Interest in plasma biomarkers for neurodegenerative disorders is growing, but their reliance on glomerular filtration makes kidney function a key potential confounder. This study assesses the effect of kidney function (eGFR) on plasma biomarkers of neurodegeneration and on their accuracy for detecting cerebral amyloidosis. This observational study aims at studying the effect of kidney function on blood biomarkers through simultaneous measurements of creatinine, plasma, and CSF biomarkers (Aβ42, Aβ40, p-tau181, p-tau217, neurofilament light chain [NfL], glial fibrillary acidic protein [GFAP], and brain-derived tau [BD-tau]), as well as plasma biomarker ratios (Aβ42/Aβ40, p-tau217/Aβ42, NfL/p-tau217, and p-tau181/Aβ42), in the ALZAN cohort of patients. This prospective multicenter cohort (#NCT05427448), recruited across Montpellier, Nîmes, and Perpignan hospitals, included patients from November 2022 to July 2024 who met the following criteria: age ≥18 years, informed consent, and concomitant CSF and blood sampling. To determine the association between plasma biomarkers and kidney function, we performed univariable linear regression analyses. A total of 420 patients were included (mean age: 71.1 years, %female: 53.2) and subdivided into 3 groups according to eGFR value (ml/minute/1.73 m2): <60 (n = 36), [60-90] (n = 194), and >90 (n = 190). All mean plasma biomarker levels were significantly higher in the eGFR < 60 group. Except for p-tau217, a statistically significant inverse correlation was observed between eGFR and individual plasma biomarkers. Furthermore, age-adjusted univariable linear regression analysis revealed an association between eGFR and all plasma biomarkers. Kidney dysfunction significantly impaired the specificity of several biomarkers (p-tau181, GFAP, NfL, and BD-tau; p < 0.001) for detecting cerebral amyloidosis (CSF Aβ42/Aβ40 < 7%), whereas p-tau217 was unaffected. It is important to note that ratio-based plasma biomarkers were not influenced by reduced kidney function. Impaired kidney function was linked to increased plasma cerebral amyloidosis biomarkers, but ratio-based measures (especially p-tau217/Aβ42) showed stable sensitivity and specificity for detecting cerebral amyloidosis across all eGFR groups. Additional studies including more patients with lower eGFR values in diverse diagnostic settings are needed to clarify the influence of kidney function on these biomarkers. This Class II evidence shows that kidney function influences individual blood biomarkers used for cerebral amyloidosis detection, but not their ratios. NCT05427448.

The aim of this study was to identify biological processes associated with neuroaxonal degeneration in multiple sclerosis (MS) by analyzing protein patterns linked to neurofilament light (NfL) protein in CSF and serum samples. The highly sensitive proximity extension assay technology was used to quantify protein levels in paired CSF and serum samples from treatment-naïve, early-stage active MS patients (n = 114). The cohort was stratified into above and below median of CSF-NfL level. A discovery phase identified proteins upregulated in CSF, and a validation cohort (n = 128) confirmed findings in a more clinically diverse MS population, including patients receiving disease-modifying therapies. In the discovery cohort, 13 proteins were upregulated in CSF (leukocyte immunoglobulin like receptor B4, CXCL6, CXCL5, cluster of differentiation 38, CCL19, CXCL11, IMPA1, macrophage scavenger receptor 1 (MSR1), CXCL10, monocyte chemotactic protein 2, ITM2A, TNFRSF12A, and CCL23). It is important to note that associations with CCL19, CXCL11, MSR1, CXCL10, TNFRSF12A, and CCL23 were replicated in a validation MS cohort. By contrast, no consistent serum protein profiles associated with serum levels of NfL could be discerned in this group-based analysis. Furthermore, 75 CSF proteins showed a positive adjusted linear association with CSF-NfL, whereas no such significant association remained in the corresponding analysis in serum. The identified and replicated CSF protein profile indicates distinct inflammatory processes associated with ongoing neuroaxonal degeneration. All of these most robust 6 proinflammatory markers-CCL19, CXCL11, MSR1, CXCL10, TNFRSF12A, and CCL23-independently replicated and were individually observed to be relevant in the context of MS. These findings may further elucidate the immunologic pathways underlying disease processes leading to neuroaxonal degeneration.

Blood biomarkers of frailty and cognition: A scoping review.

Alzheimer's disease (AD) presents a critical global challenge, accounting for over 60 % of the 57 million current dementia cases worldwide, with prevalence projected to exceed 100 million by 2050. Traditional diagnostic approaches, such as cerebrospinal fluid (CSF) analysis and neuroimaging are constrained by invasiveness, high costs, and limited accessibility, particularly problematic in aging population where early detection is crucial for effective intervention. This review synthesizes recent advances in blood-based biomarkers for AD, specifically phosphorylated tau proteins (p-tau217, p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and the amyloid-β42/40 ratio. These minimally invasive biomarkers demonstrate exceptional diagnostic accuracy with p-tau217 achieving AUC values greater 0.93 and 91 % positive predictive value in detecting AD pathology, Critically, these biomarkers can identify pathological changes 15-20 years before symptom onset, with plasma p-tau217 levels increasing over 8.5 % annually during preclinical stages. We propose that dried blood spots (DBS), containing both arterial and venous blood components, offer superior representation of brain-derived substances at their first systematic distribution after cardiac output. Ultrasensitive technologies like Simoa and mass spectrometry now enable femtomolar-level detection, revolutionizing of AD diagnostics. However, challenges persist in assay standardization persist in assay standardization, and population-specific validation. Overcoming these barriers to integrate blood biomarkers with DBS technology represents a transformative shift toward accessible, scalable screening in aging communities, offering a paradigm shift in preventing age-related neurodegeneration through early detection and timely intervention.

Plasma biomarkers of neurodegeneration and intraindividual cognitive variability: Comparing variability across test at one time point and using repeated ecological momentary assessment.

Hypertension in midlife is associated with increased dementia risk, yet its relationship with early pathological changes of Alzheimer's disease and related dementias (ADRD) remains unclear. Unlike office blood pressure (BP), 24-h ambulatory BP (ABPM) may better reflect cardiovascular risk, but associations between 24-h BP measures with ADRD biomarkers are unknown. This cross-sectional study examined associations between BP and cerebrospinal fluid biomarkers of ADRD in mid-to-late life. Dementia-free participants (n = 77; mean age = 67 [SD, 6]; 39% women) from the community-based Brain and Cognitive Health (BACH) cohort underwent office and 24-h ABPM assessments to calculate mean BP, nocturnal dipping, blood pressure variability (BPV, coefficient of variation) across 24-h, awake and asleep periods. Participants also completed a lumbar puncture to assess ADRD biomarkers: Aβ42/Aβ40 ratio, phosphorylated tau at threonine 217 (pTau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Linear regression models examined associations between BP and ADRD biomarkers, adjusting for age, sex, BMI, smoking, anti-hypertensive medication use, and APOE ε4 status. Higher 24-h and awake mean BP were associated with higher GFAP (24-h: per 1-SD unit increase, β = 1606.6pg/mL, p = .03; awake: β = 1668.pg/mL, p = .03) and NfL (24-h: β = 172.3pg/mL, p = .03; awake: β = 162.3pg/mL, p = .04) levels. Elevated asleep BPV was associated with higher Aβ42/Aβ40 ratio (β = 0.01, p = .01). No, other clear associations were identified for the other BP metrics (p > .05 for all). Findings indicate that elevated BP is associated with neuronal injury and astrocytic reactivity, suggesting possible pathways through which BP may relate to neurodegenerative processes, independent of overt amyloid or tau.

Neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) are known biomarkers of brain injury in adults, but their significance in very preterm (VPT) infants remains unclear. Given the strong link between inflammation, oxidative stress, and brain injury in this population, we investigated associations between NFL, GFAP, and inflammatory and oxidative stress markers in VPT infants. As part of the prospective Finnish PreBaby study on metabolism in VPT infants, serum NFL and GFAP levels were measured at three timepoints from birth to term-equivalent age (TEA) to assess their associations with IL-6 protein levels depicting inflammation, oxidative stress marker urinary 8-isoprostane, and postmenstrual age (PMA). Serum NFL levels showed a strong positive correlation with IL-6 levels (Spearman correlation coefficient 0.784, p < 0.001). Higher NFL concentrations were associated with lower PMA and decreased towards TEA. A weaker correlation was observed between NFL and the oxidative stress marker 8-isoprostane. Serum GFAP levels were not associated with inflammation. Serum levels of neurofilament light chain are linked to inflammation in very preterm infants. The potential of NFL as an early biomarker of brain injury, potentially guiding preventive interventions and therapy in very preterm infants, should be investigated further.

Prior investigations of how lifetime blast exposure relates to blood biomarkers of brain injury have been limited by small sample sizes and have produced conflicting results. This investigation examined how lifetime blast exposure relates to glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, and hyperphosphorylated tau (p-tau) in service members and veterans (SMVs) with and without uncomplicated mild TBI (mTBI). Participants were 422 SMVs prospectively enrolled in a Defense and Veterans Brain Injury Center-Traumatic Brain Injury Center of Excellence Longitudinal TBI Study. Participants were divided into four groups based on self-reported lifetime blast exposure history as assessed by a single question: none (n = 93), low (n = 136), medium (n = 71), and high (n = 122). Analysis of Covariance was used to examine group differences on GFAP, UCH-L1, NfL, tau, and p-tau. There was a significant effect of blast exposure group on NfL (p = 0.002, ηp 2= 0.034) and GFAP (p = 0.035, ηp 2= 0.021), but not UCH-L1, tau, or p-tau. Post hoc comparisons with Bonferroni correction indicated NfL was higher in the No Blast group compared with the Low Blast (p = 0.004) group, but not the Medium Blast (p = 0.069) or High Blast (p = 1.0) groups. GFAP did not significantly differ between the groups after Bonferroni correction (ps > 0.05). Overall, the lone finding that survived correction for multiple comparisons suggested that participants with low levels of self-reported blast exposure exhibited lower levels of NfL than participants with no history of blast exposure. There were no differences in UCH-L1, tau, or p-tau based on self-reported blast exposure in a large sample of SMVs with and without mTBI.

Depression is the most common psychiatric comorbidity in patients with epilepsy (PWE) but remains frequently underdiagnosed. Identifying objective biomarkers may improve early detection and intervention. Neurofilament light chain (NfL), a marker of neuroaxonal injury, has been linked to both epilepsy-related neuronal damage and depression, yet its role in comorbidity is unclear. We conducted a cross-sectional study including 152 adult PWE recruited from a large tertiary hospital in Northeast China. Depressive symptoms were assessed using the Hamilton Depression Scale (HAMD), and plasma NfL concentrations were measured by enzyme-linked immunosorbent assay. Binary logistic regression models were applied to examine the association between plasma NfL and depressive symptoms, and linear regression models with HAMD scores as a continuous outcome were performed as sensitivity analyses. Both approaches were conducted with adjustment for potential confounders. Receiver operating characteristic (ROC) analysis was conducted to evaluate the discriminative performance of plasma NfL, and k-fold cross-validation (k = 5) was performed to assess the robustness of the ROC analysis. Of the 152 participants, 61 (40.1%) had depressive symptoms. Higher plasma NfL levels were independently associated with both increased odds of depressive symptoms and higher HAMD scores. ROC analysis demonstrated good discriminative accuracy (area under the curve [AUC] = .838), with an optimal cutoff value of 44.85 pg/mL yielding a sensitivity of .82 and a specificity of .74. The mean AUC obtained from k-fold cross-validation was .842, which was consistent with the overall ROC result. These findings suggest that plasma NfL may serve as a candidate biomarker for identifying comorbid depression in epilepsy and provide new insight into shared neurobiological mechanisms.

Increased neurofilament light chain (NfL) in cerebrospinal fluid and blood indicates recent neuroinflammatory damage and is prognostic of disease worsening (JAMA Neurol 2023;80:1317-25). These studies evaluate the analytical performance of the Siemens Healthineers Atellica IM NfL assay, testing serum and plasma, on the Atellica IM analyzer. Detection capability, linearity, dilution recovery, precision, interfering substance testing, specimen equivalence, method comparison studies, and determination of expected values are all described and performed according to CLSI standards. The limit of blank, detection, and quantitation were 1.5, 2.0, and 3.0 pg/mL, respectively. The analytical measuring interval was 3.0 to 300.0 pg/mL with on-board dilutions extending the reportable range to 3000 pg/mL. Repeatability and within-lab precision ranged from 0.9% to 5.7% CV and 1.5% to 8.6% CV, respectively. No significant interference was detected for biotin or 38 other substances. Serum SST and plasma EDTA samples provided equivalent NfL results. Comparison of the NfL assay across Siemens Healthineers platforms (Atellica IM, ADVIA Centaur XP/XPT systems) showed strong alignment; the Atellica IM NfL assay also strongly aligns to the early phase certified reference material (Clin Chem Lab Med 2023;61:1245-54). Age-specific expected values for healthy adults were provided, with an overall central 95th percentile range of 3.7 to 18.9 pg/mL. The Siemens Healthineers Atellica IM NfL assay demonstrated strong performance in all categories of assay development and verification; importantly, results from both healthy and multiple sclerosis patients fall within the reportable range. The Atellica IM NfL assay is for in vitro diagnostic use in the quantitative measurement of NfL in human serum and plasma (EDTA) using the Atellica IM analyzer.

The relationship between peripheral and central biomarkers in mild cognitive impairment (MCI), and the potential role of blood-brain barrier (BBB) dysfunction in this process, remain unclear. MCI, an intermediate state between normal aging and dementia, is characterized by early neuroinflammation and neuronal injury, yet how systemic markers reflect central pathology is poorly understood. In this study, we enrolled 74 participants, including 37 MCI patients and 37 cognitively normal controls. Based on the CSF/serum albumin ratio, subjects were classified into four groups-NC (cognitively normal with intact BBB), NMCI (MCI with intact BBB), BC (cognitively normal with BBB disruption), and BMCI (MCI with BBB disruption)-and further grouped as BBB-intact or BBB-disrupted. Serum and cerebrospinal fluid (CSF) levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light (Nf-L) were measured using enzyme-linked immunosorbent assay. Spearman correlation analysis was applied to examine peripheral-central associations. No significant correlations were observed in NC or NMCI groups. A moderate serum-CSF GFAP correlation was found in the BC group (r = 0.446, P = 0.033), which became markedly stronger in the BMCI group (r = 0.753, P < 0.001). In the BBB-disrupted group, significant correlations were detected for GFAP (r = 0.652, P < 0.001), IL-4 (r = 0.412, P = 0.003), IL-6 (r = 0.296, P = 0.035), and TNF-α (r = 0.352, P = 0.011), with GFAP showing the strongest association. In contrast, within the BBB-intact group, only serum-CSF IL-6 correlation reached significance (r = 0.469, P = 0.024). These findings suggest that BBB disruption markedly enhances peripheral-central biomarker associations, especially for GFAP, highlighting the regulatory role of BBB integrity in linking systemic inflammation, neuronal injury, and MCI pathophysiology.

Guidelines discourage prediction of neurological outcome in comatose patients within the first 72 h after cardiac arrest. Increasing evidence suggests that patients with the most severe brain injury and those with no or minimal brain injury may be identified before 72 h using novel methods. We present a protocol for the EARLY-NEURO study, which aims to evaluate whether good and poor outcomes can be reliably predicted already from 24 h after cardiac arrest using the most commonly available methods. Protocol for a prospective international multicenter substudy within the Sedation, TEmperature and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial where adults post-arrest are randomized to minimal or deep sedation, fever treatment with or without a temperature management device and to two different targets of mean arterial blood pressure. Patients sedated or still unconscious at 24 h are examined with head computed tomography (CT) and electroencephalogram (EEG). Blood samples are collected at 24 h after randomization, and stored for analysis of the brain injury marker neurofilament light. CT and EEG examinations will be centrally evaluated for signs of a likely poor or good outcome applying standardized criteria by raters blinded to treatment allocations and patient outcomes. Intensive care treatment, neurological prognostication, and criteria for withdrawal of care will be according to the STEPCARE protocol. Timepoint and reasons for withdrawal of life-sustaining therapy (WLST) will be recorded. WLST prior to 72 h after randomization based on a presumed futile neurological prognosis is strongly discouraged. Primary outcome will be good or poor functional outcome, assessed by the modified Rankin Scale (dichotomized as 0-3 versus 4-6) at 6 months. Results will be reported in accordance with the Standards for Reporting Diagnostic Accuracy (STARD). Earlier prognostication aims to balance the avoidance of premature treatment withdrawal in patients with favorable potential against the prevention of unnecessary intervention in patients with a definitely poor prognosis.

Serum Neurofilament Light Levels in Patients with Cerebrotendinous Xanthomatosis: a Pilot Study.

Data on changes in biomarkers of brain health, and their associations with cognitive function in adults commencing either dual- or triple-antiretroviral therapy (ART) are sparse. Plasma biomarkers (neurofilament light [NfL], glial fibrillary acidic protein [GFAP], sCD14, CXCL10, neopterin and IL-6) were measured at baseline and after 96 weeks on ART in individuals randomized to darunavir/ritonavir and either tenofovir-DF/emtricitabine (triple-ART, n = 119) or raltegravir (dual-ART, n = 119) in NEAT-001/ANRS143. Regression models examined associations of baseline and week-96 biomarker concentrations with HIV clinical parameters, composite cognitive test scores (Standardized neuropsychological test [NPZ], 7-domains) and treatment arm. In 238 individuals, median age was 38 (interquartile range [IQR] 31, 46) years, 87% male and 83% of white ethnicity. Baseline median log10 HIV RNA 4.73 (IQR 4.23, 5.11) copies/mL and CD4 350 (IQR 285, 412) cells/mm3. At baseline, higher biomarker concentrations were associated with lower CD4 (NfL, GFAP, CXCL10; p < 0.03), higher log10 HIV RNA (sCD14, neopterin, CXCL10; p < 0.02) and longer known duration of HIV (sCD14; p = 0.044). At week-96, 94% had plasma HIV <50 copies/mL, and a decline in biomarker concentrations was observed: GFAP -14.4%, sCD14 -6.8%, neopterin -47.4%, CXCL10 -58.8%, IL-6 -29.5% (all p < 0.001) and NfL -4.4% (p = 0.075). NPZ improved by 0.21 mean points. Change in GFAP, CXCL10, sCD14, neopterin and NfL was negatively associated with change in CD4 (all p ≤ 0.002) but not change in NPZ (p > 0.05). A greater decline in neopterin concentration was observed with dual- (-50.2%) versus triple-ART (-44.3%; p = 0.022). Plasma biomarkers of brain health improved following ART initiation, associated predominantly with improvements in CD4 count and partly with treatment arm.

Mitochondrial dysfunction is central to the pathogenesis of Parkinson's disease (PD), integrating both genetic and environmental factors. Therefore, reliable blood-based biomarkers reflecting mitochondrial alterations are needed. Emerging evidence suggests that somatic changes to mitochondrial DNA (mtDNA) may reflect early disease-associated processes relevant to PD conversion and clinical manifestation. In this study, we analysed somatic mtDNA major arc deletions as a measure of mitochondrial genome integrity and evaluated 7S DNA abundance as well as copy number as complementary readouts in whole blood (n=776) from a large cohort, including idiopathic and genetic PD patients, individuals at risk, PD converters, patients with primary mitochondrial disease, and healthy controls. This work was complemented by analyses in CSF samples (n=72). Finally, mtDNA measures were integrated with genetic, protein, and clinical data, including mitochondrial polygenic risk scores, alpha-synuclein seeding assays, and serum neurofilament light chain levels. In blood, the strongest effects occurred in PINK1/PRKN-PD (deletions: P<0.0001; 7S DNA: P<0.0001) and early-onset idiopathic PD (7S DNA: P=0.0009-0.0030). Individuals with prodromal signs conferring a high risk for PD also showed increased mtDNA deletions (P=0.0045) and reduced 7S DNA (P=0.0046). In PD converters, these alterations were detectable prior to clinical diagnosis (deletions: P=0.0024; 7S DNA: P=0.0091). In CSF-derived extracellular vesicles, we observed an age-associated increase in mtDNA copy number in healthy controls (R2=0.121, P=0.035) that was absent in idiopathic PD (R2=0.014, P=0.548). Across all PD patients, those with the highest mtDNA deletion burden and lowest 7S DNA exhibited a higher risk of developing cognitive impairment and depression, while also showing a longer time to postural instability (deletions: P=0.0187; 7S DNA: P=0.0281). Integration of mtDNA readouts, mitochondrial polygenic risk scores, alpha-synuclein seeding, and serum neurofilament light chain levels revealed complementary contributions to biological heterogeneity in PD, with receiver operating characteristic analyses showing moderate group-level discrimination using mtDNA measures alone (AUC=0.66) and substantially improved discrimination when combined with alpha-synuclein and neurodegeneration markers (AUC up to 0.96). Alpha-synuclein seeding activity was associated with later age at onset, whereas mtDNA deletion burden showed an inverse association, indicating that these biomarkers capture distinct biological dimensions of PD. MtDNA damage markers, particularly deletion burden, capture mitochondrial dysfunction arising from both genetic and environmental influences and are detectable across early clinical stages of PD. While not serving as stand-alone diagnostic biomarkers, mtDNA measures provide complementary biological information within a multimodal framework and may support patient stratification based on mitochondrial involvement using a minimally invasive approach.

BackgroundIsolated REM sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Evaluating trajectories of phenoconversion is crucial in this population. Plasma neurofilament light chain (NfL), a marker of axonal injury, has emerged as a promising candidate for tracking disease progression.ObjectivesTo assess plasma NfL levels in iRBD patients, examine their associations with clinical features, particularly neurogenic orthostatic hypotension (nOH), and explore their potential role in predicting phenoconversion.MethodsPlasma NfL was measured in 54 iRBD subjects, 54 PD, 54 healthy controls and 16 MSA. Participants underwent motor, cognitive, and non-motor symptoms assessments. Longitudinal follow-up data have been collected for iRBD subjects. NfL was quantified using the Ella platform; analyses were performed with Prism 9.ResultsNfL levels were significantly higher in iRBD compared to controls and similar to PD. iRBD-nOH+ patients had significantly higher NfL than nOH- counterparts, with values overlapping PD and MSA. nOH was inversely associated with hyposmia, supporting phenotypic divergence. NfL correlated positively with SCOPA-AUT and BDI scores. At follow-up, all four MSA converters had nOH at baseline.ConclusionsPlasma NfL elevation in iRBD supports its role as a marker of early neurodegeneration. Its association with nOH suggests that this autonomic feature may identify a biologically more severe iRBD phenotype, possibly on a trajectory toward MSA. These findings warrant extended longitudinal validation and support the integration of clinical and biological markers, including NfL, for stratifying conversion risk.

Neurofilament light chain (NfL) is a pivotal biomarker for neuroaxonal damage. However, its quantification in volume-limited matrices, such as mouse aqueous humor (AH) (2 to 6 µL per eye), has historically required pooling samples from multiple animals due to the low sensitivity and high sample volume requirements of standard immunoassays. Such pooling increases animal requirements and precludes individual-level data analysis. To overcome these limitations, we developed and evaluated a NfL HomeBrew (HB) assay using the NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) technology. NULISA offers superior analytical sensitivity and requires less than 10 µL volume. Our results demonstrate that the NfL HB NULISA performs comparably to the Simoa reference assay and provides superior sensitivity to the Ella platform. Crucially, the assay reliably quantified NfL in as little as 2 µL of individual mouse AH, with 90% of samples yielding quantifiable results. This approach eliminates the need for sample pooling, effectively reducing animal use by up to eightfold while preserving data integrity at the individual animal level. These findings establish the NULISA platform as a highly sensitive, ethically advantageous solution for neurobiological research in volume-restricted models.

Blood-based biomarkers offer a widely available, scalable, and noninvasive method to study neurodegeneration. However, the association between blood-based biomarkers of neurodegeneration and long-term risk of mortality, as well as dementia-specific mortality in a racially diverse cohort, remains understudied. The goal of this study was to determine whether baseline biomarkers of neurodegeneration are associated with long-term risk of all-cause and dementia-specific mortality in a biracial cohort. The REasons for Geographic and Racial Differences in Stroke cohort study enrolled 30,239 Black and White participants across the continental United States from 2003 to 2007, with ongoing follow-up. Plasma neurofilament light chain (NfL), total tau, glial fibrillary acidic protein (GFAP), and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) were measured in baseline plasma from a random sample of participants. All-cause mortality, dementia-specific mortality, cardiovascular-specific mortality, and other causes of death were adjudicated and classified using medical records, the Social Security Death Index, and the National Death Index. Cause-specific Cox regression models accounting for competing risks were used to calculate hazard ratios (HRs) of outcomes for each biomarker separately. A total of 917 participants had a mean baseline age of 67.4 years (SD 12.1), 49.4% were female, and 48.6% self-identified as Black. With a mean follow-up of 11.1 (SD 5.7) years, 51.0% (477/935) of participants died and 9.2% experienced dementia-specific mortality (86/935). No associations were observed for total tau. In fully adjusted models for other biomarkers, HRs of all-cause mortality per standard deviation increments were 1.93 (95% CI 1.48-2.52) for GFAP, 1.90 (95% CI 1.55-2.32) for NfL, and 1.23 (95% CI 1.09-1.37) for UCH-L1. Furthermore, GFAP (HR 5.66, 95% CI 2.91-11.00) and NfL (HR 2.72, 95% CI 1.57-4.71) were associated with dementia-specific mortality in fully adjusted models. GFAP (HR 2.06, 95% CI 1.22-3.49) and NfL (HR 2.16, 95% CI 1.66-2.81) were also associated with cardiovascular-specific mortality in fully adjusted models. Plasma biomarkers of neurodegeneration, particularly GFAP and NfL, were associated with increased risk of all-cause, dementia-specific, and cardiovascular-specific mortality in a biracial cohort. These associations should be considered when assessing links between these biomarkers and other outcomes, as well as when used in clinical practice.

We report on the utility of speech-based digital endpoints measured during a Phase 1b study of VRG50635 in Amyotrophic Lateral Sclerosis (ALS). Fifty-four participants with ALS were enrolled and participated in an 8-week pretreatment run-in, followed by three 8-week dosing periods and an 8-week follow-up. They completed a speech assessment every two weeks in the clinic or at home. We observed moderate to high correlations between digital measures of speech timing and articulatory motor function, and the ALS Functional Rating Scale-Revised, slow vital capacity and plasma neurofilament light chain. Furthermore, speech measures can show functional decline before the ALSFRS-R does, while also capturing differences between participants with bulbar symptoms and those without. The results support the feasibility and utility of digital speech endpoints to study disease impact in ALS clinical trials.

We investigated the basis and clinical correlates of a negative cerebrospinal fluid (CSF) alpha-synuclein (α-syn) seed amplification assay result in patients with a clinical diagnosis of sporadic or GBA1-associated PD formulated by movement disorder specialists. Out of 473 participants with a confirmed PD diagnosis at the last follow-up, 62 (13.1%) were α-syn negative. Among them, 3 out of 15 with available longitudinal CSF samples converted to α-syn positive. Alpha-syn negative participants had more severe axial motor impairment, lower odds of hyposmia, REM sleep behaviour disorder and constipation. There were no differences in motor and cognitive progression between groups. CSF neurofilament light chain values were not associated with α-syn status. Besides possible misdiagnosis, the results indicate that α-syn negative PD comprises a distinct patient subgroup, possibly associated with a low burden or absence of Lewy body pathology. The results support the use of CSF α-syn SAA in PD patient stratification.