Higher NfL Research Articles

Plasma neurofilament light, glial fibrillary acid protein, and phosphorylated tau 181 as biomarkers for neuropsychiatric symptoms and related clinical disease progression

BackgroundNeuropsychiatric symptoms (NPS) are common in older people, may occur early in the development of dementia disorders, and have been associated with faster cognitive decline. Here, our objectives were to investigate whether plasma levels of neurofilament light chain (NfL), glial fibrillary acid protein (GFAP), and tau phosphorylated at threonine 181 (pTau181) are associated with current NPS and predict future NPS in non-demented older people. Furthermore, we tested whether the presence of NPS combined with plasma biomarkers are useful to predict Alzheimer’s disease (AD) pathology and cognitive decline.MethodsOne hundred and fifty-one participants with normal cognition (n = 76) or mild cognitive impairment (n = 75) were examined in a longitudinal brain aging study at the Memory Centers, University Hospital of Lausanne, Switzerland. Plasma levels of NfL, GFAP, and pTau181 along with CSF biomarkers of AD pathology were measured at baseline. NPS were assessed through the Neuropsychiatric Inventory Questionnaire (NPI-Q), along with the cognitive and functional performance at baseline and follow-up (mean: 20 months). Different regression and ROC analyses were used to address the associations of interest.ResultsNone of the three plasma biomarker was associated with NPS at baseline. Higher GFAP levels were associated with the presence of NPS at follow-up (OR = 2.8, p = .002) and both, higher NfL and higher GFAP with an increase in the NPI-Q severity score over time (β = 0.25, p = .034 and β = 0.30, p = .013, respectively). Adding NPS and the plasma biomarkers to a reference model improved the prediction of future NPS (AUC 0.72 to 0.88, p = .002) and AD pathology (AUC 0.78 to 0.87, p = .010), but not of cognitive decline (AUC 0.79 to 0.85, p = .081).ConclusionPlasma NfL and GFAP are both associated with future NPS and NPS severity change. Considering the presence of NPS along with blood-based AD-biomarkers may improve the prediction of clinical progression of NPS over time and inform clinical decision-making in non-demented older people.

Neurofilament Light Chain and Risk of Stroke in Patients With Atrial Fibrillation.

Biomarkers reflecting brain injury are not routinely used in risk assessment of stroke in atrial fibrillation (AF). Neurofilament light chain (NFL) is a novel biomarker released into blood after cerebral insults. We investigated the association between plasma concentrations of NFL, other biomarkers, and risk of stroke and death in patients with AF not receiving oral anticoagulation. For this observational study, baseline plasma samples were available from 3077 patients with AF randomized to aspirin in ACTIVE A (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; 2003 to 2008) and AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; 2007 to 2009). Median follow-up was 1.5 years. NFL was analyzed with a Single Molecule Array (Simoa). Associations with outcomes (total stroke or systemic embolism, ischemic stroke, cardiovascular death, and all-cause death) were explored with Cox regression models. In the combined cohort, the median NFL level was 16.9 ng/L (interquartile range, 11.1-26.5 ng/L), the median age was 71 years, 58% were men, and 13% had a history of previous stroke. NFL was associated with older age, higher creatinine, lower body mass index, previous stroke, female sex, and diabetes but not cardiac rhythm. Higher NFL was associated with a higher risk of stroke or systemic embolism (n=206) independently of clinical characteristics (hazard ratio, 1.27 [95% CI, 1.10-1.46] per doubling of NFL) and other biomarkers (hazard ratio, 1.18 [95% CI, 1.01-1.37]) and including in patients without previous stroke (hazard ratio, 1.23 [95% CI, 1.02-1.48]). NFL was also independently associated with cardiovascular (n=219) and all-cause (n=311) death. The C index for stroke using only NFL was 0.642, on par with the currently used clinical risk scores. Addition of information on NFL improved discrimination in a model also including clinical information, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and high-sensitivity cardiac troponin T, yielding a C index of 0.727. NFL reflects overt and covert episodes of cerebral ischemia and improves risk assessment of stroke and death in patients with AF without oral anticoagulation, including in patients without previous stroke. The combination of NFL with information on age, history of stroke, and other biomarkers should be explored as a future avenue for stroke risk assessments in patients with AF.

Pathologic and cognitive correlates of plasma biomarkers in neurodegenerative disease.

We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog). Participants were NormCog (n=132) and ImpCog (n=461), with confirmed β-amyloid (Aβ+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aβ+ from Aβ-. Survival analyses tested time to clinical dementia rating (global CDR) progression. Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aβ+ in NormCog (ROCAUC=0.87) and ImpCog (ROCAUC=0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aβ+ (hazard ratio [HR]=2.94; p=8.1e-06) and Aβ- individuals (HR=3.11; p=2.6e-09). Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease. Participants were clinically heterogeneous, with autopsy- or biomarker-confirmed Aβ. Combining plasma p-tau181, GFAP, and NfL improved diagnostic accuracy for Aβ status. Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD. Plasma analytes show independent associations with tau PET and post mortem Aβ/tau. Plasma NfL predicted longitudinal cognitive decline in both Aβ+ and Aβ- individuals.

CSF biomarkers of immune activation and Alzheimer's disease for predicting cognitive impairment risk in the elderly.

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aβ42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aβ42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aβ42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome.

People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aβ)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years). In general linear models lower plasma Aβ42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

ACCELERATED BIOLOGICAL AGE IS ASSOCIATED WITH DELIRIUM AND PLASMA NEUROFILAMENT LIGHT IN GERIATRIC HIP FRACTURE

Abstract Background Biological age may be distinct from chronological age. Epigenetic clocks (e.g., PhenoAge) estimate biological age by quantifying changes in DNA methylation (DNAm). Biological age is “accelerated” (AgeAccel) when epigenetic>chronological age. AgeAccel predicts age-related diseases but its association with delirium or neuronal injury markers (e.g., neurofilament light “NfL”) is unknown. Methods Adults age 65+ hospitalized for acute hip fracture underwent daily delirium screening with the Confusion Assessment Method Long Form. DNAm status of 850,000 CpG sites was measured in triplicate from pre-op peripheral blood mononuclear cells using Illumina MethylationEPIC arrays. AgeAccel represented the residual of the linear regression model of PhenoAge regressed on chronological age. Plasma NfL was measured in duplicate using Simoa immunoassays. Group differences calculated by T-test. Results Of 12 subjects (enrollment ongoing): mean age 79±8, 75% women, 42% with dementia, 33% were delirious on pre-op blood collection day. Mean AgeAccel was 4.4 years (p=0.02) in delirious vs non-delirious subjects (Fig1A). Those with positive (vs negative) AgeAccel had higher mean NfL (Fig1B, p=0.002). Delirious (vs non-delirious) subjects had higher mean NfL (p=0.004). We found no difference in either AgeAccel or NfL by dementia status. Conclusions In this geriatric hip fracture pilot, accelerated biological age was associated with higher delirium prevalence and NfL. Delirium was also associated with higher NfL. This pilot demonstrates feasibility and utility of measuring biological aging in delirium that warrants study in a larger cohort.

Associations between neuropsychiatric symptoms and ADRD serum biomarkers in Mexican American and non‐Hispanic white adults with mild cognitive impairment

AbstractBackgroundMild cognitive impairment (MCI) is a heterogenous diagnostic category with trajectories ranging from reversion to unimpaired cognition to progression to dementia. Neuropsychiatric symptoms such as depression and irritability are common and influence quality of life of patients and caregivers. The role of neuropsychiatric symptoms on disease biology, presentation, and course remains poorly understood. The goal of this study was to evaluate the associations between neuropsychiatric symptoms and serum ADRD biomarkers in Mexican American and non‐Hispanic white participants diagnosed with MCI.MethodParticipants from the Texas Alzheimer’s Research and Care Consortium underwent a blood draw and clinical evaluation, including psychopathological and cognitive assessments. Diagnoses of MCI were adjudicated in consensus reviews. The presence and severity of neuropsychiatric symptoms were assessed by informant report using the Neuropsychiatric Inventory (NPI). Serum levels of total tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were assessed using Simoa HD‐X Analyzer. Associations between NPI total score and individual items with serum biomarker levels were assessed using linear regression adjusted for age and sex.ResultA total of 425 participants (mean age: 71 ± 9 years, 62% female, 74% Mexican American) had a diagnosis of MCI and serum ADRD biomarkers (Table 1). Total NPI score was not associated with total tau (ß = 0.002, p = 0.609), NfL (ß = 0.001, p = 0.658), or GFAP (ß = 0.001, p = 0.777). However, endorsement of appetite changes was associated with higher NfL (ß = 0.077, p = 0.006) and GFAP (ß = 0.088, p = 0.002) levels. Stratified analyses indicated associations of appetite changes with serum NfL (ß = 0.108, p = 0.002) and GFAP (ß = 0.095, p = 0.003) in Mexican Americans, but not in non‐Hispanic whites (NfL: ß = 0.022, p = 0.633, GFAP: ß = 0.102, p = 0.066).There were no other significant associations between individual items on the NPI with serum biomarkers (p>0.05, Bonferroni adjustment p±0.003).ConclusionWithin Mexican American adults with MCI, changes in appetite were associated with higher serum NFL and GFAP levels. As elevations in circulating NfL and GFAP levels are associated with ADRD pathology and accelerated disease progression, appetite changes, a non‐invasive and easily discernible behavioral phenotype, may predict higher likelihood of worsening cognitive course. Future longitudinal studies will be necessary to confirm predictive utility of appetite changes for disease progression.

Comparing associations of Alzheimer’s disease plasma biomarkers with remote self‐administered cognitive measures versus in‐person neuropsychological tests

AbstractBackgroundBrief self‐administered cognitive assessments deployed remotely and combined with plasma biomarkers of Alzheimer’s disease (AD) are well suited to assess clinical symptoms and underlying biology in large‐scale decentralized studies. We investigated whether associations of self‐administered cognitive measures and plasma biomarkers were comparable to associations of in‐person cognitive measures and plasma biomarkers.MethodParticipants included 327 adults from the Mayo Clinic Study of Aging (mean age = 70.8; 48% female; mean education = 16.0 years; 96.9% white). Most (94.5%) were cognitively unimpaired; 5.5% had consensus diagnosis of mild cognitive impairment. Participants completed Mayo Test Drive (MTD; Stricker et al., 2022), a remote, self‐administered, multi‐device compatible web‐based cognitive assessment comprised of the Stricker Learning Span (SLS) and Symbols test that are combined into a MTD composite. Participants also completed in‐person neuropsychological assessment (global‐z; Mayo Preclinical Alzheimer’s disease Cognitive Composite [Mayo‐PACC]) and fasting venipuncture. Plasma was assayed via HD‐X simoa platform for amyloid‐beta (Aβ)‐42 and Aβ‐40 to create an Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) using the N4PE Quanterix kit as well as phosphorylated‐tau protein 181 (p‐tau181). P‐tau181, GFAP, and NfL were log10‐transformed. Multiple regression analyses adjusting for age, sex, and education examined associations between plasma biomarkers and composite and subtest scores from remote and in‐person measures. Davidson‐Mackinnon J‐test compared R‐squared values of models with remote versus in‐person composites.ResultLower performances on MTD, global‐z, and Mayo‐PACC (Table 1) were associated with higher GFAP (p’s≤.02), NfL (p’s≤.003), and p‐tau181 (p’s = .04). For memory, worse SLS and AVLT sum of trials were associated with higher GFAP (p’s≤.01) and NfL (p’s≤.03). For processing speed/executive function, worse Symbols and Trails B were associated with higher p‐tau181 (p’s≤.02). Worse Trails B and Digit Symbol Coding were associated with higher NfL (p’s≤.02), and worse Digit Symbol Coding was associated with lower Aβ42/40 (p = 0.03; Table 2). A multivariable model with MTD explained significantly more variance (p = .04) for NfL (adjusted R‐squared = 0.461) than a multivariable model with Mayo‐PACC (adjusted R‐squared = 0.447); remote and in‐person composite measures were comparable for other associations (p’s>.05).ConclusionRemote and in‐person composite measures showed comparable associations with AD‐related plasma biomarkers, supporting MTD’s criterion validity.

Comparing associations of Alzheimer’s disease plasma biomarkers with remote self‐administered cognitive measures versus in‐person neuropsychological tests

AbstractBackgroundBrief self‐administered cognitive assessments deployed remotely and combined with plasma biomarkers of Alzheimer’s disease (AD) are well suited to assess clinical symptoms and underlying biology in large‐scale decentralized studies. We investigated whether associations of self‐administered cognitive measures and plasma biomarkers were comparable to associations of in‐person cognitive measures and plasma biomarkers.MethodParticipants included 327 adults from the Mayo Clinic Study of Aging (mean age = 70.8; 48% female; mean education = 16.0 years; 96.9% white). Most (94.5%) were cognitively unimpaired; 5.5% had consensus diagnosis of mild cognitive impairment. Participants completed Mayo Test Drive (MTD; Stricker et al., 2022), a remote, self‐administered, multi‐device compatible web‐based cognitive assessment comprised of the Stricker Learning Span (SLS) and Symbols test that are combined into a MTD composite. Participants also completed in‐person neuropsychological assessment (global‐z; Mayo Preclinical Alzheimer’s disease Cognitive Composite [Mayo‐PACC]) and fasting venipuncture. Plasma was assayed via HD‐X simoa platform for amyloid‐beta (Aß)‐42 and Aß‐40 to create an Aß42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) using the N4PE Quanterix kit as well as phosphorylated‐tau protein 181 (p‐tau181). P‐tau181, GFAP, and NfL were log10‐transformed. Multiple regression analyses adjusting for age, sex, and education examined associations between plasma biomarkers and composite and subtest scores from remote and in‐person measures. Davidson‐Mackinnon J‐test compared R‐squared values of models with remote versus in‐person composites.ResultLower performances on MTD, global‐z, and Mayo‐PACC (Table 1) were associated with higher GFAP (p’s = .02), NfL (p’s = .003), and p‐tau181 (p’s = .04). For memory, worse SLS and AVLT sum of trials were associated with higher GFAP (p’s = .01) and NfL (p’s = .03). For processing speed/executive function, worse Symbols and Trails B were associated with higher p‐tau181 (p’s = .02). Worse Trails B and Digit Symbol Coding were associated with higher NfL (p’s = .02), and worse Digit Symbol Coding was associated with lower Aß42/40 (p = 0.03; Table 2). A multivariable model with MTD explained significantly more variance (p = .04) for NfL (adjusted R‐squared = 0.461) than a multivariable model with Mayo‐PACC (adjusted R‐squared = 0.447); remote and in‐person composite measures were comparable for other associations (p’s>.05).ConclusionRemote and in‐person composite measures showed comparable associations with AD‐related plasma biomarkers, supporting MTD’s criterion validity.

The Role of Alzheimer’s Disease Pathology in Cognition, Brain Volume, and Plasma Biomarker Concentrations in Traumatic Encephalopathy Syndrome

AbstractBackgroundPatients with a history of repetitive head impacts (RHI) risk progressive memory loss and executive dysfunction consistent with traumatic encephalopathy syndrome (TES). TES is a clinical phenotype sensitive but non‐specific to underlying chronic traumatic encephalopathy (CTE). Cognitive symptoms overlap with Alzheimer’s disease (AD), and features of AD pathology like beta‐amyloid (Aβ) plaques often co‐occur with CTE. We investigated whether Alzheimer’s neuropathological changes influences cognition, brain volume, and plasma biomarkers in patients with RHI or TES.MethodsWe studied 154 patients who underwent Aβ‐PET, including 33 with RHI/TES (age 61.5±11.5, 100% male, 11/33 Aβ[+]), 62 with AD and no prior RHI (age 67.1±10.2, 48% male, 62/62 Aβ[+]), and 59 healthy controls without RHI (HC; age 73.0±6.2, 40% male, 0/59 Aβ[+]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (regions of interest: frontal, temporal, parietal, occipital, hippocampus) and provided plasma samples analyzed for GFAP and NfL. Patients with RHI/TES were stratified as Aβ[+] or Aβ[‐] and compared to each other and with AD and HC groups (ANCOVA adjusting for age and sex).ResultsCognitively, Aβ[+] RHI/TES performed worse than Aβ[‐] RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing brain volume, Aβ[+] RHI/TES, but not Aβ[‐] RHI/TES, had lower parietal volume than HC (p = .003, d = 1.3). Conversely, Aβ[‐] RHI/TES had lower hippocampal volume than patients with AD (p = .03, d = 0.77). Comparing plasma biomarkers, Aβ[+] RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and similar GFAP levels to patients with AD (p = .26, d = 0.38). Conversely, Aβ[‐] RHI/TES had higher NfL than HC (p = .004, d = 0.93) and a trend towards higher plasma NfL than Aβ[+] RHI/TES (p = .11; d = 0.61).ConclusionsPatients with RHI/TES and positive Aβ‐PET have cognitive, brain volume, and plasma biomarker changes that more closely align to patients with AD than patients with Aβ[‐] RHI/TES. Visuospatial impairment and associated parietal atrophy may suggest the presence of AD pathology in participants with RHI. The suggestion of greater neuronal injury in patients with Aβ[‐] RHI/TES warrants further evaluation in supporting a diagnosis of TES due to suspected underlying CTE. Measuring these biomarkers in patients with RHI/TES could guide precise clinical management.

The association of blood‐based biomarkers of neuropathology with cognitive performance and dementia in a diverse, population‐based sample of US adults

AbstractBackgroundThe association of blood‐based biomarkers of neuropathology with cognition and dementia, including potential variation by race/ethnicity (whites, blacks and Hispanics), has not been examined in large, diverse, population‐based samples of adults.MethodThe sample included Health and Retirement Study (HRS) respondents over age 50 with blood‐based neuropathology biomarker, demographic, and cognitive data (n = 4,214). A𝛃‐40, A𝛃‐42, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured in plasma (Quanterix Neurology 4‐Plex E kit), and phosphorylated tau (pTau‐181) was measured in serum (Quanterix Advantage V2.0 kit). Cognitive tests included immediate and delayed word recall, serial 7s, and backward counting (total score 0‐27). Dementia classification relied on a diagnostic algorithm previously validated in HRS. Linear and unconditional logistic regressions were weighted to account for sample design and used to model associations between the biomarkers and the cognitive score/dementia classification after controlling for age, sex, and batch effects.ResultAbout 80% of the sample was white, 10% black, and 10% Hispanic. Correlations were modest among pTau‐181, NfL, and GFAP (r = 0.29‐0.46).When the biomarkers were analyzed individually, higher A𝛃‐42/A𝛃‐40 ratio was associated with higher cognitive score among whites. Higher NfL was associated with lower cognitive score in the total sample and in each race/ethnic group (whites, blacks and Hispanics). Higher pTau‐181 was associated with lower cognitive score in the total and white sample. Higher GFAP was related to lower cognitive score in the total, white, and Hispanic samples. In a model that included all four biomarkers, GFAP remained significantly related to cognitive performance in the total sample, and NfL remained significantly related to cognitive performance in the total sample and in each race/ethnic group.When the biomarkers were analyzed individually, higher NfL was associated with higher likelihood of dementia in the total sample. Higher pTau‐181 was associated with higher likelihood of dementia among whites. Higher GFAP was associated with dementia in the total and white samples, alone and in the fully adjusted model with all four biomarkers.ConclusionThese results show the importance of examining blood‐based biomarkers of neuropathology as predictors of cognitive performance and dementia in diverse, population‐based samples.

Associations between normal cognitive aging and neurodegeneration

AbstractBackgroundMultiple cognitive domains, including learning, memory and psychomotor speed, show significant reductions with age. These changes are thought to reflect normal cognitive aging. However, since cerebrospinal fluid (CSF) neurodegenerative biomarkers, such as total‐tau (t‐tau) and Neurofilament light chain (NfL), also show age‐related increases in normal aging, we aimed to investigate whether age‐associated cognitive decline may be mediated by age‐associated neurodegenerative changes.MethodWe included 114 cognitively healthy participants aged 40‐80 years from The Norwegian Dementia Disease Initiation Study. All had normal concentrations of CSF Aβ42/40 ratio. Cognitively healthy was defined as demographically adjusted T‐scores ≥35 on standardized cognitive tests. We fitted mediation models using structural equation modelling (SEM), with either CSF NfL or t‐tau as a mediator between age and CERAD learning, CERAD recall, TMT‐A and TMT‐B. All variables were standardized prior to analyses; in addition, both t‐tau and NfL were log transformed due to skewness.ResultsSee table 1 for demographic and clinical characteristics. Whilst neither NfL nor t‐tau showed statistically significant mediation of age‐related cognitive decline, our results nevertheless suggest a partial mediation of NfL on age‐related cognitive decline. Here, relationships between age and CERAD learning, CERAD Recall, and TMT‐A performance were weakened whereas higher NfL was associated with worse performance, in particular for delayed memory recall. This was not observed for t‐tau in any models. See figure 1‐2.ConclusionAge‐related decline in verbal learning, memory and psychomotor speed may be partially attributable to NfL‐associated neurodegenerative changes in cognitively healthy adults. As NfL reflects axonal degeneration, these results may reflect white matter neurodegeneration in aging.

Plasma neurofilament light chain in relation to 10-year change in cognition and neuroimaging markers: a population-based study

Neurofilament light chain (NfL) is a promising biomarker for risk stratification and disease monitoring of dementia, but its utility in the preclinical disease stage remains uncertain. We determined the association of plasma NfL with (change in) neuroimaging markers and cognition in the population-based Rotterdam Study, using linear and logistic regression and mixed-effects models. Plasma NfL levels were measured using the Simoa NF-light™ assay in 4705 dementia-free participants (mean age 71.9 years, 57% women), who underwent cognitive assessment and brain MRI with repeated assessments over a 10-year follow-up period. Higher plasma NfL was associated with worse cognitive performance at baseline (g-factor: β = − 0.12 (− 0.15; − 0.09), p < 0.001), and accelerated cognitive decline during follow-up on the Stroop color naming task (β = 0.04 (0.02; 0.06), p < 0.001), with a smaller trend for decline in global cognition (g-factor β = − 0.02 (− 0.04; 0.00), p = 0.044). In the subset of 975 participants with brain MRI, higher NfL was associated with poorer baseline white matter integrity (e.g., global mean diffusivity: β = 0.12 (0.06; 0.19), p < 0.001), with similar trends for volume of white matter hyperintensities (β = 0.09 (0.02; 0.16), p = 0.011) and presence of lacunes (OR = 1.55 (1.13; 2.14), p = 0.007). Plasma NfL was not associated with volumes or thickness of the total gray matter, hippocampus, or Alzheimer signature regions. In conclusion, higher plasma NfL levels are associated with cognitive decline and larger burden of primarily white matter pathology in the general population.

Alzheimer’s pathology is associated with altered cognition, brain volume, and plasma biomarker patterns in traumatic encephalopathy syndrome

BackgroundTraumatic encephalopathy syndrome (TES) is a clinical phenotype sensitive but non-specific to underlying chronic traumatic encephalopathy (CTE) neuropathology. However, cognitive symptoms of TES overlap with Alzheimer’s disease (AD), and features of AD pathology like beta-amyloid (Aβ) plaques often co-occur with CTE, making clinical-to-pathological conclusions of TES diagnoses challenging. We investigated how Alzheimer’s neuropathological changes associated with cognition, brain volume, and plasma biomarkers in patients with repetitive head impacts (RHI)/TES, clinical AD, or typically aging controls.MethodsWe studied 154 participants including 33 with RHI/TES (age 61.5 ± 11.5, 100% male, 11/33 Aβ[ +]), 62 with AD and no known prior RHI (age 67.1 ± 10.2, 48% male, 62/62 Aβ[ +]), and 59 healthy controls without RHI (HC; age 73.0 ± 6.2, 40% male, 0/59 Aβ[ +]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (voxel-based morphometry analysis), and provided plasma samples analyzed for GFAP, NfL, IL-6, IFN-γ, and YKL-40. For cognition and plasma biomarkers, patients with RHI/TES were stratified as Aβ[ +] or Aβ[ −] and compared to each other plus the AD and HC groups (ANCOVA adjusting for age and sex). Differences with at least a medium effect size (Cohen’s d > 0.50) were interpreted as potentially meaningful.ResultsCognitively, within the TES group, Aβ[ +] RHI/TES performed worse than Aβ[-] RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing voxel-wise brain volume, both Aβ[ +] and Aβ[ −] RHI/TES had lower medial and anterior temporal lobe volume than HC and did not significantly differ from AD. Comparing plasma biomarkers, Aβ[ +] RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and did not significantly differ from AD. Conversely, Aβ[ −] RHI/TES had higher NfL than HC (p = .004, d = 0.93) and higher IL-6 than all other groups (p’s ≤ .004, d’s > 1.0).ConclusionsPresence of Alzheimer’s pathology in patients with RHI/TES is associated with altered cognitive and biomarker profiles. Patients with RHI/TES and positive Aβ-PET have cognitive and plasma biomarker changes that are more like patients with AD than patients with Aβ[ −] RHI/TES. Measuring well-validated Alzheimer’s biomarkers in patients with RHI/TES could improve interpretation of research findings and heighten precision in clinical management.

Prognostic performance of blood neurofilament light chain protein in hospitalized COVID-19 patients without major central nervous system manifestations: an individual participant data meta-analysis.

To investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19). We conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU)admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL. We identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with ahigher likelihood of ICU admission, need ofMV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need ofMV and ICU admission, respectively. Blood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.

Electrochemical Impedance Immunoassay for ALS-Associated Neurofilament Protein: Matrix Effect on the Immunoplatform

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, which has complex diagnostic steps. Electrochemical immunoassays may make the diagnosis simpler and faster. Here, we present the detection of ALS-associated neurofilament light chain (Nf-L) protein through an electrochemical impedance immunoassay on reduced graphene oxide (rGO) screen-printed electrodes. The immunoassay was developed in two different media, i.e., buffer and human serum, to compare the effect of the media on their figures of merit and calibration models. The label-free charge transfer resistance (RCT) of the immunoplatform was used as a signal response to develop the calibration models. We found that exposure of the biorecognition layer to human serum improved the impedance response of the biorecognition element with significantly lower relative error. Moreover, the calibration model obtained in the human serum environment has higher sensitivity and a better limit of detection (0.087 ng/mL) than the buffer medium (0.39 ng/mL). The analyses of the ALS patient samples show that concentrations obtained from the buffer-based regression model was higher than the serum-based model. However, a high Pearson correlation (r = 1.00) between the media suggests that concentration in one medium may be useful to predict the concentration in the other medium. Moreover, the Nf-L concentration appears to increase with age in both male and female groups, while overall higher Nf-L was found in the male group than the female group.

Depression and Plasma Biomarkers of Alzheimer’s Disease in a Diverse Community Cohort: The Impact of Ethnicity and Level of Depression

Background: Depression is both a risk factor for and early symptom of Alzheimer’s disease. Numerous studies have investigated the relationship between AT(N) biomarkers of AD and depression; however, the majority of these have utilized CSF in Non-Hispanic White populations. Objective: To investigate the relationship between plasma total Tau, Aβ40, Aβ42, NFL and depression in Mexican-Americans and Non-Hispanic Whites. Methods: The study was a cross-sectional comparison of 645 Mexican American and 644 Non-Hispanic White older adults in a community-based study of cognitive aging who had been categorized as having unimpaired cognition using a consensus based algorithmic approach. Plasma biomarkers were assayed using Simoa technology. The Geriatric Depression Scale assessed depression. Results: Mexican Americans had significantly higher scores on the GDS. Non-Hispanic Whites had higher Aβ40, and Aβ42 and MAs had higher NFL and Tau. For Mexican Americans, linear regression analyses found NfL and Aβ42 significant predictors of GDS scores whereas for the Non-Hispanic White group none of the biomarkers was significantly related to GDS total score or any of the subscale scores. Those scoring in the depressed range had significantly higher levels of Aβ40, Aβ42, and NFL. When analyzed by ethnicity the depressed Mexican Americans had significantly higher levels of Aβ40, Aβ42, and NFL than the non-depressed. No difference between the depression levels on any of the biomarkers was found for Non-Hispanic Whites. Conclusions: Findings support the importance of evaluating the effect of ethnicity and level of depressive symptoms when assessing the relationship of AD biomarkers to depression. In cognitively unimpaired MAs depression is related to the Alzheimer’s Disease biomarkers but this is not the case for Non-Hispanic Whites. Higher levels of these biomarkers among depressed cognitively unimpaired Mexican Americans may be an indicator of increased risk for cognitive impairment but not for Non-Hispanic Whites. Longitudinal research is needed to clarify the effect of ethnicity on the biomarker-depression relationship.

Longitudinal change in plasma biomarkers by amyloid PET status

AbstractBackgroundIt is important to better understand the longitudinal trajectories of plasma measures of proteins implicated in Alzheimer’s disease among cognitively normal older adults.MethodWe investigated whether baseline levels and longitudinal rates of change of three Quanterix SIMOA plasma measures (amyloid‐beta 42 to 40 ratio [Aβ42/Aβ40], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NfL]) differ by amyloid group as determined using Pittsburgh compound B (PiB) PET in the Baltimore Longitudinal Study of Aging (N=147 PiB– and 57 PiB+; 640 longitudinal measures). All participants were cognitively normal at baseline. We used linear mixed effects models with longitudinal plasma measures as the outcome. We conducted an unadjusted analysis that included binary PiB group, time from baseline, and their interaction. We also conducted an adjusted analysis that additionally included the following explanatory variables: baseline age and its interaction with time, sex, APOE ε4 carrier vs noncarrier, race, and estimated glomerular filtration rate (eGFR) from serum creatinine concurrent with plasma measurements. All variables except time were mean‐centered.ResultParticipant characteristics are presented in Table 1. Figures 1 and 2 illustrate plasma biomarkers versus age and longitudinal visit schedule per participant, respectively. PiB+ individuals had lower Aβ42/Aβ40, higher GFAP, and higher NfL at baseline (Table 2). Both PiB groups exhibited longitudinal increases in GFAP and NfL (Table 3). Aβ42/Aβ40 declined longitudinally in the PiB– group, but annual change in the PiB+ group was not statistically significant. PiB group difference in rates of change in plasma measures was statistically significant for Aβ42/Aβ40 but not for NfL. Difference in rate of change in GFAP was statistically significant in the unadjusted model only. Adjusted model fixed effect estimates are depicted in Figure 3.ConclusionSteeper decline in plasma Aβ42/Aβ40 in the PiB– group suggests that individuals may exhibit decline in this measure prior to the onset of amyloid PET positivity. Despite exhibiting baseline PiB group differences, plasma GFAP and NfL have similar rates of increase in both PiB groups. Reliable detection of such changes at the individual level, prior to the onset of cognitive impairment, may enable better personalized prediction of future outcomes.

Spectral signatures associated with cognitive aging, APOE4, amyloid‐β and measures of axonal integrity in cognitively unimpaired adults

AbstractBackgroundOscillatory brain rhythms are a defining feature of neuronal activity that support cognition in humans. Previous studies that showed associations of spectral changes in individuals who harbor high risk for Alzheimer’s disease (AD) were limited to identify abnormalities within select brain regions defined apriori. Comprehensive whole‐brain spatiotemporal patterns of oscillatory changes associated with cognitive‐aging and with AD risk are only partly known. Our main goals were to understand how frequency specific spectral changes relate to cognitive abilities in normal aging and to identify oscillatory signatures that indicate pre‐symptomatic AD pathophysiological processes in cognitively unimpaired elderly.MethodsWe used magnetoencephalography (MEG) to study the spectral signatures within delta‐theta (2‐7Hz), alpha (8‐12Hz) and beta (13‐35Hz) oscillations, in cognitively unimpaired adults (n=70). Using a partial‐least‐square regression, we correlated spectral patterns to executive, memory, and processing‐speed abilities (n=40). Next, we compared the spectral signatures between amyloid‐β (Aβ)+ vs. Aβ‐ and between APOE‐Ɛ4+ vs. APOE‐Ɛ4‐, in sub‐cohorts evaluated with Aβ‐PET (n=46) and APOE4 (n=65), respectively. In a subset of participants (n=19), we also examined associations between spectral signatures and cerebrospinal fluid (CSF) markers indicating damage to: presynaptic (growth‐associated protein‐43, GAP43); postsynaptic (neurogranin, NG); axonal (neurofilament light chain, NFL), levels.ResultsAn age dependent, low‐grade, increase in alpha power and decrease in delta‐theta power were associated with better cognitive performance in memory, executive and processing speed (Figure‐1). APOE4+ individuals showed reduced alpha power within bilateral medial temporal and right precuneus, compared to APOE4‐. Aβ+ individuals showed a dual pattern of alpha change with increased frontal and reduced medial and lateral temporal cortex pattern and a frontally distributed increased delta‐theta power (Figure‐2). Higher CSF‐NFL was correlated with lower alpha power.ConclusionsOur findings demonstrate that higher alpha power indicates a positive spectral change towards better cognitive health in aging. Importantly, a reduced alpha power signature indicated early neurodegenerative changes, as demonstrated by: (1)Aβ+ individuals and APOE‐Ɛ4+ individuals showing reduced alpha power within the regions known for earliest tau accumulations; (2) lower alpha correlating with higher NFL, which reflects Aβ‐independent neurodegeneration. Collectively alpha signatures may indicate tau related neuropathology with aging and in early AD.

Associations of plasma phosphorylated tau181 and neurofilament light chain with brain amyloid burden and cognition in objectively defined subtle cognitive decline patients.

There is increasing evidence that plasma biomarkers are specific biomarkers for Alzheimer's disease (AD) pathology, but their potential utility in Obj-SCD (objectively defined subtle cognitive decline) remains unclear. A total of 234 subjects, including 65 with brain amyloid beta (Aβ) negative normal cognition (Aβ- NC), 58 with Aβ-positive NC (Aβ+ NC), 63 with Aβ- Obj-SCD, and 48 with Aβ+ Obj-SCD were enrolled. Plasma Aβ42, Aβ40, Aβ42/Aβ40 ratio, phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), and total tau (T-tau) were measured using Simoa assays. Logistic and linear regression analyses were used to examine the relationship between plasma biomarkers and brain amyloid, cognition, and imaging measures adjusting for age, sex, education, APOE ε4 status, and vascular risk scores. Receiver operating characteristics were used to evaluate the discriminative validity of biomarkers. After adjustment, only plasma p-tau181 and NfL were significantly elevated in Aβ+ Obj-SCD participants compared to Aβ- NC group. Elevated p-tau181 was associated with brain amyloid accumulation, worse cognitive performance (visual episodic memory, executive function, and visuospatial function), and hippocampal atrophy. These associations mainly occurred in Aβ+ individuals. In contrast, higher NfL was correlated with brain amyloid burden and verbal memory decline. These associations predominantly occurred in Aβ- individuals. The adjusted diagnostic model combining p-tau181 and NfL levels showed the best performance in identifying Aβ+ Obj-SCD from Aβ- NC [area under the curve (AUC)=0.814], which did not differ from the adjusted p-tau181 model (AUC=0.763). Our findings highlight that plasma p-tau181, alone or combined with NfL, contributes to identifying high-risk AD populations.