Neurofilament Light Concentrations Research Articles

Blood‐based biomarker profiles of community cohort of rural‐dwelling older adults

AbstractBackgroundGeography may influence Alzheimer’s disease risk, but there have been few prospective studies with biomarker characterization among rural‐dwelling individuals. We present preliminary biomarker data from the rural cohort followed by the Nevada Exploratory Alzheimer’s Disease Research Center, with comparisons to a harmonized urban cohort.MethodCommunity‐dwelling adults over age 50 are enrolled and followed annually. Core assessments include medical exam, cognitive assessment, and blood‐based biomarkers of neurofilament light (NFL), phosphorylated tau (pTau181), and glial fibrillary acidic protein (GFAP) measured from plasma samples via the Quanterix Single Molecular Array (Simoa) HD‐X platform. Biomarker values exceeding 3 standard deviations from the combined sample mean were removed from analyses. Primary comparisons included ANCOVAs with main between‐group effects of cohort and cognitive status, accounting for both age and sex; interactions between cohort and impairment status were also explored. Correlations between biomarkers and cognitive screening (MoCA) were also assessed. Raw biomarker data were log transformed prior to analysis.ResultNFL was associated with age (F(1,143) = 53.26, p<.001) main effects of impairment status were found (F(1,143) = 9.81, p<.001) but there was no association with sex or differences between urban and rural cohorts. The interaction between impairment status and cohort was significant, such that NFL concentrations were lower for cognitively normal rural‐dwellers, but higher among those with impairment (F(1,143) = 9.95, p<.01). GFAP was associated with age (F(1,136) = 31.05), p<.001) and sex (F(1,136) = 12.46), p<.001), but there were no main effects of cohort or impairment status, and there was no interaction. Tau was associated with age (F(1,153) = 11.08, p<.01) but not sex, and there were no main effects of cohort or impairment status, and no interaction was found. NFL was not correlated with cognition in the urban cohort (r = ‐.11), but was inversely correlated in the rural cohort (r = ‐.34). All other correlations were significant.ConclusionRural‐dwelling older adults with cognitive impairment had higher concentrations of NFL compared to an urban cohort from the same region, though among cognitively unimpaired individuals, rural‐dwellers had lower concentrations of NFL. There were no rural‐urban differences in pTau or GFAP. Neurodegeneration may be a more sensitive indicator of cognitive impairment relative to other biomarkers, which may facilitate detection of geographic health disparities.

Plasma Neurofilament Light and Markers of Sensorimotor Function in a Predominantly Hispanic Population of Older Adults in San Antonio, Texas

AbstractBackgroundSensorimotor and blood‐based biomarkers are promising dementia biomarkers with high accessibility and limited invasiveness. Although sensorimotor changes appear with aging, more severe changes may precede cognitive decline, dementia, and other neurological diseases. Additionally, blood‐based neurofilament light (NfL), a broad marker of neuroaxonal injury, is commonly elevated in many types of neurological disease. Prior studies have suggested that increased blood levels of NfL in conjunction with sensorimotor decline may allow for earlier neurological disease diagnosis and/or prediction of disease severity, but little is known about the correlation of these markers in the general population. We examined the association between NfL and sensorimotor markers in a predominantly Hispanic population in San Antonio, Texas.MethodOur sample included older adults from our San Antonio MarkVCID and South Texas Alzheimer’s Disease Research Center (ADRC) cohorts (n = 152, mean age 71.2±7.63, 60.4% women, 79.5% Hispanic) with available plasma NfL, olfaction (B‐SIT age‐adjusted percentile), grip strength, and touch (monofilament) data (Table 1). NfL concentrations were log‐transformed to achieve a normal distribution. We used linear or logistic regression models, as appropriate, to assess the association between NfL and sensorimotor outcomes, adjusting for age, sex, race, ethnicity, and cognitive diagnosis.ResultHigher plasma NfL was significantly associated with decreased olfaction score percentiles (Beta [95% Confidence Interval], β = ‐8.79; [95% CI ‐16.89; ‐0.12], p = 0.05), grip strength in either hand (left: β = ‐3.62; [95% CI ‐5.51; ‐1.74], p = 0.0002; right: β = ‐2.99; [95% CI ‐5.01; ‐1.03], p = 0.003), and impaired touch perception (Odds Ratio [95% CI], OR = 2.56; [95% CI 1.01; 6.48]; p = 0.05), independent of the potential confounders listed above.ConclusionThese results highlight the association of plasma NfL with several markers of sensorimotor function, which may reflect central and peripheral neuroaxonal injury. Additional studies are needed in larger community samples to confirm these findings and explore the potential of NfL as a marker of functional decline in longitudinal studies. We plan to continue collecting these markers, as well as gait and balance, longitudinally to gain a better understanding of the link between neurodegeneration, sensorimotor markers, and neurological disease trajectory in our unique South Texas population.

The Association Between Levels of Plasma Biomarkers and Cognitive Performance in the Oldest Old

AbstractBackgroundLower cognitive performance in Alzheimer’s Disease (AD) patients has been correlated with changes in blood‐based biomarkers Amyloid‐βeta‐40 (Aβ40), Amyloid‐βeta‐42 (Aβ42), phosphorylated Tau (pTau), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). However, it is still unclear whether there is an association between cognitive performance and plasma biomarkers in the oldest old. Here we investigate I) The association of plasma biomarkers with age across a wide age‐continuum until extreme age (≥100 years); II) To what extent plasma biomarkers associate with cognitive performance ≥100 years.MethodThe Dutch 100‐plus study cohort comprises of self‐reported cognitively healthy centenarians. Biomarkers were measured in 202 centenarians (137 females) on the Simoa platform. We also included centenarian siblings, offspring and their respective partners (N = 318), who were cognitively healthy. I) To investigate the relationship between age and biomarkers, we standardized all biomarkers and performed linear regression analyses. II) Cognitive performance in centenarians was determined using a comprehensive neuropsychological test battery assessing several cognitive domains. Biomarker concentrations were divided into tertiles. Cognitive performance was assessed adjusting for age, sex and education.ResultI) We observed an age‐related increase Aβ40 (rs = 0.70; range 46.5‐286.5 pg/mL), Aβ42 (rs = 0.53; range 1.4‐17.7 pg/mL), pTau‐181(rs = 0.68; range 0.5‐12.8 pg/mL), NfL (rs = 0.81; range 4.5‐378.7 pg/mL) and GFAP (rs = 0.76; range 24.4‐1085.1 pg/mL), or decrease in Aβ42/40 (rs = ‐0.43; range 0.01–0.10 pg/mL; P<0.001 for all biomarkers, Figure 1). II) Lower Aβ42/40 was associated with lower cognitive performance on global cognition (based on composite z‐score of all tests) β(95%CI) 0.26(0.00–0.51), P = 0.002) and domain executive functioning β(95%CI) 0.16(‐0.07–0.40), P = 0.039), but not with the Mini‐Mental State Examination (MMSE) or the other cognitive domains. Higher concentrations of NfL were associated with lower cognitive performance on MMSE β(95%CI) ‐0.22(‐1.48–1.04), P = 0.005), but not with the separate cognitive domains tested.ConclusionLevels of plasma biomarkers rise with age, also in cognitively healthy individuals. However, correlation with cognitive performance varies across biomarkers and cognitive tests, and deserves further evaluation.

Abstract 14308: Perioperative Cyclohexanone Exposure During Neonatal Congenital Heart Surgery Potentiates Brain Injury

Introduction: Neurodevelopmental delay is hallmark for children with congenital heart defects. Risk factors include industrial contaminants in medical devices, such as cyclohexanone. Hypothesis: To evaluate associations between perioperative cyclohexanone and cyclohexanone metabolites with perioperative biomarkers of brain injury. Methods: From 75 neonates who underwent congenital heart surgery involving cardiopulmonary bypass (CPB), we assayed perioperative serum samples (preoperation, post-CPB, 24 hours postoperation) for cyclohexanone, two cyclohexanone metabolites (trans-1,2- and trans-1,4-cyclohexanediol), and biomarkers of brain injury: glial fibrillary acidic protein (GFAP), neurofilament light (NF-L), and Tau. We calculated the molar sum of cyclohexanone metabolites (Σmetabolites), and at each timepoint we used quantile regression to evaluate differences in median brain injury biomarker concentrations (pg/mL) per doubling in concentration of cyclohexanone or Σmetabolites (ng/mL). We adjusted associations for cyclohexanone assay batch, postnatal age at surgery (days), weight at surgery (kg), The Society of Thoracic Surgeons and The European Association for Cardio-Thoracic Surgery (STAT) mortality risk category, and total duration of CPB (min). Results: In adjusted analyses, a doubling in preoperation cyclohexanone concentration was associated with a 19 pg/mL (95% CI: 3, 35) greater median Tau concentration. Similarly, a doubling in post CPB cyclohexanone was associated with an 88 pg/mL (95% CI: 20, 156) greater median concentration of Tau and 137 pg/mL (95% CI: 54, 220) greater median concentration of NF-L. Associations with Σmetabolites were generally null, though a doubling in post-CPB concentration was associated with a 34.7 pg/mL (95% CI: -0.8, 70) greater NF-L and 54.1 pg/mL (95% CI: 15, 94) greater Tau concentration. Associations with GFAP at all timepoints were null. Conclusions: Perioperative cyclohexanone exposure is associated with worse neurodevelopmental outcomes and in this study, cyclohexanone levels were associated with NF-L and Tau which are measures of axonal damage. Interventions to reduce cyclohexanone exposure may improve long term neurodevelopment.

Serum total tau, neurofilament light, and glial fibrillary acidic protein are associated with mortality in a population study.

Total tau (t-tau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) are neuronal cytoskeletal biomarkers that may indicate greater risk of poor outcomes in age-related conditions, including mortality. Health disparities experienced by some racial minority subgroups may influence biomarker expression and effects on longevity. We aimed to examine (a) associations of serum t-tau, NfL, and GFAP with overall and cardiovascular mortality and (b) differences in associations by racial background. Data came from 1327 older participants from the Chicago Health and Aging Project (CHAP), a longitudinal population-based study. Cox proportional hazards regression models were used to examine associations between concentrations of serum t-tau, NfL, and GFAP biomarker(s) and mortality (overall/cardiovascular mortality based on age at death). Interaction terms were used to examine differences between African-American and European-American participants. Models were adjusted for age, sex, education, the APOE-ε4 allele, body mass index, chronic health conditions, and cognitive and physical functioning. Models showed that fivefold higher concentrations of t-tau (HR = 1.46, 95% CI: 1.27, 1.68), NfL (HR = 2.13, 95% CI: 1.76, 2.58), and GFAP (HR = 1.43, 95% CI: 1.08, 1.90) were separately associated with increased risk of overall mortality, with higher risk in African Americans in t-tau or NfL. In models with all biomarkers, NfL (HR = 2.17, 95% CI: 1.65, 2.85) was associated with risk of overall mortality, with racial differences in t-tau. Higher concentrations of t-tau (HR = 1.32, 95% CI: 1.02, 1.70), NfL (HR = 1.95, 95% CI: 1.40, 2.72), and GFAP (HR = 1.87, 95% CI: 1.18, 2.98) were separately associated with risk of cardiovascular mortality, with racial differences in t-tau, NfL, or GFAP. In combined models, NfL (HR = 1.73, 95% CI: 1.08, 2.78) was associated with cardiovascular mortality. Serum t-tau, NfL, and GFAP may be early indicators for mortality outcomes among older adults, with racial differences among associations.

B - 92 Poor Olfaction Prior to Cardiac Surgery: Associations with Cognition, Plasma Neurofilament Light and Postoperative Delirium in a Prospective Nested Cohort Study.

This study examined the association between pre-operative olfactory performance and delirium after cardiac surgery. As a secondary aim, we examined the relationship between baseline olfaction, cognitive functioning, and plasma neurofilament light (NfL). Individuals undergoing cardiac surgery were recruited as part of a clinical trial in which blood pressure during bypass was targeted using cerebral autoregulation monitoring. There were 189 participants (mean age = 70years; 75% men). At baseline, olfaction, cognition, and plasma concentrations of NfL were assessed using the 12-item Brief Smell Identification Test (BSIT), a battery of neuropsychological tests, and the Simoa™ NF-Light Assay, respectively. Impaired olfaction was defined as a score of ≤8 for men and ≤ 9 for women. Delirium was assessed using the Confusion Assessment Method (CAM) and CAM-ICU, and delirium severity was assessed using the Delirium Rating Scale-Revised-1998 (DRS-R-98). The association of baseline olfaction and delirium and delirium severity was examined in regression models adjusting for age, duration of bypass, a surgery risk score, and baseline cognitive performance. In adjusted models, impaired olfaction at baseline was associated with both incident delirium (OR = 2.25, p = 0.04) and greater delirium severity (OR = 2.10, p = 0.04) after cardiac surgery. Furthermore, worse baseline olfaction was associated with impaired cognition (p < 0.001) and increased perioperative concentrations of plasma NfL (p = 0.04). Pre-operative olfactory testing may provide insight into brain vulnerability, cognitive dysfunction, and delirium risk in individuals undergoing cardiac surgery. Psychophysical olfactory assessment may inform strategies for patient risk stratification and early identification of individuals at risk for post-operative delirium, allowing for delirium-prevention strategies.

SIMOA-based analysis of plasma NFL levels in MCI and AD patients: a systematic review and meta-analysis

BackgroundThe single-molecule array assay (SIMOA)-based detection of neurofilament light (NFL) chain could be useful in diagnosing mild cognitive impairment (MCI) and Alzheimer’s disease (AD). This meta-analysis aimed to evaluate the circulating concentration of NFL in AD and MCI patients compared with healthy controls using the SIMOA technique.MethodsTo this end, Google Scholar, PubMed, Scopus, Web of Science, and the reference lists of relevant articles were systematically searched for studies reporting serum NFL chain levels in healthy controls, MCI, and AD patients. Appropriate statistical methods were employed to achieve the study purpose.ResultsFifteen eligible studies including 3086 patients were pooled out of a total of 347 publications. Fixed effect model analysis showed that NFL chain level was significantly higher in the serum of patients with MCI (0.361 SMD, 95% CI, 0.286–0.435, p = 0.000, I2 = 49.179) and AD (0.808 SMD, 95% CI, 0.727–0.888, p = 0.000, I2 = 39.433) compared with healthy individuals. The analysis also showed that the NFL chain levels in plasma were significantly different between patients with MCI and AD (0.436 SMD, 95% CI, 0.359–0.513, p = 0.000, I2 = 37.44). The overall heterogeneity of the studies was modest.ConclusionsThis study highlights the potential of serum NFL chain detected using SIMOA in differentiating MCI, AD, and healthy controls.

Effect of Neurotoxin Exposure on Blood Biomarkers of Neurodegeneration and Alzheimer Disease.

To determine whether exposure to neurotoxins in midlife is associated with changes in blood-based biomarkers of neurodegeneration and Alzheimer disease pathology. Blood cadmium, lead, neurofilament light (NfL) chain, total tau (TTau), and amyloid beta (Aβ) 40 and Aβ42 concentrations were measured in 1516 participants in the Beaver Dam Offspring Study. Linear mixed-effect models were used to determine associations between baseline cadmium and lead levels and baseline NfL, TTau, and Aβ42/Aβ40, and 10-year change in concentrations using repeated measures of these biomarkers as the outcome. In women, higher cadmium and lead levels were associated with higher baseline TTau concentrations. A higher baseline cadmium level was associated with lower baseline Aβ42/Aβ40 in both men and women. In age-sex-adjusted models, a doubling in baseline cadmium level was associated with a 0.2% (95% CI: 0.0, 0.3) higher increase per year in NfL concentrations. In men, a doubling of baseline lead level was associated with a 0.9% (95% CI: 0.1, 1.7) higher increase per year in TTau concentration. Participants with relatively higher levels of cadmium and lead had blood biomarker concentrations consistent with more neuronal damage and Alzheimer disease pathology. Environmental exposure to neurotoxins may contribute to neurodegeneration.

A blunted TH17 cytokine signature in women with mild cognitive impairment: insights from inflammatory profiling of a community-based cohort of older adults.

People with dementia have an increase in brain inflammation, caused in part by innate and adaptive immune cells. However, it remains unknown whether dementia-associated diseases alter neuro-immune reflex arcs to impact the systemic immune system. We examined peripheral immune cells from a community-based cohort of older adults to test if systemic inflammatory cytokine signatures associated with early stages of cognitive impairment. Human peripheral blood mononuclear cells were cultured with monocyte or T-cell-targeted stimuli, and multiplex assays quantitated cytokines in the conditioned media. Following T-cell-targeted stimulation, cells from women with cognitive impairment produced lower amounts of TH17 cytokines compared with cells from cognitively healthy women, while myeloid-targeted stimuli elicited similar amounts of cytokines from cells of both groups. This TH17 signature correlated with the proportion of circulating CD4+ and CD8+ T cells and plasma glial fibrillary acidic protein and neurofilament light concentrations. These results suggest that decreases in TH17 cytokines could be an early systemic change in women at risk for developing dementia. Amelioration of TH17s cytokines in early cognitive impairment could, in part, explain the compromised ability of older adults to respond to vaccines or defend against infection.

Neurofilament light protein as a cerebrospinal fluid marker after whiplash trauma

The purpose was to investigate if a whiplash trauma may cause an increased concentration of the Neurofilament Light (NFL) protein, and if so; is this related to the injury severity and the radiological findings? Adult car occupants, with neck problems after rear-end collisions, were investigated in a study on Whiplash-Associated Disorders (WAD) in 1997-2001. The study protocol included a neurological examination, plain radiography and MRT of the cervical spine, and a lumbar puncture for Cerebrospinal Fluid (CSF) within six weeks after the accident. Similar CSF samples were also taken three and twelve months later. All CSF samples were analyzed for NFL. Of 52 subjects who entered the study, 43 completed it. The WAD grade was I in two of the 43 cases, II in 13, and III in 28. No one had radiological signs, indicating injuries to the cervical spine or spinal cord. Six subjects showed an increased NFL concentration at the primary examination. This was judged to be caused by whiplash trauma in three of them (7%). There was no relation between an increased NFL concentration and the number of pathological changes on plain radiographs or MRT. Neither was there a relation between the NFL concentration and the WAD grade. An increased NFL concentration can be found in some WAD patients. It might be difficult to relate such an increase to clinical or radiological findings. Further studies should investigate NFL as a marker for injuries to the central nervous system in whiplash trauma, including minimal traumatic brain injuries.

Triangulating brain alterations in anorexia nervosa: a multimodal investigation of magnetic resonance spectroscopy, morphometry and blood-based biomarkers

The acute state of anorexia nervosa (AN) is associated with widespread reductions in cortical gray matter (GM) thickness and white matter (WM) volume, suspected changes in myelin content and elevated levels of the neuronal damage marker neurofilament light (NF-L), but the underlying mechanisms remain largely unclear. To gain a deeper understanding of brain changes in AN, we applied a multimodal approach combining advanced neuroimaging methods with analysis of blood-derived biomarkers. In addition to standard measures of cortical GM thickness and WM volume, we analyzed tissue-specific profiles of brain metabolites using multivoxel proton magnetic resonance spectroscopy, T1 relaxation time as a proxy of myelin content leveraging advanced quantitative MRI methods and serum NF-L concentrations in a sample of 30 female, predominately adolescent patients with AN and 30 age-matched female healthy control participants. In patients with AN, we found a reduction in GM cortical thickness and GM total N-acetyl aspartate. The latter predicted higher NF-L levels, which were elevated in AN. Furthermore, GM total choline was elevated. In WM, there were no group differences in either imaging markers, choline levels or N-acetyl aspartate levels. The current study provides evidence for neuronal damage processes as well as for increased membrane lipid catabolism and turnover in GM in acute AN but no evidence for WM pathology. Our results illustrate the potential of multimodal research including tissue-specific proton magnetic resonance spectroscopy analyses to shed light on brain changes in psychiatric and neurological conditions, which may ultimately lead to better treatments.

Perioperative brain injury marker concentrations in neonatal open-heart surgery: a prospective observational study.

Neonates with critical congenital heart defects undergoing open-heart surgery on cardiopulmonary bypass circulation are at risk for white matter brain injury. This article reports on pre- and postoperative plasma concentrations of brain injury markers glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and Tau, and their respective associations with white matter lesions detected on postoperatively performed brain MRI. Forty term newborns with isolated critical congenital heart defects were included in a prospective observational study. Brain injury marker plasma concentrations were determined prior to surgery and at postoperative days 1, 2 and 3. Brain magnetic resonance imaging was performed pre- and postoperatively. Concentrations of brain injury markers were analysed using ultrasensitive single molecule array technology. Absolute pre- and postoperative plasma biomarker concentrations, and postoperative concentrations adjusted for preoperative concentrations were used for subsequent analysis. Plasma concentrations of GFAP, NfL and Tau displayed a well-defined temporal trajectory after neonatal cardiopulmonary bypass circulation. GFAP and Tau reached peak concentrations at postoperative day 2 (median concentrations 170.5 and 67.2 pg/ml, respectively), whereas NfL continued to increase throughout the study period (median concentration at postoperative day 3 191.5 pg/ml). Adjusted Tau at postoperative day 2 was significantly higher in infants presenting with white matter lesions on postoperative MRI compared to infants without white matter injury.

Hypotension during transsphenoidal pituitary surgery associated with increase in plasma levels of brain injury markers.

Patients undergoing pituitary surgery may experience short- and long-term postoperative morbidity. Intraoperative factors such as hypotension might be a contributing factor. Our aim was to investigate the association between intraoperative hypotension and postoperative plasma levels of tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) as markers of perioperative brain injury. Between June 2016 and October 2017, 35 patients from the Gothenburg Pituitary Tumor Study were included. For tau, NfL, and GFAP, concentrations were measured in plasma samples collected before and immediately following surgery, and on postoperative days 1 and 5. The difference between the highest postoperative value and the value before surgery was used for analysis (∆taupeak , ∆NfLpeak , ∆GFAPpeak ). Intraoperative hypotension was defined as the area under the curve of an absolute threshold below 70 mmHg (AUC70) and a relative threshold below 20% (AUC20%) of the baseline mean arterial blood pressure. Plasma tau and GFAP were highest immediately following surgery and on day 1, while NfL was highest on day 5. There was a positive correlation between AUC20% and both ∆taupeak (r2 = .20, p < .001) and ∆NfLpeak (r2 = .26, p < .001). No association was found between AUC20% and GFAP or between AUC70 and ∆taupeak , ∆NfLpeak or ∆GFAPpeak . Intraoperative relative, but not absolute, hypotension was associated with increased postoperative plasma tau and NfL concentrations. Patients undergoing pituitary surgery may be vulnerable to relative hypotension, but this needs to be validated in future prospective studies.

Serum and CSF brain damage markers NFL and GFAP correlate with tick-borne encephalitis disease severity - a multicenter study on Lithuanian and Swedish patients.

Our aim was to examine the correlation between biomarkers of neuronal and glial cell damage and severity of disease in patients with tick-borne encephalitis. One hundred and fifteen patients with tick-borne encephalitis diagnosed in Lithuania and Sweden were prospectively included, and CSF and serum samples obtained shortly after hospitalization. Using pre-defined criteria, cases were classified as mild, moderate, or severe TBE. Additionally, the presence of spinal nerve paralysis (myelitis) and/or cranial nerve affection were noted. Concentrations of brain cell biomarkers glial fibrillary acidic protein (GFAP), YKL40, S-100B, neurogranin, neurofilament light (NFL), and tau were analyzed in CSF, and in addition, NFL, GFAP and S-100B levels were measured in serum. The Jonckheere Terpstra test was used for group comparisons of continuous variables and Spearman's partial correlation test to adjust for age. CSF and serum concentrations of GFAP and NFL correlated with disease severity, independent of age, and with presence of nerve paralysis. The markers neurogranin, YKL40, tau and S-100B in CSF and S-100B in serum were detected, but their concentrations did not correlate with disease severity. Neuronal cell damage and astroglial cell activation with increased NFL and GFAP in CSF and serum were associated with a more severe disease, independent of age. Increased GFAP and NFL concentrations in CSF and NFL in serum were also indicative of spinal and/or cranial nerve damage. NFL and GFAP are promising prognostic biomarkers in TBE, and future studies should focus on determining the association between these biomarkers and long-term sequelae.

Plasma Neurofilament Light (NfL) associated with retest learning effects on ambulatory cognitive assessments of processing speed: Results from the Einstein Aging Study (EAS)

AbstractBackgroundMeasurement burst designs, using ambulatory cognitive assessments facilitate the dissociation of retest effects from optimal (“asymptotic”) performance. Dissociating these features via cognitive process modeling may reveal indices of subtle cognitive impairment that signal risk for neurocognitive decline. We investigated cross‐sectional associations between plasma NfL (a biomarker of neurodegeneration), retest improvements, and optimal performance on the Symbol Match task, which assesses processing speed by response time (RT), in a racially/ethnically diverse community‐based EAS Study cohort.MethodAnalyses included 283 EAS participants free of dementia (Mean age = 77.4 years, SD = 4.8, Range = 70‐91; 67% Female; 46% Non‐Hispanic White, 40% Non‐Hispanic Black). Among them, 82 met the Jak/Bondi criteria of mild cognitive impairment (MCI). Participants completed a smartphone cognitive battery, resulting in up to 96 assessment sessions (six times per day for 16 days). Plasma NfL concentration was measured using a Single molecule array assay. A mixed‐effect negative exponential model was used to examine the associations between plasma NfL and indices of subtle cognitive impairment adjusting for covariates including age, gender, education, and race/ethnicity. Retest improvement was measured by the exponential decrease in RT across sessions and optimal performance was measured by asymptotic RT (fastest performance).ResultOn average, the RT of the Symbol Match task was 3.4 seconds (SD = 0.9). Mean plasma NfL level was 23.9 pg/mL (SD = 17.5). Higher plasma NfL levels were associated with a reduced retest improvement rate per session (estimate = ‐0.011, 95% confidence interval (‐0.013, ‐0.008) corresponding to one SD increase in plasma NfL, p&lt;0.001). No significant association between plasma NfL and optimal cognitive performance was found. Stratified analyses showed NfL’s association with retest improvement was larger in non‐Hispanic Whites than in non‐Hispanic Blacks (‐0.009 vs ‐0.002), although formal testing of the interaction between NfL and race was not significant. Results remained very similar excluding participants with MCI.ConclusionHigher plasma NfL was associated with a reduced retest improvement rate on a smartphone processing speed task, highlighting its potential value for identifying subtle cognitive impairment. Longitudinal data from larger samples, a broader array of biomarkers and of ambulatory cognitive tests, are required to fully explore these issues.

Using Plasma NfL and GFAP to Monitor Response to Anti-CD20 Treatment in MS (P1-3.010)

<h3>Objective:</h3> To compare changes in plasma concentrations of Neurofilament light (NfL) and Glial Fibrillary Acidic Protein (GFAP) in individuals with relapsing multiple sclerosis (RMS) vs progressive multiple sclerosis (PMS), treated with anti-CD20 immunotherapy (rituximab or ocrelizumab) <h3>Background:</h3> Blood biomarkers, especially NfL, can augment clinical and radiographic data in MS treatment monitoring. Few studies have investigated longitudinal change in NfL or GFAP in PMS patients taking anti-CD20s or compared changes in these biomarkers between RMS and PMS. <h3>Design/Methods:</h3> Subjects were selected by MS diagnosis, anti-CD20 treatment for at least 6 months, and presence of multiple blood samples in our Center’s Biorepository. Demographic/clinical information was extracted by chart review. SIMOA plasma assays of NfL and GFAP were conducted at baseline and follow-up (between 3 and 12 months) on Quanterix SR-X. Biomarker concentrations were log transformed. Summary statistics and longitudinal regression analyses, correcting for age, were generated. <h3>Results:</h3> 37 subjects and 67 samples were analyzed (n=7 had no follow-up samples between 3 and 12 months). 64.9% were female. RMS (n=19) had mean(SD) age 38.7(9.2). PMS (n=18) had mean age 56.1(10.4). Age-adjusted mean concentrations of NfL and GFAP did not differ significantly between RMS and PMS at baseline. Geometric mean NfL declined between baseline (6.8, 95%CI 4.2–11.0) and follow-up (4.9, 95%CI 3.3–7.3) in RMS but stayed stable in PMS. Geometric mean GFAP increased between baseline (52.4, 95%CI 35.2–77.9) and follow-up (60.8, 95%CI 40.4–91.4) in PMS but stayed stable in RMS. The changes for both NfL and GFAP differed statistically significantly between MS types. <h3>Conclusions:</h3> With anti-CD20 treatment, plasma NfL levels decreased in RMS by 27.6% while staying stable in PMS; GFAP levels increased in PMS by 16% while remaining stable in RMS. Results correlate with clinical evidence showing greater benefit of anti-CD20 immunotherapy in RMS compared to PMS. Future studies will include more subjects, longer observation, and different immunotherapies. <b>Disclosure:</b> Dr. Gross has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for AP Expert Group. The institution of Stefan Sillau has received research support from Alzheimer’s Association. The institution of Stefan Sillau has received research support from Hewitt Family Foundation; State of Colorado. The institution of Stefan Sillau has received research support from PCORI. The institution of Stefan Sillau has received research support from NINR. The institution of Stefan Sillau has received research support from Michael J. Fox Foundation. The institution of Stefan Sillau has received research support from Department of Defense. The institution of Stefan Sillau has received research support from Colorado Department of Public Health and Environment. The institution of Stefan Sillau has received research support from Benign Essential Blepharospasm Research Foundation. Stefan Sillau has a non-compensated relationship as a Statistician with Novartis that is relevant to AAN interests or activities. Stefan Sillau has a non-compensated relationship as a Statistician with Biogen that is relevant to AAN interests or activities. Sean Selva has nothing to disclose. Mrs. Ritchie has nothing to disclose.

Plasma NfL is associated with the APOE ε4 allele, brain imaging measurements of neurodegeneration, and lower recall memory scores in cognitively unimpaired late-middle-aged and older adults

BackgroundPlasma neurofilament light (NfL) is an indicator of neurodegeneration and/or neuroaxonal injury in persons with Alzheimer’s disease (AD) and a wide range of other neurological disorders. Here, we characterized and compared plasma NfL concentrations in cognitively unimpaired (CU) late-middle-aged and older adults with two, one, or no copies of the APOE ε4 allele, the major genetic risk factor for AD. We then assessed plasma NfL associations with brain imaging measurements of AD-related neurodegeneration (hippocampal atrophy and a hypometabolic convergence index [HCI]), brain imaging measurements of amyloid-β plaque burden, tau tangle burden and white matter hyperintensity volume (WMHV), and delayed and total recall memory scores.MethodsPlasma NfL concentrations were measured in 543 CU 69 ± 9 year-old participants in the Arizona APOE Cohort Study, including 66 APOE ε4 homozygotes (HM), 165 heterozygotes (HT), and 312 non-carriers (NC). Robust regression models were used to characterize plasma NfL associations with APOE ε4 allelic dose before and after adjustment for age, sex, and education. They were also used to characterize plasma NfL associations with MRI-based hippocampal volume and WMHV measurements, an FDG PET-based HCI, mean cortical PiB PET measurements of amyloid-β plaque burden and meta-region-of-interest (meta-ROI) flortaucipir PET measurements of tau tangle burden, and Auditory Verbal Learning Test (AVLT) Delayed and Total Recall Memory scores.ResultsAfter the adjustments noted above, plasma NfL levels were significantly greater in APOE ε4 homozygotes and heterozygotes than non-carriers and significantly associated with smaller hippocampal volumes (r = − 0.43), greater tangle burden in the entorhinal cortex and inferior temporal lobes (r = 0.49, r = 0.52, respectively), and lower delayed (r = − 0.27), and total (r = − 0.27) recall memory scores (p < 0.001). NfL levels were not significantly associated with PET measurements of amyloid-β plaque or total tangle burden.ConclusionsPlasma NfL concentrations are associated with the APOE ε4 allele, brain imaging biomarkers of neurodegeneration, and less good recall memory in CU late-middle-aged and older adults, supporting its value as an indicator of neurodegeneration in the preclinical study of AD.

Preanalytical stability of plasma biomarkers for Alzheimer's disease pathology.

Plasma tests have demonstrated high diagnostic accuracy for identifying Alzheimer's disease pathology. To facilitate the transition to clinical utility, we assessed whether plasma storage duration and temperature affect the biomarker concentrations. Plasma samples from 13 participants were stored at +4°C and +18°C. Concentrations of six biomarkers were measured after 2, 4, 6, 8, 10, and 24h by single molecule array assays. Phosphorylated tau 181 (p-tau181), phosphorylated tau 231 (p-tau231), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) concentrations were unchanged both when stored at +4°C and +18°C. Amyloid-β 40 (Aβ40) and amyloid-β 42 (Aβ42) concentrations were stable for 24h at +4°C but declined when stored at +18°C for longer than 6h. This decline did not affect the Aβ42/Aβ40 ratio. Plasma samples can be stored for 24h at +4°C or +18°C and result in valid assay results for p-tau181, p-tau231, Aβ42/Aβ40 ratio, GFAP, and NfL. Plasma samples were stored for 24h at +4°C and +18°C, mimicking clinical practice.Concentrations for Alzheimer's disease biomarkers were measured at six time-points.p-tau181, p-tau231, NfL, and GFAP concentrations were unchanged during the experiment.Storage at +18°C affected Aβ40 and Aβ42 concentrations while storage at +4°C did not. The Aβ42/Aβ40 ratio was unaffected.These plasma tests seem suitable for use in general practice.

Serum neurofilament light concentrations are associated with cortical thinning in anorexia nervosa.

Anorexia nervosa (AN) is characterized by severe emaciation and drastic reductions of brain mass, but the underlying mechanisms remain unclear. The present study investigated the putative association between the serum-based protein markers of brain damage neurofilament light (NF-L), tau protein, and glial fibrillary acidic protein (GFAP) and cortical thinning in acute AN. Blood samples and magnetic resonance imaging scans were obtained from 52 predominantly adolescent, female patients with AN before and after partial weight restoration (increase in body mass index >14%). The effect of marker levels before weight gain and change in marker levels on cortical thickness (CT) was modeled at each vertex of the cortical surface using linear mixed-effect models. To test whether the observed effects were specific to AN, follow-up analyses exploring a potential general association of marker levels with CT were conducted in a female healthy control (HC) sample (n = 147). In AN, higher baseline levels of NF-L, an established marker of axonal damage, were associated with lower CT in several regions, with the most prominent clusters located in bilateral temporal lobes. Tau protein and GFAP were not associated with CT. In HC, no associations between damage marker levels and CT were detected. A speculative interpretation would be that cortical thinning in acute AN might be at least partially a result of axonal damage processes. Further studies should thus test the potential of serum NF-L to become a reliable, low-cost and minimally invasive marker of structural brain alterations in AN.

Plasma biomarkers for diagnosis of Alzheimer's disease and prediction of cognitive decline in individuals with mild cognitive impairment.

The last few years have seen major advances in blood biomarkers for Alzheimer's Disease (AD) with the development of ultrasensitive immunoassays, promising to transform how we diagnose, prognose, and track progression of neurodegenerative dementias. We evaluated a panel of four novel ultrasensitive electrochemiluminescence (ECL) immunoassays against presumed CNS derived proteins of interest in AD in plasma [phosphorylated-Tau181 (pTau181), total Tau (tTau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)]. Two sets of banked plasma samples from the Massachusetts Alzheimer's Disease Research Center's longitudinal cohort study were examined: A longitudinal prognostic sample (n = 85) consisting of individuals with mild cognitive impairment (MCI) and 4 years of follow-up and a cross-sectional sample (n = 238) consisting of individuals with AD, other neurodegenerative diseases (OND), and normal cognition (CN). Participants with MCI who progressed to dementia due to probable AD during follow-up had higher baseline plasma concentrations of pTau181, NfL, and GFAP compared to non-progressors. The best prognostic discrimination was observed with pTau181 (AUC = 0.83, 1.7-fold increase) and GFAP (AUC = 0.83, 1.6-fold increase). Participants with autopsy- and/or biomarker verified AD had higher plasma levels of pTau181, tTau and GFAP compared to CN and OND, while NfL was elevated in AD and further increased in OND. The best diagnostic discrimination was observed with pTau181 (AD vs CN: AUC = 0.90, 2-fold increase; AD vs. OND: AUC = 0.84, 1.5-fold increase) but tTau, NfL, and GFAP also showed good discrimination between AD and CN (AUC = 0.81-0.85; 1.5-2.2 fold increase). These new ultrasensitive ECL plasma assays for pTau181, tTau, NfL, and GFAP demonstrated diagnostic utility for detection of AD. Moreover, the absolute baseline plasma levels of pTau181 and GFAP reflect cognitive decline over the next 4 years, providing prognostic information that may have utility in both clinical practice and clinical trial populations.