step workflow overall accuracy for detecting Aß-PET status was 88.2%, 90.5% and 92.0%, respectively, while reducing the number of necessary CSF tests by 85.9%, 72.7% and 61.2%, respectively. In secondary analyses, an adapted version of the BioFINDER-1 model led to successful validation of the two-step workflow with a different plasma p-tau217 immunoassay in patients with cognitive impairment from the TRIAD cohort (n = 84). In conclusion, using a plasma p-tau217-based model for risk stratification of patients with MCI can substantially reduce the need for confirmatory testing while accurately classifying patients, offering a cost-effective strategy to detect AD in memory clinic settings.

Plasma amyloid-ß42/40 and apolipoprotein E for amyloid PET pre-screening in secondary prevention trials of Alzheimer's disease.

The extent to which newly developed blood-based biomarkers could reduce screening costs in secondary prevention trials of Alzheimer's disease is mostly unexplored. We collected plasma amyloid-ß42/40, apolipoprotein E ε4 status and amyloid PET at baseline in 181 cognitively unimpaired participants [the age of 72.9 (5.3) years; 61.9% female; education of 11.9 (3.4) years] from the Swedish BioFINDER-1 study. We tested whether a model predicting amyloid PET status from plasma amyloid-ß42/40, apolipoprotein E status and age (combined) reduced cost of recruiting amyloid PET + cognitively unimpaired participants into a theoretical trial. We found that the percentage of cognitively unimpaired participants with an amyloid PET + scan rose from 29% in an unscreened population to 64% [(49, 79); P < 0.0001] when using the biomarker model to screen for high risk for amyloid PET + status. In simulations, plasma screening also resulted in a 54% reduction of the total number of amyloid PET scans required and reduced total recruitment costs by 43% [(31, 56), P < 0.001] compared to no pre-screening when assuming a 16× PET-to-plasma cost ratio. Total savings remained significant when the PET-to-plasma cost ratio was assumed to be 8× or 4×. This suggests that a simple plasma biomarker model could lower recruitment costs in Alzheimer's trials requiring amyloid PET positivity for inclusion.

Optimal combinations of CSF biomarkers for predicting cognitive decline and clinical conversion in cognitively unimpaired participants and mild cognitive impairment patients: A multi-cohort study.

INTRODUCTION: Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases. METHODS: We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of Aß42, Aß40, phosphorylated tau at threonine-181 (p-tau), neurofilament light (NfL), neurogranin, α-synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL-40, S100b, and interleukin 6 (IL-6) (Elecsys NeuroToolKit). RESULTS: Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/Aß42 alone (R2 ≥ 0.31) or together with NfL (R2  = 0.25), while p-tau/Aß42 (R2 ≥ 0.19) was sufficient to accurately predict change of the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P-tau/Aß42 (AUC ≥ 0.87) and p-tau/Aß42 together with NfL (AUC ≥ 0.75) were the best predictors of conversion to AD and all-cause dementia, respectively. DISCUSSION: P-tau/Aß42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all-cause dementia conversion and cognitive decline.

Robustness of CSF Aß42/40 and Aß42/P-tau181 measured using fully automated immunoassays to detect AD-related outcomes.

INTRODUCTION: This study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (Aß)42/Aß40 or Aß42/phosphorylated tau (p-tau)181 and the effects of measurement variability when predicting Alzheimer's disease (AD)-related outcomes (i.e., Aß-positron emission tomography [PET] visual read and AD neuropathology). METHODS: We studied 750 participants (BioFINDER study, Alzheimer's Disease Neuroimaging Initiative [ADNI], and University of California San Francisco [UCSF]). Youden's index was used to identify cutoffs and to calculate accuracy (Aß-PET visual read as outcome). Using longitudinal variability in Aß-negative controls, we identified a gray zone around cut-points where the risk of an inconsistent predicted outcome was >5%. RESULTS: For Aß42/Aß40, cutoffs across cohorts were <0.059 (BioFINDER), <0.057 (ADNI), and <0.058 (UCSF). For Aß42/p-tau181, cutoffs were <41.90 (BioFINDER), <39.20 (ADNI), and <46.02 (UCSF). Accuracy was ≈90% for both Aß42/Aß40 and Aß42/p-tau181 using these cutoffs. Using Aß-PET as an outcome, 8.7% of participants fell within a gray zone interval for Aß42/Aß40, compared to 4.5% for Aß42/p-tau181. Similar findings were observed using a measure of overall AD neuropathologic change (7.7% vs. 3.3%). In a subset with CSF and plasma Aß42/40, the number of individuals within the gray zone was ≈1.5 to 3 times greater when using plasma Aß42/40. DISCUSSION: CSF Aß42/p-tau181 was more robust to the effects of measurement variability, suggesting that it may be the preferred Elecsys-based measure in clinical practice and trials.

Tau-PET is superior to phospho-tau when predicting cognitive decline in symptomatic AD patients.

INTRODUCTION: Biomarkers for the prediction of cognitive decline in patients with amnestic mild cognitive impairment (MCI) and amnestic mild dementia are needed for both clinical practice and clinical trials. METHODS: We evaluated the ability of tau-PET (positron emission tomography), cortical atrophy on magnetic resonance imaging (MRI), baseline cognition, apolipoprotein E gene (APOE) status, plasma and cerebrospinal fluid (CSF) levels of phosphorylated tau-217, neurofilament light (NfL), and amyloid beta (Aß)42/40 ratio (individually and in combination) to predict cognitive decline over 2 years in BioFINDER-2 and Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: Baseline tau-PET and a composite baseline cognitive score were the strongest independent predictors of cognitive decline. Cortical thickness and NfL provided some additional information. Using a predictive algorithm to enrich patient selection in a theoretical clinical trial led to a significantly lower required sample size. DISCUSSION: Models including baseline tau-PET and cognition consistently provided the best prediction of change in cognitive function over 2 years in patients with amnestic MCI or mild dementia.

Test-retest variability of plasma biomarkers in Alzheimer's disease and its effects on clinical prediction models.

INTRODUCTION: The effect of random error on the performance of blood-based biomarkers for Alzheimer's disease (AD) must be determined before clinical implementation. METHODS: We measured test-retest variability of plasma amyloid beta (Aß)42/Aß40, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau (p-tau)217 and simulated effects of this variability on biomarker performance when predicting either cerebrospinal fluid (CSF) Aß status or conversion to AD dementia in 399 non-demented participants with cognitive symptoms. RESULTS: Clinical performance was highest when combining all biomarkers. Among single-biomarkers, p-tau217 performed best. Test-retest variability ranged from 4.1% (Aß42/Aß40) to 25% (GFAP). This variability reduced the performance of the biomarkers (≈ΔAUC [area under the curve] -1% to -4%) with the least effects on models with p-tau217. The percent of individuals with unstable predicted outcomes was lowest for the multi-biomarker combination (14%). DISCUSSION: Clinical prediction models combining plasma biomarkers-particularly p-tau217-exhibit high performance and are less effected by random error. Individuals with unstable predicted outcomes ("gray zone") should be recommended for further tests.

Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease.

Importance: There is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD). Objective: To describe longitudinal [18F]RO948 tau positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the strongest associations with longitudinal tau PET and best optimized clinical trial enrichment. Design, Setting, and Participants: This longitudinal cohort study consecutively enrolled amyloid-ß (Aß)-negative cognitively unimpaired (CU) participants, Aß-positive CU individuals, Aß-positive individuals with mild cognitive impairment (MCI), and individuals with AD dementia between September 2017 and November 2020 from the Swedish BioFINDER-2 (discovery cohort) and BioFINDER-1 (validation cohort) studies. Exposures: Baseline plasma and cerebrospinal fluid Aß42/Aß40, tau phosphorylated at threonine-217 (p-tau217), p-tau181 and neurofilament light, magnetic resonance imaging, amyloid PET ([18F]flutemetamol), and tau PET ([18F]RO948 in the BioFINDER-2 study; [18F]flortaucipir in the BioFINDER-1 study). Main Outcomes and Measures: Baseline tau PET standardized uptake value ratio (SUVR) and annual percent change in tau PET SUVR across regions of interest derived using a data-driven approach combining clustering and event-based modeling. Regression models were used to examine associations between individual biomarkers and longitudinal tau PET and to identify which combinations best predicted longitudinal tau PET. These combinations were then entered in a power analysis to examine how their use as an enrichment strategy would affect sample size in a simulated clinical trial. Results: Of 343 participants, the mean (SD) age was 72.56 (7.24) years, and 157 (51.1%) were female. The clustering/event-based modeling-based approach identified 5 regions of interest (stages). In Aß-positive CU individuals, the largest annual increase in tau PET SUVR was seen in stage I (entorhinal cortex, hippocampus, and amygdala; 4.04% [95% CI, 2.67%-5.32%]). In Aß-positive individuals with MCI and with AD dementia, the greatest increases were seen in stages II (temporal cortical regions; 4.45% [95% CI, 3.41%-5.49%]) and IV (certain frontal regions; 5.22% [95% CI, 3.95%-6.49%]), respectively. In Aß-negative CU individuals and those with MCI, modest change was seen in stage I (1.38% [95% CI, 0.78%-1.99%] and 1.80% [95% CI, 0.76%-2.84%], respectively). When looking at individual predictors and longitudinal tau PET in the stages that showed most change, plasma p-tau217 (R2 = 0.27, P < .005), tau PET (stage I baseline SUVR; R2 = 0.13, P < .05) and amyloid PET (R2 = 0.10, P < .05) were significantly associated with longitudinal tau PET in stage I in Aß-positive CU individuals. In Aß-positive individuals with MCI, plasma p-tau217 (R2 = 0.24, P < .005) and tau PET (stage II baseline SUVR; R2 = 0.44, P < .001) were significantly associated with longitudinal tau PET in stage II. Findings were replicated in BioFINDER-1 using longitudinal [18F]flortaucipir. For the power analysis component, plasma p-tau217 with tau PET resulted in sample size reductions of 43% (95% CI, 34%-46%; P < .005) in Aß-positive CU individuals and of 68% (95% CI, 61%-73%; P < .001) in Aß-positive individuals with MCI. Conclusions and Relevance: In trials using tau PET as the outcome, plasma p-tau217 with tau PET may prove optimal for enrichment in preclinical and prodromal AD. However, plasma p-tau217 was most important in preclinical AD, while tau PET was more important in prodromal AD.

Plasma biomarkers of Alzheimer's disease improve prediction of cognitive decline in cognitively unimpaired elderly populations.

Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. We therefore tested if plasma measurements of amyloid-ß (Aß)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average of 4.8 ± 1.7 years in the BioFINDER study. A combination of all three plasma biomarkers and basic demographics best predicted change in cognition (Pre-Alzheimer's Clinical Composite; R2 = 0.14, 95% CI [0.12-0.17]; P < 0.0001) and subsequent AD dementia (AUC = 0.82, 95% CI [0.77-0.91], P < 0.0001). In a simulated clinical trial, a screening algorithm combining all three plasma biomarkers would reduce the required sample size by 70% (95% CI [54-81]; P < 0.001) with cognition as trial endpoint, and by 63% (95% CI [53-70], P < 0.001) with subsequent AD dementia as trial endpoint. Plasma ATN biomarkers show usefulness in cognitively unimpaired populations and could make large clinical trials more feasible and cost-effective.

The ANTsX ecosystem for quantitative biological and medical imaging.

The Advanced Normalizations Tools ecosystem, known as ANTsX, consists of multiple open-source software libraries which house top-performing algorithms used worldwide by scientific and research communities for processing and analyzing biological and medical imaging data. The base software library, ANTs, is built upon, and contributes to, the NIH-sponsored Insight Toolkit. Founded in 2008 with the highly regarded Symmetric Normalization image registration framework, the ANTs library has since grown to include additional functionality. Recent enhancements include statistical, visualization, and deep learning capabilities through interfacing with both the R statistical project (ANTsR) and Python (ANTsPy). Additionally, the corresponding deep learning extensions ANTsRNet and ANTsPyNet (built on the popular TensorFlow/Keras libraries) contain several popular network architectures and trained models for specific applications. One such comprehensive application is a deep learning analog for generating cortical thickness data from structural T1-weighted brain MRI, both cross-sectionally and longitudinally. These pipelines significantly improve computational efficiency and provide comparable-to-superior accuracy over multiple criteria relative to the existing ANTs workflows and simultaneously illustrate the importance of the comprehensive ANTsX approach as a framework for medical image analysis.

Accelerated inflammatory aging in Alzheimer's disease and its relation to amyloid, tau, and cognition.

It is unclear how pathological aging of the inflammatory system relates to Alzheimer's disease (AD). We tested whether age-related inflammatory changes in cerebrospinal fluid (CSF) and plasma exist across different stages of AD, and whether such changes related to AD pathology. Linear regression was first used model chronological age in amyloid-ß negative, cognitively unimpaired individuals (Aß- CU; n = 312) based on a collection of 73 inflammatory proteins measured in both CSF and plasma. Fitted models were then applied on protein levels from Aß+ individuals with mild cognitive impairment (Aß+ MCI; n = 150) or Alzheimer's disease dementia (Aß+ AD; n = 139) to test whether the age predicted from proteins alone ("inflammatory age") differed significantly from true chronological age. Aß- individuals with subjective cognitive decline (Aß- SCD; n = 125) or MCI (Aß- MCI; n = 104) were used as an independent contrast group. The difference between inflammatory age and chronological age (InflammAGE score) was then assessed in relation to core AD biomarkers of amyloid, tau, and cognition. Both CSF and plasma inflammatory proteins were significantly associated with age in Aß- CU individuals, with CSF-based proteins predicting chronological age better than plasma-based counterparts. Meanwhile, the Aß- SCD and validation Aß- CU groups were not characterized by significant inflammatory aging, while there was increased inflammatory aging in Aß- MCI patients for CSF but not plasma inflammatory markers. Both CSF and plasma inflammatory changes were seen in the Aß+ MCI and Aß+ AD groups, with varying degrees of change compared to Aß- CU and Aß- SCD groups. Finally, CSF inflammatory changes were highly correlated with amyloid, tau, general neurodegeneration, and cognition, while plasma changes were mostly associated with amyloid and cognition. Inflammatory pathways change during aging and are specifically altered in AD, tracking closely with pathological hallmarks. These results have implications for tracking AD progression and for suggesting possible pathways for drug targeting.

Current advances in plasma and cerebrospinal fluid biomarkers in Alzheimer's disease.

PURPOSE OF REVIEW: This review provides a concise overview of recent advances in cerebrospinal fluid (CSF) and blood-based biomarkers of Alzheimer's disease lesions. RECENT FINDINGS: Important recent advances for CSF Alzheimer's disease biomarkers include the introduction of fully automated assays, the development and implementation of certified reference materials for CSF Aß42 and a unified protocol for handling of samples, which all support reliability and availability of CSF Alzheimer's disease biomarkers. Aß deposition can be detected using Aß42/Aß40 ratio in both CSF and plasma, though a much more modest change is seen in plasma. Tau aggregation can be detected using phosphorylated tau (P-tau) at threonine 181 and 217 in CSF, with similar accuracy in plasma. Neurofilament light (NfL) be measured in CSF and shows similar diagnostic accuracy in plasma. Though total tau (T-tau) can also be measured in plasma, this measure is of limited clinical relevance for Alzheimer's disease in its current immunoassay format. SUMMARY: Alzheimer's disease biomarkers, including Aß, P-tau and NfL can now be reliably measured in both CSF and blood. Plasma-based measures of P-tau show particular promise, with potential applications in both clinical practice and in clinical trials.

Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations.

We developed models for individualized risk prediction of cognitive decline in mild cognitive impairment (MCI) using plasma biomarkers of ß-amyloid (Aß), tau and neurodegeneration. A total of 573 patients with MCI from the Swedish BioFINDER study and the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included in the study. The primary outcomes were longitudinal cognition and conversion to Alzheimer's disease (AD) dementia. A model combining tau phosphorylated at threonine 181 (P-tau181) and neurofilament light (NfL), but not Aß42/Aß40, had the best prognosis performance of all models (area under the curve = 0.88 for 4-year conversion to AD in BioFINDER, validated in ADNI), was stronger than a basic model of age, sex, education and baseline cognition, and performed similarly to cerebrospinal fluid biomarkers. A publicly available online tool for individualized prognosis in MCI based on our combined plasma biomarker models is introduced. Combination of plasma biomarkers may be of high value to identify individuals with MCI who will progress to AD dementia in clinical trials and in clinical practice.

Comparing progression biomarkers in clinical trials of early Alzheimer's disease.

OBJECTIVE: To investigate the statistical power of plasma, imaging, and cognition biomarkers as Alzheimer's disease (AD) clinical trial outcome measures. METHODS: Plasma neurofilament light, structural magnetic resonance imaging, and cognition were measured longitudinally in the Alzheimer's Disease Neuroimaging Initiative (ADNI) in control (amyloid PET or CSF Aß42 negative [Aß-] with Clinical Dementia Rating scale [CDR] = 0; n = 330), preclinical AD (Aß + with CDR = 0; n = 218) and mild AD (Aß + with CDR = 0.5-1; n = 697) individuals. A statistical power analysis was performed across biomarkers and groups based on longitudinal mixed effects modeling and using several different clinical trial designs. RESULTS: For a 30-month trial of preclinical AD, both the temporal composite and hippocampal volumes were superior to plasma neurofilament light and cognition. For an 18-month trial of mild AD, hippocampal volume was superior to all other biomarkers. Plasma neurofilament light became more effective with increased trial duration or sampling frequency. Imaging biomarkers were characterized by high slope and low within-subject variability, while plasma neurofilament light and cognition were characterized by higher within-subject variability. INTERPRETATION: MRI measures had properties that made them preferable to cognition and pNFL as outcome measures in clinical trials of early AD, regardless of cognitive status. However, pNfL and cognition can still be effective depending on inclusion criteria, sampling frequency, and response to therapy. Future trials will help to understand how sensitive pNfL and MRI are to detect downstream effects on neurodegeneration of drugs targeting amyloid and tau pathology in AD.

Cardiac Surgery is Associated with Biomarker Evidence of Neuronal Damage.

BACKGROUND: Anesthesia and surgery is commonly associated with central nervous system sequelae and cognitive symptoms, which may be caused by neuronal injury. Neuronal injury can be monitored by plasma concentrations of the neuronal biomarkers tau and neurofilament light protein (NFL). Currently, there are no studies examining whether neuronal injury varies between surgical procedures. OBJECTIVE: Our aim was to investigate if neuronal damage is more frequent after cardiac than after otolaryngeal surgery, as estimated by tau and NFL concentrations in plasma. METHODS: Blood samples were drawn before, during, and after surgery and concentrations of tau, NFL, Aß40, and Aß42 were measured in 25 patients undergoing cardiac surgery (9 off-pump and 16 on-pump) and 26 patients undergoing otolaryngeal surgery. RESULTS: Tau increased during surgery (1752%, p = 0.0001) and NFL rose seven days post-surgery (1090%, p < 0.0001) in patients undergoing cardiac surgery; even more in patients on-pump than off-pump. No changes were observed in patients undergoing otolaryngeal surgery and only minor fluctuations were observed for Aß40 and Aß42. CONCLUSION: Cardiac surgery is associated with neuronal injury, which is aggravated by extracorporeal circulation. Analyses of NFL and tau in blood may guide development of surgical procedures to minimize neuronal damage, and may also be used in longitudinal clinical studies to assess the relationship of surgery with future neurocognitive impairment or dementia.

NFL is a marker of treatment response in children with SMA treated with nusinersen.

BACKGROUND: Recently, the anti-sense oligonucleotide drug nusinersen was approved for spinal muscular atrophy (SMA) and our aim was to find a response marker for this treatment. METHODS: Twelve children with SMA type 1 and two copies of the SMN2 gene were included in a consecutive single-center study. The children were sampled for CSF at baseline and every time nusinersen was given intrathecally. The neuronal biomarkers NFL and tau and the glial biomarker GFAP were measured. Motor function was assessed using CHOP INTEND. Eleven similarly aged children, who were investigated to rule out neurological or infectious disease, were used as controls. RESULTS: Baseline levels of NFL (4598 ± 981 vs 148 ± 39, P = 0.001), tau (939 ± 159 vs 404 ± 86, P = 0.02), and GFAP (236 ± 44 vs 108 ± 26, P = 0.02) were significantly higher in SMA children than controls. Motor function improved by nusinersen treatment in median 13 points corresponding to 5.4 points per month of treatment (P = 0.001). NFL levels typically normalized ( < 380 pg/ml) between the fourth and fifth doses [- 879.5 pg/mL/dose, 95% CI (- 1243.4, - 415.6), P = 0.0001], tau levels decreased [- 112.6 pg/mL/dose, 95% CI (- 206-7, - 18.6), P = 0.01], and minor decreases in GFAP were observed [- 16.9 pg/mL/dose, 95% CI (- 22.8, - 11.2), P = 0.02] by nusinersen treatment. Improvement in motor function correlated with reduced concentrations of NFL (rho = - 0.64, P = 0.03) and tau (rho = - 0.85, P = 0.0008) but not GFAP. CONCLUSIONS: Nusinersen normalized the axonal damage marker NFL and correlated with motor improvement in children with SMA. NFL may, therefore, be a novel biomarker to monitor treatment response early in the disease course.

Dynamics of extracellular matrix proteins in cerebrospinal fluid and serum and their relation to clinical outcome in human traumatic brain injury.

Background Brevican, neurocan, tenascin-C and tenascin-R are extracellular matrix proteins present in brain that show increased expression in experimental animal models of brain injury. However, little is known about the dynamics of these proteins in human body fluids, such as cerebrospinal fluid (CSF) and serum, after traumatic brain injury (TBI). The aims of this study were to investigate if matrix proteins in CSF and serum are associated with functional outcome following traumatic brain injury, if their concentrations change over time and to compare their levels between brain injured patients to controls. Methods In total, 42 traumatic brain injury patients, nine healthy controls and a contrast group consisting of 38 idiopathic normal pressure hydrocephalus patients were included. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the concentrations of proteins. Results Increased concentrations of brevican, tenascin-C and tenascin-R in CSF correlated with unfavourable outcome, with stronger outcome prediction ability compared to other biomarkers of brain tissue injury. CSF brevican, tenascin-R and serum neurocan gradually decreased with time (p = 0.04, p = 0.008, p = 0.005, respectively), while serum tenascin-C (p = 0.01) increased. CSF concentrations of brevican, neurocan and tenascin-R (only in time point 3) after TBI were lower than in the idiopathic normal pressure hydrocephalus group (p < 0.0001, p < 0.0001, and p = 0.0008, respectively). In serum, tenascin-C concentration was higher and neurocan lower compared to healthy controls (p = 0.02 and p = 0.0009). Conclusions These findings indicate that levels of extracellular matrix proteins are associated with clinical outcome following TBI and may act as markers for different pathophysiology than currently used protein biomarkers.

Association Between Longitudinal Plasma Neurofilament Light and Neurodegeneration in Patients With Alzheimer Disease.

Importance: Plasma neurofilament light (NfL) has been suggested as a noninvasive biomarker to monitor neurodegeneration in Alzheimer disease (AD), but studies are lacking. Objective: To examine whether longitudinal plasma NfL levels are associated with other hallmarks of AD. Design, Setting, and Participants: This North American cohort study used data from 1583 individuals in the multicenter Alzheimer's Disease Neuroimaging Initiative study from September 7, 2005, through June 16, 2016. Patients were eligible for inclusion if they had NfL measurements. Annual plasma NfL samples were collected for up to 11 years and were analyzed in 2018. Exposures: Clinical diagnosis, Aß and tau cerebrospinal fluid (CSF) biomarkers, imaging measures (magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography), and tests on cognitive scores. Main Outcomes and Measures: The primary outcome was the association between baseline exposures (diagnosis, CSF biomarkers, imaging measures, and cognition) and longitudinal plasma NfL levels, analyzed by an ultrasensitive assay. The secondary outcomes were the associations between a multimodal classification scheme with Aß, tau, and neurodegeneration (ie, the ATN system) and plasma NfL levels and between longitudinal changes in plasma NfL levels and changes in the other measures. Results: Of the included 1583 participants, 716 (45.2%) were women, and the mean (SD) age was 72.9 (7.1) years; 401 had no cognitive impairment, 855 had mild cognitive impairment, and 327 had AD dementia. The NfL level was increased at baseline in patients with mild cognitive impairment and AD dementia (mean levels: cognitive unimpairment, 32.1 ng/L; mild cognitive impairment, 37.9 ng/L; and AD dementia, 45.9 ng/L; P < .001) and increased in all diagnostic groups, with the greatest increase in patients with AD dementia. A longitudinal increase in NfL level correlated with baseline CSF biomarkers (low Aß42 [P = .001], high total tau [P = .02], and high phosphorylated tau levels [P = .02]), magnetic resonance imaging measures (small hippocampal volumes [P < .001], thin regional cortices [P = .009], and large ventricular volumes [P = .002]), low fluorodeoxyglucose-positron emission tomography uptake (P = .01), and poor cognitive performance (P < .001) for a global cognitive score. With use of the ATN system, increased baseline NfL levels were seen in A-T+N+ (P < .001), A+T-N+ (P < .001), and A+T+N+ (P < .001), and increased rates of NfL levels were seen in A-T+N- (P = .009), A-T+N+ (P = .02), A+T-N+ (P = .04), and A+T+N+ (P = .002). Faster increase in NfL levels correlated with faster increase in CSF biomarkers of neuronal injury, faster rates of atrophy and hypometabolism, and faster worsening in global cognition (all P < .05 in patients with mild cognitive impairment; associations differed slightly in cognitively unimpaired controls and patients with AD dementia). Conclusions and Relevance: The findings suggest that plasma NfL can be used as a noninvasive biomarker associated with neurodegeneration in patients with AD and may be useful to monitor effects in trials of disease-modifying drugs.

The intact postsynaptic protein neurogranin is reduced in brain tissue from patients with familial and sporadic Alzheimer's disease.

Synaptic degeneration and neuronal loss are early events in Alzheimer's disease (AD), occurring long before symptom onset, thus making synaptic biomarkers relevant for enabling early diagnosis. The postsynaptic protein neurogranin (Ng) is a cerebrospinal fluid (CSF) biomarker for AD, also in the prodromal phase. Here we tested the hypothesis that during AD neurodegeneration, processing of full-length Ng into endogenous peptides in the brain is increased. We characterized Ng in post-mortem brain tissue and investigated the levels of endogenous Ng peptides in relation to full-length protein in brain tissue of patients with sporadic (sAD) and familial Alzheimer's disease (fAD), healthy controls and individuals who were cognitively unaffected but amyloid-positive (CU-AP) in two different brain regions. Brain tissue from parietal cortex [sAD (n = 10) and age-matched controls (n = 10)] and temporal cortex [sAD (n = 9), fAD (n = 10), CU-AP (n = 13) and controls (n = 9)] were included and all the samples were analyzed by three different methods. Using high-resolution mass spectrometry, 39 endogenous Ng peptides were identified while full-length Ng was found to be modified including disulfide bridges or glutathione. In sAD parietal cortex, the ratio of peptide-to-total full-length Ng was significantly increased for eight endogenous Ng peptides compared to controls. In the temporal cortex, several of the peptide-to-total full-length Ng ratios were increased in both sAD and fAD cases compared to controls and CU-AP. This finding was confirmed by western blot, which mainly detects full-length Ng, and enzyme-linked immunosorbent assay, most likely detecting a mix of peptides and full-length Ng. In addition, Ng was significantly associated with the degree of amyloid and tau pathology. These results suggest that processing of Ng into peptides is increased in AD brain tissue, which may reflect the ongoing synaptic degeneration, and which is also mirrored as increased levels of Ng peptides in CSF.