NfL Increase Research Articles

Serum neurofilament light at diagnosis: a prognostic indicator for accelerated disease progression in Parkinson’s Disease

Neurofilament light chain (NFL) is elevated in neurodegenerative diseases, including Parkinson’s disease (PD). This study aimed to investigate serum NFL in newly diagnosed PD and its association with cognitive and motor decline over 10 years. Serum NFL levels were measured in PD patients and controls from the ParkWest study at diagnosis (baseline) and after 3 and 5 years. Mixed-effects regression analyzed changes in NFL and the association with annual changes in MMSE and UPDRS-III scores over 10 years. PD patients had elevated serum NFL at all visits and a faster annual increase over 5 years compared to controls (0.09 pg/mL per year; p = 0.029). Higher baseline NFL predicted faster cognitive decline β −0.77 transformed MMSE; p = 0.010), and a 40% NFL increase predicted future motor decline (β 0.28 UPDRS-III; p = 0.004). Elevated serum NFL in early PD is linked to faster cognitive and motor impairment, suggesting its prognostic value in PD biomarker panels.

Neurofilament Light Chain as a Biomarker of Global Cognition in Individuals With Possible Vascular Mild Cognitive Impairment.

Neurofilament Light Chain (NfL) is a biomarker of axonal injury elevated in mild cognitive impairment (MCI) and Alzheimer's disease dementia. Blood NfL also inversely correlates with cognitive performance in those conditions. However, few studies have assessed NfL as a biomarker of global cognition in individuals demonstrating mild cognitive deficits who are at risk for vascular-related cognitive decline. To assess the relationship between blood NfL and global cognition in individuals with possible vascular MCI (vMCI) throughout cardiac rehabilitation (CR). Additionally, NfL levels were compared to age/sex-matched cognitively unimpaired (CU) controls. Participants with coronary artery disease (vMCI or CU) were recruited at entry to a 24-week CR program. Global cognition was measured using the Montreal Cognitive Assessment (MoCA) and plasma NfL level (pg/ml) was quantified using a highly sensitive enzyme-linked immunosorbent assay. Higher plasma NfL was correlated with worse MoCA scores at baseline (β = -.352, P = .029) in 43 individuals with vMCI after adjusting for age, sex, and education. An increase in NfL was associated with worse global cognition (b[SE] = -4.81[2.06], P = .023) over time, however baseline NfL did not predict a decline in global cognition. NfL levels did not differ between the vMCI (n = 39) and CU (n = 39) groups (F(1, 76) = 1.37, P = .245). Plasma NfL correlates with global cognition at baseline in individuals with vMCI, and is associated with decline in global cognition during CR. Our findings increase understanding of NfL and neurobiological mechanisms associated with cognitive decline in vMCI.

Longitudinal change of plasma biomarkers with incident mild cognitive impairment or Alzheimer’s disease in a multi‐ethnic cohort

AbstractBackgroundThe utility of plasma‐based Alzheimer’s biomarkers in differentiating cognitively healthy individuals from those with Mild Cognitive Impairment (MCI) or Alzheimer’s disease (AD) has been widely investigated in cross‐sectional studies. There are fewer data on longitudinal change of these biomarkers over time, particularly in multi‐ethnic cohorts.MethodBased on a community‐based, multi‐ethnic cohort study, the Washington Heights Inwood Columbia Aging Project, we included 610 cognitively normal individuals with three plasma samples collected over a mean period of 6.7 years. We used AD biomarkers, including Aβ40, Aβ42, tau, phosphorylated tau‐181 (P‐tau181), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL), and two calculated ratio measures (Aβ42/Aβ40, P‐tau181/Aβ42). During the follow‐up, 156 individuals developed MCI, 50 developed AD, and 404 remained cognitively unimpaired. We used generalized estimating equations to examine whether those who developed MCI and AD had different rates of change in plasma biomarkers than controls. Analyses were adjusted for age, years of education, sex, race and ethnicity, and APOE ɛ4 status. Similar analyses were performed to examine whether the rate of biomarker change differed by race and ethnicity, sex, and APOE ɛ4 status.ResultThe initial mean age of individuals was 73.1 (SD = 5.6) years, 419 (69%) were women, and 25.9% carried APOE e4. Individuals self‐identified as non‐Hispanic White (28.9%), non‐Hispanic Black (25.4%), or Hispanic (45.7%). Compared to controls, individuals with incident MCI had an accelerated increase in P‐tau181 (b = 0.029, p = 0.048), NfL (b = 0.027, p = 0.010), GFAP (b = 0.029, p = 0.002), and a more rapid decrease in Aβ42/Aβ40 ratio (b = ‐0.015, p = 0.033). Individuals with incident AD also had a greater increase in NfL (b = 0.041, p = 0.027) and GFAP (b = 0.04, p = 0.006) than controls. Hispanics had a faster increase in NfL (b = 0.033, p = 0.002) and GFAP (b = 0.034, p<0.001), and Black participants had a faster increase in NfL (b = 0.028, p = 0.023), compared to Whites. Neither sex nor APOE ɛ4 genotype affected rates of biomarker changes.ConclusionLongitudinal change in plasma biomarkers may have clinical utility, since incident MCI and AD are accompanied by faster increases in P‐tau181, NfL, and GFAP, and a faster decrease in Aβ42/ Aβ40 ratio. The trajectories of AD biomarker change may also vary by race and ethnicity.

The Association of Plasma Biomarkers and Survival in the Oldest Old

AbstractBackgroundPrevious research showed that plasma NfL (neurofilament light chain) associated with survival. Here we perform exploratory analyses to associate a broader range of plasma biomarkers Amyloid‐βeta‐40 (Aβ40), Amyloid‐βeta‐42 (Aβ42), phosphorylated Tau‐181 (pTau‐181), NfL and glial fibrillary acidic protein (GFAP), with survival after reaching 100 years.MethodThe longitudinal Dutch 100‐plus study cohort comprises of self‐reported cognitively healthy centenarians. Biomarkers were measured in 202 centenarians (137 females, ISCED education level median [IQR] 3 [2–4]) on the Simoa platform. Information on survival was obtained via family report until January 2023. Centenarians who were alive were censored at date of last visit or date last confirmed alive. We investigated the relationship between biomarkers and survival by cox regression analyses, adjusting for age at blood draw, sex and cognitive functioning. We performed maximally selected log‐rank statistics between all plasma biomarkers and survival rate to find an optimal cut‐off, and constructed Kaplan‐Meier survival curves.ResultOf 202 centenarians (median age [IQR] at blood draw 101.4 [100.4‐102.9]), 173 (85.6%) were deceased (median age [IQR] at death 103.2 [102.0‐104.3]). The median (IQR) survival time after blood draw was 14.4 (5.5‐25.1) months. All biomarkers Aβ40, Aβ42, pTau‐181, NfL and GFAP intercorrelated (rs = 0.17–0.79; all P‐values<0.05). Cox regression analyses showed that for each standard deviation increase in NfL, adjusted for age, sex, and MMSE score, the risk of mortality increased by 28% (HR 1.28; 95% CI, 1.11–1.47; P<0.001), Table 1. Maximally selected log‐rank statistics split up NfL into survival groups high and low (cut‐off 70.34 pg/mL, M = 3.803, P = 0.003, Figure 1). The median (IQR) shorter survival time of high versus low NfL was 7.8 (5.38‐9.27) months. No statistically significant cut‐off values were identified for the remaining biomarkers.ConclusionOur results indicate that elevated levels of NfL, but not Aβ40, Aβ42, pTau‐181 and GFAP, associate with lower survival. Furthermore, we were able to find an optimal cut‐off for NfL at which survival in centenarians could be split twofold.

Characterizing plasma biomarkers of Alzheimer’s Disease in aging marmosets and genetically engineered PSEN1 mutation carriers.

AbstractBackgroundAlzheimer’s Disease (AD) is a progressive disease that presents as a continuum evolution from preclinical AD to mild cognitive impairment and, ultimately, dementia. The phenotypic characterization of AD was unified under a biological construct research framework supported by the National Institutes on Aging and Alzheimer’s Association (NIA‐AA). This framework, referred to as ATN, is based on the presence of biomarkers for amyloid (Aβ, A), pathologic tau (T), and neurodegeneration (N). The present studies aimed to establish normative values of these biomarkers in our colony of outbred marmosets from infancy through aged individuals and compare them to the values from our population of marmosets genetically engineered with early onset familial mutations in the PSEN1 gene.MethodPlasma (EDTA) and fibroblast media from skin biopsies were evaluated using MesoScale Discovery (MSD) Aβ peptide panel 4G8 ELISA and Human Neurofilament L (NfL) per the manufacturer’s protocols for each kit.ResultThere was a significant increase in the plasma Aβ42:40 ratio in PSEN1 mutation carriers relative to age‐ and sex‐matched wild‐type (WT) controls, which was also observed in culture media generated from fibroblasts of the same individuals. Longitudinal analysis of plasma Aβ revealed consistent levels in WT controls across multiple samplings with persistent increases in PSEN1 carriers. An increase in Nfl was observed in aging WT marmosets relative to young subjects.ConclusionWe have optimized the detection of plasma biomarkers for amyloid and NfL in marmosets and established normative values within our colony. Importantly, these results demonstrate the sensitivity and validity of these reagents for tracking plasma Aβ longitudinally across the marmoset lifespan. Other clinically utilized commercially available reagents are in the process of being optimized and validated to enable an analogous marmoset ATN. Pilot studies are ongoing evaluating the potential of pTau plasma biomarkers as part of the longitudinal assessments. The application of the NIA‐AA Research Framework to marmosets will attain a more accurate characterization and understanding of the etiological sequence of events that lead to AD development, in line with the currently used framework in AD patients.

Serum biomarkers indicate sex differences in response to pathology inhibition in aged mice with tau pathology

AbstractBackgroundThe failure of some clinical trials using drugs that remove brain amyloid to prevent progression of dementia suggest that neurodegenerative disease may not progress in a linear fashion and threshold levels of one pathology may initiate alterations that are unable to be reversed upon removal of the initiating pathological process. We used the inducible Tg4510 mouse tauopathy model to determine whether neurodegeneration could be halted following removal of transgene expression in mice aged to 18 monthsMethodPathology was induced in mice from 8 weeks until 18 months of age (n = 20 equal male/female; both tau transgenic and non‐transgenic) by removal of doxycycline (dox) diet. Dox diet was returned to half the animals from 18‐23 months to inhibit pathology. Levels of serum Nfl were measured using SIMOA assay throughout disease progression and p‐tau181 along with other serum biomarkers were measured at endpoint. Immunohistochemical assays were performed to quantitate numbers of neurons (NeuN) and tau load (PHF‐tau) in hippocampus.ResultSerum Nfl increased over aging in all mice and was significantly higher in tau transgenics relative to non‐transgenics at 18 months (p<0.05). Between 18 and 23 months, the rate of serum Nfl increase was significantly(p<0.05) reduced in male transgenic mice on dox compared to female transgenic mice, so that by 23 months levels were not different from non‐transgenic mice. Similarly, the numbers of neurons in the hippocampus of male mice on dox at 23 months was significantly higher than their female counterparts (p<0.05). When looking at levels of serum p‐tau181 at 23 months, there was significantly (p<0.05) higher levels in male mice on dox than female miceConclusionThese data suggest that aged female mice have ongoing neurodegeneration following removal of pathology induction that is similar to mice with continued pathology induction. The differences in serum p‐tau‐181 may indicate that female mice fail to clear pathological tau from the brain. Further studies will examine the relationship between histopathology and blood biomarkers and determine whether female mice on dox have a higher tau pathology load than their male counterparts.

Cluster analysis of the longitudinal progression of plasma biomarkers and amyloid imaging in the Wisconsin Registry for Alzheimer’s Prevention

AbstractBackgroundThe analysis of the longitudinal progression of plasma biomarkers and amyloid imaging might lead to new insights in the early pattern of biomarker changes.MethodPlasma Aß42/Aß40, pTau231/Aß42, pTau181/Aß42, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) were measured for n = 223 subjects and 1673 total visits in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) using Quanterix Simoa assays at the University of Gothenburg. Global distribution volume ratio (DVR) was computed from 11C‐Pittsburgh compound B PET scans. Inclusion criteria included Amyloid or CSF Amyloid positive status, and at least one plasma serial value. Trajectories spanning age 46.9 to 80.3 years old for the DVR and plasma biomarkers were estimated by fitting a vector field to the longitudinal data (https://arxiv.org/abs/2206.15215). A Louvain community clustering analysis was performed. The time from Amyloid positivity (DVR = 1.19; centiloid of 22) was also computed for all individual trajectories that crossed this threshold.ResultThe Louvain community clustering algorithm resulted in three distinct communities (Fig 1): no increase in DVR or plasma biomarkers (Green, n = 88(39.5%)); increase in DVR and all plasma biomarkers except NFL (Red, 41(18.4%)); and mixed DVR plus GFAP and NFL increase (Blue, 94(42.2%)). Time since Amyloid positivity (TSAP) was computed for the subset of subjects (n = 84) expected to cross the Amyloid positivity threshold. The Louvain communities as a function of TSAP are shown in Fig 2.ConclusionWe identified three communities regarding the longitudinal progression of amyloid PET and plasma biomarker levels. Plasma biomarkers were dynamic up to 30 years before Amyloid positivity.

Cluster analysis of the longitudinal progression of plasma biomarkers and amyloid imaging in the Wisconsin Registry for Alzheimer’s Prevention

AbstractBackgroundThe analysis of the longitudinal progression of plasma biomarkers and amyloid imaging might lead to new insights in the early pattern of biomarker changes.MethodPlasma Aβ42/Aβ40, pTau231/Aβ42, pTau181/Aβ42, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) were measured for n = 223 subjects and 1673 total visits in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) using Quanterix Simoa assays at the University of Gothenburg. Global distribution volume ratio (DVR) was computed from 11C‐Pittsburgh compound B PET scans. Inclusion criteria included Amyloid or CSF Amyloid positive status, and at least one plasma serial value. Trajectories spanning age 46.9 to 80.3 years old for the DVR and plasma biomarkers were estimated by fitting a vector field to the longitudinal data (https://arxiv.org/abs/2206.15215). A Louvain community clustering analysis was performed. The time from Amyloid positivity (DVR = 1.19; centiloid of 22) was also computed for all individual trajectories that crossed this threshold.ResultThe Louvain community clustering algorithm resulted in three distinct communities (Fig 1): no increase in DVR or plasma biomarkers (Green, n = 88(39.5%)); increase in DVR and all plasma biomarkers except NFL (Red, 41(18.4%)); and mixed DVR plus GFAP and NFL increase (Blue, 94(42.2%)). Time since Amyloid positivity (TSAP) was computed for the subset of subjects (n = 84) expected to cross the Amyloid positivity threshold. The Louvain communities as a function of TSAP are shown in Fig 2.ConclusionWe identified three communities regarding the longitudinal progression of amyloid PET and plasma biomarker levels. Plasma biomarkers were dynamic up to 30 years before Amyloid positivity.

Plasma Biomarkers of Alzheimer Disease in Women With and Without HIV

Blood-based biomarkers associated with increased risk of Alzheimer disease (AD) are understudied in people living with and without HIV, particularly women. To determine whether baseline or 1-year changes in plasma amyloid-β40 (Aβ40), Aβ42, ratio of Aβ42 to Aβ40, total tau (t-tau), phosphorylated tau 231 (p-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NFL) are associated with neuropsychological performance (NP) among women living with HIV (WLWH) and women living without HIV (WLWOH). This longitudinal, prospective, cohort study with 1-year repeated clinical measures (NP only measured once) and biospecimen collection occurred between 2017 and 2019. Participants were women aged 40 years or older from 10 clinical research sites in cities across the US that were part of the Women's Interagency HIV Study. Data analysis was conducted from April to December 2022. Laboratory-confirmed HIV status and AD biomarkers. Sociodemographically adjusted NP T-scores (attention and working memory, executive function, processing speed, memory, learning, verbal fluency, motor function, and global performance) were the primary outcomes. Baseline and 1-year fasting plasma Aβ40, Aβ42, t-tau, p-tau231, GFAP, and NFL levels were measured and analyzed using multivariable linear regression. The study consisted of 307 participants (294 aged ≥50 years [96%]; 164 African American or Black women [53%]; 214 women with a high school education or higher [70%]; 238 women who were current or former smokers [78%]; and 236 women [77%] who were overweight or obese [body mass index >25]) including 209 WLWH and 98 WLWOH. Compared with WLWOH at baseline, WLWH performed worse on learning (mean [SD] T-score 47.8 [11.3] vs 51.4 [10.5]), memory (mean [SD] T-score 48.3 [11.6] vs 52.4 [10.2]), verbal fluency (mean [SD] T-score 48.3 [9.8] vs 50.7 [8.5]), and global (mean [SD] T-score 49.2 [6.8] vs 51.1 [5.9]) NP assessments. Baseline median Aβ40, GFAP, and NFL levels were higher among WLWH vs WLWOH. There were no differences in 1-year biomarker change by HIV serostatus. Lower learning, memory, and motor NP were associated with 1-year Aβ40 increase; lower learning and motor with Aβ42 increase; lower motor with p-tau231 increase; and lower processing speed, verbal fluency and motor with NFL increase in the entire sample. Among WLWH, a 1-year increase in Aβ40 from baseline to follow-up was associated with worse learning, memory, and global NP; a 1-year increase in t-tau with worse executive function; and a 1-year increase in NFL with worse processing speed. Among WLWOH, a 1-year increase in Aβ40 and Aβ42 were associated with poorer memory performance and NFL was associated with poorer motor performance. These findings suggest that increases in certain plasma AD biomarkers are associated with NP in WLWH and WLWOH and may be associated with later onset of AD, and measuring these biomarkers could be a pivotal advancement in monitoring aging brain health and development of AD among women with and without HIV.

Plasma neurofilament light chain in association to late-life depression in the general population.

Investigating what is underlying late-life depression is becoming increasingly important with the rapidly growing elderly population. Yet, the associations between plasma biomarkers of neuroaxonal damage and late-life depression remain largely unclear. Therefore, we determined cross-sectional and longitudinal associations of neurofilament light chain (NfL) with depression in middle-aged and elderly individuals, and total tau, β-amyloid 40 and 42 for comparison. We included 3,895 participants (71.78 years [SD = 7.37], 53.4% women) from the population-based Rotterdam Study. Between 2002 and 2005, NfL, total tau, β-amyloid 40 and β-amyloid 42 were determined in blood and depressive symptoms were measured with the Center for Epidemiologic Studies Depression scale (CES-D). Incident depressive events (clinically relevant depressive symptoms, depressive syndromes, major depressive disorders) were measured prospectively with the Center for Epidemiologic Studies Depression, a clinical interview and follow-up of medical records over a median follow-up of 7.0 years (interquartile range 1.80). We used linear and Cox proportional hazard regression models. Each log2 pg./mL increase in NfL was cross-sectionally associated with more depressive symptoms (adjusted mean difference: 0.32, 95% CI 0.05-0.58), as well as with an increased risk of any incident depressive event over time (hazard ratio: 1.22, 95% CI 1.01-1.47). Further, more amyloid-β 40 was cross-sectionally associated with more depressive symptoms (adjusted mean difference: 0.70, 95% CI 0.15-1.25). Higher levels of NfL are cross-sectionally associated with more depressive symptoms and a higher risk of incident depressive events longitudinally. The association was stronger for NfL compared to other plasma biomarkers, suggesting a potential role of neuroaxonal damage in developing late-life depression.

Clinical Value of Longitudinal Serum Neurofilament Light Chain in Prodromal Genetic Frontotemporal Dementia.

Elevated serum neurofilament light chain (NfL) is used to identify carriers of genetic frontotemporal dementia (FTD) pathogenic variants approaching prodromal conversion. Yet, the magnitude and timeline of NfL increase are still unclear. Here, we investigated the predictive and early diagnostic value of longitudinal serum NfL for the prodromal conversion in genetic FTD. In a longitudinal observational cohort study of genetic FTD pathogenic variant carriers, we examined the diagnostic accuracy and conversion risk associated with cross-sectional and longitudinal NfL. Time periods relative to prodromal conversion (>3, 3-1.5, 1.5-0 years before; 0-1.5 years after) were compared with values of participants who did not convert. Next, we modeled longitudinal NfL and MRI volume trajectories to determine their timeline. We included 21 participants who converted (5 chromosome 9 open-reading frame 72 [C9orf72], 10 progranulin [GRN], 5 microtubule-associated protein tau [MAPT], and 1 TAR DNA-binding protein [TARDBP]) and 61 who did not (20 C9orf72, 30 GRN, and 11 MAPT). Participants who converted had higher NfL levels at all examined periods before prodromal conversion (median values 14.0-18.2 pg/mL; betas = 0.4-0.7, standard error [SE] = 0.1, p < 0.046) than those who did not (6.5 pg/mL) and showed further increase 0-1.5 years after conversion (28.4 pg/mL; beta = 1.0, SE = 0.1, p < 0.001). Annualized longitudinal NfL change was only significantly higher in participants who converted (vs. participants who did not) 0-1.5 years after conversion (beta = 1.2, SE = 0.3, p = 0.001). Diagnostic accuracy of cross-sectional NfL for prodromal conversion (vs. nonconversion) was good-to-excellent at time periods before conversion (area under the curve range: 0.72-0.92), improved 0-1.5 years after conversion (0.94-0.97), and outperformed annualized longitudinal change (0.76-0.84). NfL increase in participants who converted occurred earlier than frontotemporal MRI volume change and differed by genetic group and clinical phenotypes. Higher NfL corresponded to increased conversion risk (hazard ratio: cross-sectional = 6.7 [95% CI 3.3-13.7]; longitudinal = 13.0 [95% CI 4.0-42.8]; p < 0.001), but conversion-free follow-up time varied greatly across participants. NfL increase discriminates individuals who convert to prodromal FTD from those who do not, preceding significant frontotemporal MRI volume loss. However, NfL alone is limited in predicting the exact timing of prodromal conversion. NfL levels also vary depending on underlying variant-carrying genes and clinical phenotypes. These findings help to guide participant recruitment for clinical trials targeting prodromal genetic FTD.

Delirium, neurofilament light chain, and progressive cognitive impairment: analysis of a prospective Norwegian population-based cohort

Previous population-based, longitudinal studies have shown that delirium is associated with an increased risk of dementia and cognitive decline. However, the underlying biological mechanisms are largely unknown. We aimed to assess the effects of delirium on both cognitive trajectories and any neuronal injury, measured via neurofilament light chain (NfL). In this analysis of a prospective, 2-year follow-up, cohort study of participants aged 65 years or older living in Sandefjord municipality, Norway, we included cohort participants who were receiving domiciliary care services at least once per week between May 12, 2015, and July 8, 2016. Individuals with a life expectancy of less than 1 week, with Lewy body dementia, with psychiatric illness (except dementia), or for whom substance misuse was the principal indication for domiciliary services were excluded. Participants had a comprehensive assessment at 6-month intervals for 2 years, which included the Montreal Cognitive Assessment (MoCA) and a blood sample for NfL to measure neuronal injury. All information on clinical diagnoses and medications were cross-referenced with medical records. During any acute change in mental status or hospitalisation (ie, admission to hospital), participants were assessed once per day for delirium with Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria. We also measured NfL from blood samples taken from participants who were acutely hospitalised. Between May 12, 2015, and July 8, 2016, 210 participants were eligible for inclusion and assessed at baseline (138 [66%] of whom were female and 72 [34%] of whom were male), 203 completed cognitive assessment, and 141 were followed up for 2 years. 160 (76%) of 210 had moderate or severe frailty and 112 (53%) were living with dementia. During the 2-year follow-up, 89 (42%) of 210 participants were diagnosed with one or more episodes of delirium. Incident delirium was independently associated with a decrease in MoCA score at the next 6-month follow-up, even after adjustment for age, sex, education, previous MoCA score, and frailty (adjusted mean difference -1·5, 95% CI -2·9 to -0·1). We found an interaction between previous MoCA score and delirium (β -0·254, 95% CI -0·441 to -0·066, p=0·010), with the largest decline being observed in people with better baseline cognition. Participants with delirium and good previous cognitive function and participants with a high peak concentration of NfL during any hospitalisation had increased NfL at the next 6-month follow-up. Mediation analyses showed independent pathways from previous MoCA score to follow-up MoCA score with contributions from incident delirium (-1·7, 95% CI -2·8 to -0·6) and from previous NfL to follow-up MoCA score with contributions from acute NfL concentrations (-1·8, -2·5 to -1·1). Delirium was directly linked with a predicted value of 1·2 pg/mL (95% CI 1·02 to 1·40, p=0·029) increase in NfL. In people aged 65 years or older, an episode of delirium was associated with a decline in MoCA score. Greater neuronal injury during acute illness and delirium, measured by NfL, was associated with greater cognitive decline. For clinicians, our finding of delirium associated with both signs of acute neuronal injury, measured via NfL, and cognitive decline is important regarding the risk of long-term cognitive deterioration and to acknowledge that delirium is harmful for the brain. South-Eastern Norway Health Authorities, Old Age Psychiatry Research Network, Telemark Hospital Trust, Vestfold Hospital Trust, and Norwegian National Centre for Ageing and Health. For the Norwegian translation of the abstract see Supplementary Materials section.

Plasma and cerebrospinal fluid concentrations of neurofilament light protein correlate in patients with idiopathic normal pressure hydrocephalus

BackgroundNeurofilament light chain protein (NFL), a marker of neuronal axonal degeneration, is increased in cerebrospinal fluid (CSF) of patients with idiopathic normal pressure hydrocephalus (iNPH). Assays for analysis of NFL in plasma are now widely available but plasma NFL has not been reported in iNPH patients. Our aim was to examine plasma NFL in iNPH patients and to evaluate the correlation between plasma and CSF levels, and whether NFL levels are associated with clinical symptoms and outcome after shunt surgery.MethodsFifty iNPH patients with median age 73 who had their symptoms assessed with the iNPH scale and plasma and CSF NFL sampled pre- and median 9 months post-operatively. CSF plasma was compared with 50 healthy controls (HC) matched for age and gender. Concentrations of NFL were determined in plasma using an in-house Simoa method and in CSF using a commercially available ELISA method.ResultsPlasma NFL was elevated in patients with iNPH compared to HC (iNPH: 45 (30–64) pg/mL; HC: 33 (26–50) (median; Q1–Q3), p = 0.029). Plasma and CSF NFL concentrations correlated in iNPH patients both pre- and postoperatively (r = 0.67 and 0.72, p < 0.001). We found only weak correlations between plasma or CSF NFL and clinical symptoms and no associations with outcome. A postoperative NFL increase was seen in CSF but not in plasma.ConclusionsPlasma NFL is increased in iNPH patients and concentrations correlate with CSF NFL implying that plasma NFL can be used to assess evidence of axonal degeneration in iNPH. This finding opens a window for plasma samples to be used in future studies of other biomarkers in iNPH. NFL is probably not a very useful marker of symptomatology or for prediction of outcome in iNPH.

Longitudinal changes in Alzheimer's-related plasma biomarkers and brain amyloid.

Understanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer's progression assessment strategies. We examined the temporal order of changes in plasma amyloid-β ratio ( ), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios ( , ) relative to 11 C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB-/+). Participants (n=199) were cognitively normal at index visit with a median 6.1-year follow-up. PiB groups exhibited different rates of longitudinal change in . Change in brain amyloid correlated with change in GFAP (r=0.5, 95% CI=[0.26, 0.68]). The greatest relative decline in (-1%/year) preceded brain amyloid positivity by 41 years (95% CI=[32, 53]). Plasma may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time. HIGHLIGHTS Plasma declines over time among PiB- but does not change among PiB+. Phosphorylated-tau to Aβ42 ratios increase over time among PiB+ but do not change among PiB-. Rate of change in brain amyloid is correlated with change in GFAP and neurofilament light chain. The greatest decline in may precede brain amyloid positivity by decades.

GFAP and NfL increase during neurotoxicity from high baseline levels in pediatric CD19-CAR T-cell patients.

There is a need for biomarkers to predict and measure the severity of immune effector cell-associated neurotoxicity syndrome (ICANS). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are well-validated biomarkers of astroglial and neuronal injury, respectively. We hypothesized that pretreatment GFAP and NfL levels can predict the risk of subsequent ICANS and that increases in GFAP and NfL levels during treatment reflect ICANS severity. We measured cerebrospinal fluid GFAP (cGFAP) and NfL (cNfL) along with serum NfL (sNfL) levels at pretreatment and day 7 to 10 after chimeric antigen receptor (CAR) T-cell infusion in 3 pediatric cohorts treated with CD19- or CD19/CD22-directed CAR T cells. cGFAP and cNfL levels increased during grade ≥1 ICANS in patients treated with CD19-directed CAR T cells but not in those who received CD19/CD22-directed CAR T cells. The sNfL levels did not increase during ICANS. Prelymphodepletion cGFAP, cNfL, and sNfL levels were not predictive of subsequent ICANS. Elevated baseline cGFAP levels were associated with a history of transplantation. Patients with prior central nervous system (CNS) radiation had higher cNfL levels, and elevated baseline sNfL levels were associated with a history of peripheral neuropathy. Thus, cGFAP and cNfL may be useful biomarkers for measuring the severity of CNS injury during ICANS in children. Elevated baseline levels of cGFAP, cNfL, and sNfL likely reflect the cumulative injury to the central and peripheral nervous systems from prior treatment. However, levels of any of the 3 biomarkers before CAR T-cell infusion did not predict the risk of ICANS.

Neurofilament Light Chain serum levels after Hypoxia-Ischemia in a newborn piglet model.

Neurofilament light Chain (NfL) is a promising brain injury biomarker which may assist diagnosis and prognostication in hypoxic-ischemic encephalopathy (HIE). The aim of this study was to investigate serum NfL levels after hypoxia-ischemia (HI) in a newborn piglet model. Second, to characterize the influence of sex, weight, and treatment with remote ischemic postconditioning (RIPC) on NfL and the correlation between NfL, brain imaging and histologic brain injury. We used serum from 48 newborn piglets of both sexes subjected to 45 min of global HI, and 4 sham piglets. Blood was collected pre-HI, 2 h post-HI and 72 h post-HI. NfL was measured by single-molecule array (Simoa™). We analysed the temporal profile of NfL after HI, and correlations between NfL, magnetic resonance spectroscopy brain Lac/NAA ratios and histologic brain injury 72 h after HI. Median (IQR) NfL levels were: pre-HI: 66 pg/ml (45-87), 2 h post-HI: 105 pg/ml (77-140), and 72 h post-HI: 380 pg/ml (202-552). The increase in NfL after HI was statistically significant (p < 0.0001, mixed-effects ANOVA). Median NfL levels in sham animals were 41.4 pg/ml at baseline and 92.4 pg/ml at 72 h (p = 0.11, paired t-test). Neither sex, nor treatment with RIPC influenced NfL levels. Weight had a small, not biologically important, influence. NfL levels at 72 h were moderately correlated with histologic brain injury and brain Lac/NAA ratios. NfL 72 h post-HI > 330 pg/ml had a sensitivity of 89% (95% CI, 57%-99%) and a specificity of 52% (95% CI, 34%-69%) for predicting basal ganglia Lac/NAA ratio in the highest quartile. NfL 72 h post-HI > 445 pg/ml had a sensitivity of 90% (95% CI, 60%-99%) and a specificity of 74% (95% CI, 58%-86%) for predicting cortical brain histopathology injury in the highest quartile. NfL increased after HI, with the largest values at 72 h post-HI. Early NfL was sensitive but not very specific, whereas NfL at 72 h was both highly sensitive and specific for exposure to moderate-severe HI in this model of HI-induced brain injury. This was supported by a moderate correlation of NfL at 72 h with brain Lac/NAA ratio and histopathology.

Circulating neurodegeneration biomarkers neurofilament light protein and p‐tau181 are increased in individuals with heart failure at risk for vascular cognitive impairment

AbstractBackgroundSystemic inflammation, which is present in heart failure (HF), is known to increase risk for dementia and development of vascular cognitive impairment and dementia (VCID). Both neurofilament light protein (NfL) and tau phosphorylated at threonine‐181 (p‐tau181) are well known biomarkers of neurodegeneration in both Alzheimer’s disease and non‐Alzheimer’s disease neurodegenerative diseases. The purpose of the present study was to determine if blood levels of NfL and p‐tau181 are increased in HF patients at risk for VCID.MethodWe performed a retrospective study of 58 participants from the previously completed TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). TOPCAT participants had symptomatic HF categorized using New York Heart Association (NYHA) criteria, were &gt; 50 years of age, and had ejection fraction (LVEF) ≥45%, assessed within 6 months from study start (n=58, 52% female). Control serum samples were obtained from age‐matched adults between 50‐85 with no known health issues (n=24, 50% female). NfL was measured using Simoa Quanterix and p‐Tau181 measured with SimoaHuman pTau‐181 V2 kit. Statistical analysis was performed using GraphPad and significance tested using Welch’s ANOVA, Dunnett’s post.ResultBaseline NfL levels were significantly higher in NYHA class I/II (n=56) and III/IV (n=54, p&lt;.0001) than measured in age‐matched controls (see table for values). Over 12‐months follow‐up, participants in NYHA class I/II had an increase in NfL of 9.6±5% relative to baseline and those in class III/IV had a 31.7±17% increase from baseline. P‐tau181 levels were also significantly higher in both NYHA class I/II (n=56) and III/IV (n=54, p=.0002) as compared to age‐matched controls (see table for values) with levels were significantly higher in class III/IV than in class I/II participants (ANOVA, Dunnett’s post, p&lt;.001). Levels of p‐tau181 did not show significant changes over the 12‐month time in any group.ConclusionThese results demonstrate that 2 well‐studied biomarkers of neurodegeneration, NfL and p‐tau181, are elevated in subjects with HF. Studies are underway to determine if biomarker levels correlate with measures of cognitive function and MRI measures of brain structure and function in HF patients. (Supported by NIA U01AG066623).

Associations of Sensory and Motor Functions in Midlife with Longitudinal Blood‐Based Biomarker Levels of Alzheimer’s Disease and Neurodegeneration

AbstractBackgroundDementia has a long preclinical phase and pathological fluid biomarker levels change decades before clinical symptoms. Thus, early detection of people at risk for neurodegenerative and pathological changes, especially in midlife, might improve future treatments and preventions. Sensory and motor changes are common in aging adults and may be early markers of neurodegeneration since they are associated with cognition and risk factors of neurodegeneration. However, their associations with blood‐based neurodegenerative and AD biomarkers are not yet known. We aimed to determine if midlife sensory and motor functions are associated with long‐term changes in blood‐based biomarkers of neurodegeneration and AD (neurofilament light chain(NfL), total tau(TT), and amyloid beta(Aβ)).MethodThis longitudinal study is based on n=1529 (54% women, mean age 49years) Beaver Dam Offspring Study (BOSS) participants. The BOSS started in 2005 and had 5‐year and 10‐year follow‐up exams. We assessed sensory (pure‐tone audiometry, contrast sensitivity, olfactory identification) and motor (Grooved Pegboard) function, plus multiple potential confounding risk factors at baseline. NfL, TT, Aβ42, and Aβ40 levels were analyzed in serum samples from all three waves (SIMOA, Quanterix). We used linear mixed‐effects models with baseline hearing, vision, olfaction, and motor function as determinant and repeated biomarker levels as outcome and adjusted for age, sex, education, random intercept, random slope (if model fit was improved), and other confounders. NfL and TT were log‐transformed. Due to sex interactions, Aβ42/Aβ40 models were sex‐stratified.ResultsOverall, NfL increased 3% and TT 1% per year. Aβ42/Aβ40 decreased 0.5/year in women and 0.24/year in men. Individuals with hearing and vision impairment showed faster NfL level increase over time (0.8%/year; CI 0.3,1.4;p=.004; 0.5%/year; CI ‐0.1,1;p=.09; respectively). Worse motor function was associated with faster NfL increase (0.4%/year per 20s test time; CI 0.2,0.7;p&lt;.001). These effects compared to effects of 2‐3 months of aging. There were no significant associations with Aβ42/Aβ40 or TT.ConclusionWe found associations between midlife sensory and motor functions and long‐term changes in NfL levels, a non‐specific marker of neurodegeneration, while there were no associations with AD‐specific biomarkers. Future studies with longer follow‐up should determine if sensory and motor changes are more reflective of general neurodegenerative than AD‐specific pathology.

Amyloid status prediction by combining plasma p‐tau181 and NfL cut‐offs

AbstractBackgroundPlasma biomarkers have emerged as a promising tool for screening Alzheimer's disease(AD). However, no externally defined cut‐off values for any plasma biomarkers yet to exist to predict amyloid β (Aβ) status.MethodTaking advantage of the different plasma p‐tau181 and NfL increase profiles, we used the two plasma biomarkers to establish preliminary cut‐off values (two cut‐offs for p‐tau181, one for NfL) for screening Aβ positivity. Participants with a clinical diagnosis of AD(N=20), mild cognitive impairment(MCI)(N=12), other neurodegenerative disorders(N=19), psychiatric disorders(N=3 with depression, N= 1 with delusional disorder), and healthy controls(N=37) were recruited from the Memory Clinic at Keio University Hospital. Static 18F‐Florbetaben (FBB) PET was conducted on all the participants. A trained neuroradiologist visually assessed the acquired images to determine Aβ positivity. Each participant's p‐tau181 value was plotted against NfL values. After visualizing their distribution stratified by the Aβ status, we conducted an exhaustive search to predict Aβ positivity. We first created a ROC curve for p‐tau181 alone and then made a 'quasi‐ROC' curve by combining two p‐tau181 cut‐offs(i.e., the higher and lower cut‐offs) and one NfL cut‐off. The optimal cut‐off values for each ROC curve were determined by the Youden Index.ResultOf the 92 participants, 30(32.6%) were Aβ‐positive(Aβ+). Mean ages were 68.7 years(SD8.2) for Aβ‐ and 72.4(SD9.3) for Aβ+ group (p=0.02). Mean p‐tau181 values were 1.72pg/ml (SD0.75) for Aβ‐ and 3.58pg/ml (SD1.09) for Aβ+ group (p&lt;0.001), whereas mean NfL values were 24.47pg/ml(SD13.77) vs 27.24(SD9.96) (p=0.01). The ROC curves yielded each found the optimal cut‐off values as follows: for plasma p‐tau181 alone, ptau‐181 value, true positive rate(tpr) and false positive rate(fpr) were 5.8 pg/ml, 0.767 and 0.065, respectively. For a combination of higher and lower p‐tau181 cut‐offs and one NfL cut‐off, each biomarker value and the corresponding tpr and fpr were 3.0pg/ml, 2.0/g/ml, 35pg/ml, 0.933, and 0.177, respectively.ConclusionOur results suggest combining two cut‐off values for plasma p‐tau181 and one cut‐off for NfL may yield an excellent discriminant capacity for Aβ positivity. Further research is needed to validate the result.

Longitudinal Changes in Blood Biomarkers of Clinical Alzheimer Disease in a Biracial Population Sample.

Recent studies suggest the utility of blood biomarkers in detecting changes in neurodegenerative disorders. The objective of our research was to test the hypothesis that the longitudinal changes in total tau (t-tau), neurofilament light chain (Nf-L), and glial fibrillary acidic protein (GFAP) are associated with structural MRI and the development of clinical Alzheimer disease (AD) and cognitive decline. Data came from a population-based sample with serum concentrations of t-tau, Nf-L, and GFAP and cognitive characteristics measured over 17 years. The inclusion criteria for this investigation were based on participants with blood samples, cognitive function testing, and clinical diagnosis for AD. The longitudinal changes in the serum biomarkers were examined using linear mixed models for log10-transformed concentrations. In 1,327 participants (60% Black participants and 60% women, the concentration of t-tau increased annually by 4.8% (95% CI = 4.0-5.6) and Nf-L by 5.9% (95% CI = 5.4-6.4). The longitudinal change in GFAP was higher among Black participants than among White participants (4.4% vs 3.5% per year, p = 0.028). Baseline MRI characteristics were associated with the longitudinal changes in serum biomarkers of clinical AD. Specifically, a higher baseline third ventricular volume was associated with a higher rate of increase in the concentration of t-tau, and white matter hyperintensities predicted a higher rate of increase in Nf-L. The rate of change in concentrations of t-tau, Nf-L, and GFAP was significantly higher among those who developed clinical AD than in those with no cognitive impairment. For each standard deviation unit decline in global cognition, longitudinal change in t-tau increased by 81% (95% CI = 76-86), Nf-L by 113% (95% CI = 105-120), and GFAP by 66% (95% CI = 62-70). Blood biomarkers showed significant longitudinal changes corresponding to cognitive decline, clinical AD, and structural MRI characteristics. Our findings show that longitudinal changes in serum biomarkers were associated with several cognitive endophenotypes. The study found Class II evidence that longitudinal changes in serum t-tau, Nf-L, and GFAP were associated with cognitive decline and the development of clinical AD in people older than 65 years.