Age-Adjusted Serum Neurofilament Predicts Cognitive Decline in Parkinson's Disease (MARK-PD).

Temporal profile and utility of serum neurofilament light in a rat model of mild traumatic brain injury

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder lacking reliable biomarkers. This study investigates plasma protein levels as potential biomarkers of disease severity and progression in NIID. In this study, we enrolled 30 NIID patients and 36 age- and sex-matched controls, following them for 1-2years. Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and tau were measured using ultrasensitive single molecule array (Simoa) assays. Disease severity was evaluated with the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADL), and CNS symptom counts, in addition to neuroimaging data. Our study revealed that NIID patients has significantly higher plasma NfL (median, 35.2 vs. 8.61pg/mL, p < 0.001) and GFAP (102 vs. 79.0pg/mL, p = 0.010) levels compared to controls, with NfL emerging as a robust diagnostic marker (AUC = 0.956). NfL levels were notably higher in acute-onset NIID (77.5 vs. 28.8pg/mL, p = 0.001). NfL correlated strongly with disease severity, including MMSE (ρ = - 0.687, p < 0.001), MoCA (ρ = - 0.670, p < 0.001), ADL (ρ = 0.587, p = 0.001), CNS symptoms (ρ = 0.369, p = 0.045), and white matter hyperintensity volume (ρ = 0.620, p = 0.004). Higher baseline NfL (≥ 35.2pg/mL) associated with increased ADL scores, CNS symptoms, and white matter hyperintensity at follow-up. UCH-L1 and total tau levels showed no significant differences. Our results suggested the potential of NfL as a promising biomarker of disease severity and progression in NIID.

IntroductionWe determined the effect of baseline low density lipoprotein (LDL) and triglyceride (TG) concentrations on cognitive decline, in patients with symptomatic high grade intracranial stenosis.MethodsWe analyzed a cohort of stroke patients who had baseline and 4 months follow‐up Montreal Cognitive Assessment (MoCA) scores. MoCA score worsening after 4 months was the outcome of interest, defined as worsening of ≥ 2 points from baseline. Baseline LDL and TG concentrations (mg/dl) were assessed, and univariate and multivariate analysis using logistic regression were performed to identify predictors of worsening MoCA scores.ResultsA total of 349 patients were analyzed. 313 and 315 patients had baseline LDL and TG, respectively. 61 (17%) had a worsening of MoCA scores. The mean baseline LDL was 97.3 (39.1) in the worsening group, compared to 110.6 (44.8) in those with no worsening (p = 0.014). 23% of patients with LDL < 100 had worsening in MoCA score compared to 11% of patients with LDL ≥ 100 (p< 0.006). The mean baseline TG was 145.7 (102.2) in the worsening group, compared to 170.7 (135.4) (p = 0.053). On multivariate analysis, higher age (p = 0.014) and lower baseline LDL (p = 0.046) were predictors of worsening MoCA scores.ConclusionsPatients who did not undergo any worsening MoCA scores had higher LDL and TG levels at baseline, and only older age and lower baseline LDL scores predicted worsening scores at 4 months. Presumably, the patients with high baseline lipid levels were treated more aggressively with dietary modifications and statins, which could have led to cognitive protective effect regardless of serum lipid profile.

Introduction:Serum neurofilament light (NfL) is an emerging biomarker of traumatic brain injury (TBI). However, the effect of peripheral injuries such as long bone fracture and skeletal muscle injury on serum NfL levels is unknown. Therefore, the aim of this study was to determine whether serum NfL levels can be used as a biomarker of TBI in the presence of concomitant peripheral injuries.Methods:Rats were randomly assigned to one of four injury groups: polytrauma (muscle crush + fracture + TBI; n = 11); peripheral injuries (muscle crush + fracture + sham-TBI; n = 12); TBI-only (sham-muscle crush + sham-fracture + TBI; n = 13); and triple-sham (n = 7). At 2-days post-injury, serum levels of NfL were quantified using a Simoa HD-X Analyzer.Results:Compared to triple-sham rats, serum NfL concentrations were higher in rats with peripheral injuries-only, TBI-only, and polytrauma. When compared to peripheral injury-only rats, serum NfL levels were higher in TBI-only and polytrauma rats. No differences were found between TBI-only and polytrauma rats.Conclusion:Serum NfL levels did not differ between TBI-only and polytrauma rats, indicating that significant peripheral injuries did not affect the sensitivity and specificity of serum NfL as a biomarker of moderate TBI. However, the finding of elevated serum NfL levels in rats with peripheral injuries in the absence of a TBI suggests that the presence of such injuries may limit the utility of NfL as a biomarker of less severe TBI (eg, concussion).

Introduction: While the morbidity and mortality attributable to gliomas and brain metastases is significant, there are currently no approved biomarkers for detecting and monitoring intracranial disease and imaging remains the primary modality. Blood levels of the neurofilament light (NfL) and tau, as well as glial fibrillary acidic protein (GFAp) show promise as biomarkers for brain injury. We therefore hypothesized that these biomarkers would correlate with CNS activity of gliomas and brain metastases. Methods: Serum concentrtaions of NfL, tau and GFAp were measured using the ultrasensitive single molecule array (Simoa) technology (Quanterix, Lexington, MA). Levels of the three proteins were then correlated with status of gliomas and brain metastases in the patients. Statistical analysis was performed using GraphPad Prism7 and all p-values were 2-tailed with an accepted 2-sided alpha level of 0.05 as statistically significant. Results: 36 patients were enrolled with varying malignancies. Both serum NfL and GFAp levels were significantly associated with the state of intracranial disease (ANOVA psNfL= 0.0307; ANOVA pGFAp=0.0348). In contrast, serum tau levels were discordant with brain involvement with cancer (ANOVA pTau= 0.1453). Conclusion: Serum NfL and GFAp both apparently vary closely with presence and activity of gliomas and brain metastases. Our studies are among the first to identify possible candidate serum biomarkers for screening and monitoring cancer patients for CNS involvement with malignancy. Further studies in larger populations are needed to expand these findings. Citation Format: Jason Porter, Adriana Hepner, Manjari Pandey, Philippe Prouet, Felicia Hare, Syed S. Nasir, Madison Boles, Henrik Zetterberg, Kaj Blennow, Michael Martin. Serum neurofilament light (NfL), glial fibrillary acidic protein (GFAp) and tau protein are possible serum biomarkers for activity of brain metastases and gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1352.

Background: Sensitive and specific biomarkers for use in progressive multiple sclerosis (MS) have not been established. We investigate neurofilament light (NfL) as a treatment response biomarker in progressive MS. Objective: To evaluate whether ibudilast 100 mg/day alters serum and cerebrospinal fluid (CSF) levels of NfL in progressive MS. Methods: In a protocol-defined exploratory analysis from a 2-year, phase 2 clinical trial of ibudilast in progressive MS (NCT01982942), serum samples were collected from 239 subjects and a subset contributed CSF and assayed using single-molecule assay (SIMOA) immunoassay. A mixed model for repeated measurements yielded log(NfL) as the response variable. Results: The geometric mean baseline serum NfL was 31.9 and 28.8 pg/mL in placebo and ibudilast groups, respectively. The geometric mean baseline CSF NfL was 1150.8 and 1290.3 pg/mL in placebo and ibudilast groups, respectively. Serum and CSF NfL correlations were r = 0.52 and r = 0.78 at weeks 48 and 96, respectively. Over 96 weeks, there was no between-group difference in NfL in either serum (p = 0.76) or CSF (p = 0.46). After controlling for factors that may affect NfL, no effect of ibudilast on NfL in either serum or CSF was observed. Conclusion: Ibudilast treatment was not associated with a change in either serum or CSF NfL.

Cognitive decline in elderly patients with type 2 diabetes is associated with glycated albumin, ratio of Glycated Albumin to glycated hemoglobin, and concentrations of inflammatory and oxidative stress markers

Plasma neurofilament light (NfL) has been suggested as a noninvasive biomarker to monitor neurodegeneration in Alzheimer disease (AD), but studies are lacking. To examine whether longitudinal plasma NfL levels are associated with other hallmarks of AD. 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. Clinical diagnosis, Aβ and tau cerebrospinal fluid (CSF) biomarkers, imaging measures (magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography), and tests on cognitive scores. 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 Aβ, 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. 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 Aβ42 [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). 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.

Previous studies on sport-related concussion (SRC) may have measured brain injury blood-based biomarker, glial fibrillary acidic protein (GFAP), either before or after its peak, potentially underestimating the diagnostic value. The primary aim of this study was to evaluate the diagnostic performance of serum GFAP at 24 hours post-SRC. Secondary objectives included assessing whether the timing of sample collection relative to an Australian football match (with or without SRC) affected GFAP levels, evaluating if combining GFAP with symptoms improved discrimination of SRC compared with symptoms alone, and determining the diagnostic utility of serum neurofilament light (NfL) levels at 24 hours post-SRC. In a prospective cohort study, adult male and female Australian football players of the Victorian Amateur Football Association (Melbourne, Australia) with and without SRC had blood sampled around 24 hours postinjury/postmatch. GFAP and NfL levels were quantified using Simoa assays, and area under the curve (AUC) values were calculated for time bins of 16-24 hours, 24-32 hours, and 36-52 hours. Symptom severity at blood collection was assessed using the Sport Concussion Assessment Tool 5 (SCAT). A total of 151 athletes with SRC (median age 22.5 years; 85% male) and 97 controls (median age 24.3 years; 86% male) were sampled at a median of 24.5 hours (interquartile range [IQR] 21.7-28.0; min-max 16-51.5). Time to sample postmatch did not affect GFAP levels in controls; however, higher GFAP levels correlated with shorter time post-SRC (Spearman r = -0.25, 95% CI -0.40 to -0.09). Median GFAP concentrations were 65.9 pg/mL (IQR 49.1-81.3) in controls, and for SRC, 124.6 pg/mL (IQR 86.7-190.7) at 16-24 hours, 94.5 pg/mL (IQR 61.6-163.9) at 24-32 hours, and 59.9 pg/mL (IQR 49.1-94.7) at 36-52 hours. AUC values at 16-24 and 24-32 hours were 0.83 (95% CI 0.76-0.90) and 0.72 (95% CI 0.64-0.80), respectively. Furthermore, combining GFAP with SCAT symptoms at 16-24 hours enhanced discriminatory capability compared with SCAT symptoms alone (AUC increased from 0.91 to 0.97; z = 2.48, p = 0.01). Serum NfL had a limited diagnostic value (AUC ≤0.60). Serum GFAP measured at 16-24 hours following potential or suspected SRC may be a useful objective aid to SRC diagnosis.

Plasma neurofilament light (NfL) is a marker for neurodegenerative diseases. Few studies have examined the association of NfL with middle-aged changes in cognitive performance, and no studies have examined differential NfL effects by race. Using data from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (n = 625, Agev1: 30–66 y, 41.6% male, 56.3% African American, 27.8% below poverty), we investigated the associations of initial NfL levels and annualized change with cognitive performance over time in global mental status, verbal and visual memory, fluency, attention, and executive function. We used ordinary least squares and mixed-effects regressions stratified by race, while exploring differential associations by age group, sex, and poverty status. Over a mean follow-up of 4.3 years, we found initial NfL level was associated with a faster decline on normalized mental status scores in Whites only and in those >50 years old. Annualized increase in NfL was associated with a greater decline in verbal fluency in men. In other exploratory analyses, annualized increase in NfL was associated with a slower decline in verbal memory among individuals living above poverty; in the older group (>50 years), first-visit NfL was linked with better performance at baseline in global mental status and verbal memory. In summary, first-visit NfL was primarily associated with the global mental status decline among Whites, while exhibiting inconsistent relationships in some exploratory analyses. Plasma NfL levels can be detected and quantified in non-demented middle-aged adults and changes can be analyzed over time. More longitudinal studies are needed to address the clinical utility of this biomarker for early cognitive defects.

To improve outcome prediction following subarachnoid haemorrhage (SAH), we sought a biomarker integrating early brain injury and multiple secondary pathological processes in a prospective study of 42 non-traumatic SAH patients and 19 control individuals. Neurofilament light (NF-L) was elevated in CSF and serum following SAH. CSF and serum NF-L on Days 1–3 post-SAH strongly predicted modified Rankin score at 6 months, independent of World Federation of Neurosurgical Societies (WFNS) score. NF-L from Day 4 onwards also had a profound impact on outcome. To link NF-L to a SAH-specific pathological process, we investigated NF-L’s relationship with extracellular haemoglobin. Most CSF haemoglobin was not complexed with haptoglobin, yet was able to be bound by exogenous haptoglobin i.e. haemoglobin was scavengeable. CSF scavengeable haemoglobin was strongly predictive of subsequent CSF NF-L. Next, we investigated NF-L efflux from the brain after SAH. Serum and CSF NF-L correlated positively. The serum/CSF NF-L ratio was lower in SAH versus control subjects, in keeping with glymphatic efflux dysfunction after SAH. CSF/serum albumin ratio was increased following SAH versus controls. The serum/CSF NF-L ratio correlated negatively with the CSF/serum albumin ratio, indicating that transfer of the two proteins across the blood–brain interface is dissociated. In summary, NF-L is a strong predictive marker for SAH clinical outcome, adding value to the WFNS score, and is a promising surrogate end point in clinical trials.

Objective To explore the diagnostic value of Alzheimer-associated neuronal thread protein(AD7C-NTP)and olfactory function in the differentiation of three types of dementia, and to evaluate their clinical application value. Methods Mini-Mental State Examination(MMSE)and Montreal Cognitive Assessment(MoCA)were applied to evaluate cognitive function of all subjects with Alzheimer disease(AD), frontotemporal dementia(FTLD), or mixed dementia(MD). Enzyme-linked immunosorbent assay(ELISA)was used to detect the expression levels of AD7c-NTP in urine.T&T test method was applied to detect the olfactory function.Spearman rank correlation was used to evaluate the correlation of urine AD7c-NTP with MMSE and MoCA scores. Results There was no significant difference in the demographic profile(except age)among three types of dementia of AD, FTLD and MD(F=4.05, P=0.02). Among the three dementia groups, the mean age of the MD group was highest.The statistically significant difference in MMSE scores was found among the three groups(F=3.79, P=0.03), while there was no significant difference in MoCA and NPI scores among the three dementia groups.The levels of the urine AD7c-NTP were different among the three dementia groups, but without statistical significance(H=1.25, P=0.53). Additionally, the FTLD group had the highest urine AD7c-NTP level.Spearman rank correlation analysis showed no correlation of AD7c-NTP with MMSE and MoCA(r=0.18, P=0.25; r=0.14, P=0.39, respectively). No differences in olfactory function of the recognition domain(H=3.40, P=0.18)and in the detection domain(H=2.07, P=0.36)were found among three dementia groups of AD, FTLD and MD. Conclusions The level of urine AD7c-NTP is not of clinical significance in differentiating three types of dementia, and it is not correlated with the MMSE and MoCA scores.This study fails to find the clinical value of olfactory function test for distinguishing three types of dementia. Key words: Dementia; Alzheimer-associated neuronal thread protein; Olfactory function

BackgroundGrowing evidence supports the value of neurofilament light (NfL) as a prognostic biomarker in premanifest Huntington’s disease (HD). To date, however, there has been no longitudinal study exceeding 3 years examining either its serial dynamics or predictive power in HD. We aimed to conduct the first such study.MethodsSerum NfL was sampled using ultrasensitive immunoassay at four timepoints across a 14-year period in a cohort of HD gene carriers (n = 21) and controls (n = 14). Gene carriers were premanifest at baseline. Clinical features of HD were evaluated by Unified Huntington’s Disease Rating Scale (UHDRS TMS), Montreal Cognitive Assessment (MoCA), Trail A/B task, Symbol Digit Modalities Task and semantic/phonemic fluency tasks.Results14/21 HD gene carriers converted to prodromal or manifest disease by the final timepoint (“converters”). At baseline and each subsequent timepoint, NfL levels were higher in converters than in non-converters and controls (p = < 0.001–0.03, ηp2 = 0.25–0.66). The estimated rate of change in NfL was higher in converters than in non-converters (p = 0.03) and controls (p = 0.001). Baseline NfL was able to discriminate converters from non-converters (area under curve = 1.000, p = 0.003). A higher rate of change in NfL was predictive of more severe motor (UHDRS-TMS p = 0.007, β = 0.711, R2 = 0.468) and cognitive deficits (MoCA p = 0.007, β = − 0.798, R2 = 0.604; Trail B, p = 0.007, β = 0.772, R2 = 0.567; phonemic fluency p = 0.035, β = − 0.632, R2 = 0.345).ConclusionsOur data suggest that (1) NfL longitudinal dynamics in premanifest/transitional HD are non-constant; rising faster in those closer to disease onset, and (2) NfL can identify individuals at risk of conversion to manifest disease and predict clinical trajectory, > 10 years from disease onset.

ObjectiveThis study aimed to investigate the relationship between white matter hyperintensities (WMH) and perivascular spaces (PVS) on magnetic resonance imaging (MRI) with Montreal Cognitive Assessment (MoCA) scores in patients referred for possible lecanemab therapy based on clinical suspicion of Alzheimer’s disease (AD) prior to biomarker confirmation.Materials and methodsIn this retrospective review, 149 consecutive patients with suspected AD between November 2023 and June 2024 who were evaluated for possible lecanemab therapy were identified. All underwent brain MRI and had valid MoCA scores. WMH were graded using the Fazekas scale (0-3). PVS were visually graded (1-4) in the basal ganglia and centrum semiovale on T2-weighted images. Generalized linear models assessed the association between imaging markers and MoCA, adjusting for age, sex, hypertension (HTN), hyperlipidemia (HLD), and diabetes mellitus (DM).ResultsThe mean MoCA score was 19.56, reflecting mild to moderate cognitive impairment. The mean Fazekas score was 1.37, indicating mild to moderate WMH burden, while the mean PVS scores for basal ganglia and centrum semiovale were 1.99 and 2.37, respectively. There is no significant correlation between age and MoCA scores in our patient population. A negative association of -0.1 between the Fazekas score and MoCA score was observed after controlling for the effects of PVS. In contrast, PVS did not significantly correlate with MoCA score.ConclusionIn patients evaluated for possible lecanemab therapy, a higher WMH burden was negatively associated with global cognition, whereas PVS demonstrated no significant relationship with MoCA scores. These findings suggest that WMH may be an imaging marker of vascular pathology in those suspected of AD.

BackgroundIt is known that blood levels of neurofilament light (NF-L) and diffusion-weighted magnetic resonance imaging (DW-MRI) are both associated with outcome of patients with mild traumatic brain injury (mTBI). Here, we sought to examine the association between admission levels of plasma NF-L and white matter (WM) integrity in post-acute stage DW-MRI in patients with mTBI.MethodsNinety-three patients with mTBI (GCS ≥ 13), blood sample for NF-L within 24 h of admission, and DW-MRI ≥ 90 days post-injury (median = 229) were included. Mean fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated from the skeletonized WM tracts of the whole brain. Outcome was assessed using the Extended Glasgow Outcome Scale (GOSE) at the time of imaging. Patients were divided into CT-positive and -negative, and complete (GOSE = 8) and incomplete recovery (GOSE < 8) groups.ResultsThe levels of NF-L and FA correlated negatively in the whole cohort (p = 0.002), in CT-positive patients (p = 0.016), and in those with incomplete recovery (p = 0.005). The same groups showed a positive correlation with mean MD, AD, and RD (p < 0.001—p = 0.011). In CT-negative patients or in patients with full recovery, significant correlations were not found.ConclusionIn patients with mTBI, the significant correlation between NF-L levels at admission and diffusion tensor imaging (DTI) measurements of diffuse axonal injury (DAI) over more than 3 months suggests that the early levels of plasma NF-L may associate with the presence of DAI at a later phase of TBI.