High NFL Research Articles

Emergence delirium and postoperative delirium associated with high plasma NfL and GFAP: an observational study.

Neuroinflammation and neuronal injury have been reported to be associated with the development of postoperative delirium in both preclinical and clinical settings. This study aimed to investigate the potential correlation between biomarkers of neurofilament light chain and glial fibrillary acidic protein and emergence and postoperative delirium in elderly patients undergoing surgery. Patients who developed emergence delirium (n = 30) and postoperative delirium (n = 32), along with their matched controls, were enrolled after obtaining ethics approval and written informed consent. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit or Confusion Assessment Method scale, and blood samples were collected before and after surgery for plasma neurofilament light chain and glial fibrillary acidic protein measurements using a single-molecule array. The study found that in patients with emergence delirium, the increase in plasma neurofilament light chain protein levels during surgery was significantly higher than in non-delirium patients (P = 0.002). Additionally, in patients with postoperative delirium, both the increase in plasma neurofilament light chain protein levels (P < 0.001) and the increase in plasma glial fibrillary acidic protein levels during surgery (P = 0.008) were significantly higher than in non-delirium patients. Multivariate logistic regression analysis showed that the increase in plasma neurofilament light chain protein was associated with emergence delirium (adjusted OR = 1.872, P = 0.005), and the increase in plasma glial fibrillary acidic protein was associated with postoperative delirium (adjusted OR = 1.419, P = 0.016). Moreover, the American Society of Anesthesiologists Physical Status Classification and surgical duration were also found to be associated with delirium in elderly patients. Our findings suggest that emergence delirium is linked to elevated levels of neurofilament light chain, a biomarker of axonal injury, during surgery. Furthermore, in addition to axonal injury, postoperative delirium was also associated with an increase in glial fibrillary acidic protein, a marker of astrocyte activation.

Subtle Differences in Cognition in 70-Year-Olds with Elevated Cerebrospinal Fluid Neurofilament Light and Neurogranin: A H70 Cross-Sectional Study.

Most research on cerebrospinal fluid (CSF) neurofilament light protein (NfL) as a marker for neurodegeneration and neurogranin (Ng) for synaptic dysfunction has largely focused on clinical cohorts rather than population-based samples. We hypothesized that increased CSF levels of NfL and Ng are associated with subtle cognitive deficits in cognitively unimpaired (CU) older adults. The sample was derived from the Gothenburg H70 Birth Cohort Studies and comprised 258 CU 70-year-olds, with a Clinical Dementia Rating score of zero. All participants underwent extensive cognitive testing. CSF levels of NfL and Ng, as well as amyloid β1-42, total tau, and phosphorylated tau, were measured. Participants with high CSF NfL performed worse in one memory-based test (Immediate recall, p = 0.013) and a language test (FAS, p = 0.016). Individuals with high CSF Ng performed worse on the memory-based test Supra Span (p = 0.035). When stratified according to CSF tau and Aβ42 concentrations, participants with high NfL and increased tau performed worse on a memory test than participants normal tau concentrations (Delayed recall, p = 0.003). In participants with high NfL, those with pathologic Aβ42 concentrations performed worse on the Delayed recall memory (p = 0.044). In the high Ng group, participants with pathological Aβ42 concentrations had lower MMSE scores (p = 0.027). However, in regression analysis we found no linear correlations between CSF NfL or CSF Ng in relation to cognitive tests when controlled for important co-variates. Markers of neurodegeneration and synaptic pathology might be associated with subtle signs of cognitive decline in a population-based sample of 70-year-olds.

Extremely high energy density and long fatigue life of nano-silica/polymethylvinylsiloxane dielectric elastomer generator by interfacial design

Dielectric elastomer generator (DEG) can harvest electrical energy from various movement in nature such as human walking and ocean waves. To achieve high energy harvesting performance of DEG, dielectric elastomer (DE) composite with strong interfacial interaction, and thus high electrical breakdown strength (Eb) and long fatigue life (NFL) at high strain is a key. In this study, nano-silica (SiO2)/polymethylvinylsiloxane (PMVS) DE composite with strong interfacial interaction for DEG with extremely high energy density (w), high power conversion efficiency (PCE) and long NFL was prepared by designing and synthesizing a new polar macromolecule coupling agent (MCA), ester group grafted liquid butadiene rubber using a photoinitiated thiol-ene click reaction. Compared with the common small molecule coupling agent (SCA) modified SiO2 (SCA@SiO2)/PMVS composite, the new MCA modified SiO2 (MCA@SiO2)/PMVS composite shows much stronger interfacial interaction owing to the largely increased co-crosslinking junction and chain entanglement, resulting in the significantly improved elongation at break and Eb at high strain (400%). As a result, MCA@SiO2/PMVS DEG exhibits an up-to-date highest w (92.2 mJ/cm3) and PCE (35.8%) among the previously reported DEG using unprestretched DE film, and its NFL reaches 141000 times, 3.9 times that of SCA@SiO2/PMVS DEG (36000 times). Thus, MCA@SiO2/PMVS DEG shows the highest full-life generating energy density (9710 J/cm3), 4.8 times and 2427 times that of SCA@SiO2/PMVS DEG and commercial VHB DEG, respectively.

Cerebrospinal fluid neurofilament light chain as a potential prognostic biomarker for leptomeningeal metastasis.

The present study aimed to evaluate whether the cerebrospinal fluid (CSF) neurofilament light chain (NfL) is a potential prognostic marker for patients with leptomeningeal metastasis (LM). NfL levels were measured in CSF using a single-molecule array assay. A total of 42 patients with LM who were treated with ventriculo-lumbar perfusion (VLP) chemotherapy and had available stored CSF samples from the lumbar subarachnoid space before VLP chemotherapy were included in the present study, in order to investigate the prognostic value of CSF NfL. The median CSF NfL level in patients with LM was 8.15 ng/ml; 30% of patients who had died at the time of analysis had CSF NfL levels higher than the calculated overall prognostic cut-off value (11 ng/ml). The median overall survival after initiation of VLP chemotherapy was significantly longer in patients with LM and low CSF NfL levels compared with in patients with LM and high CSF NfL levels (P<0.001). The statistical significance remained after adjusting for other known prognostic factors and in a subgroup analysis according to age. In conclusion, CSF NfL could be considered a putative prognostic marker in patients with LM treated with VLP chemotherapy.

Neurofilament light chain in blood as a diagnostic and predictive biomarker for multiple sclerosis: A systematic review and meta-analysis.

BackgroundNeurofilament light chain (NfL) in cerebrospinal fluid (CSF) is a biomarker of multiple sclerosis (MS). However, CSF sampling is invasive and has limited the clinical application. With the development of highly sensitive single-molecule assay, the accurate quantification of the very low NfL levels in blood become feasible. As evidence being accumulated, we performed a meta-analysis to evaluate the diagnostic and predictive value of blood NfL in MS patients.MethodsWe performed literature search on PubMed, EMBASE, Web of Science and Cochrane Library from inception to May 31, 2022. The blood NfL differences between MS vs. controls, MS vs. clinically isolated syndrome (CIS), progressive MS (PMS) vs. relapsing-remitting MS (RRMS), and MS in relapse vs. MS in remission were estimated by standard mean difference (SMD) and corresponding 95% confidence interval (CI). Pooled hazard ratio (HR) and 95%CI were calculated to predict time to reach Expanded Disability Status Scale (EDSS) score≥4.0 and to relapse.ResultsA total of 28 studies comprising 6545 MS patients and 2477 controls were eligible for meta-analysis of diagnosis value, and 5 studies with 4444 patients were synthesized in analysis of predictive value. Blood NfL levels were significantly higher in MS patients vs. age-matched controls (SMD = 0.64, 95%CI 0.44–0.85, P<0.001), vs. non-matched controls (SMD = 0.76, 95%CI 0.56–0.96, P<0.001) and vs. CIS patients (SMD = 0.30, 95%CI 0.18–0.42, P<0.001), in PMS vs. RRMS (SMD = 0.56, 95%CI 0.27–0.85, P<0.001), and in relapsed patients vs. remitted patients (SMD = 0.54, 95%CI 0.16–0.92, P = 0.005). Patients with high blood NfL levels had shorter time to reach EDSS score≥4.0 (HR = 2.36, 95%CI 1.32–4.21, P = 0.004) but similar time to relapse (HR = 1.32, 95%CI 0.90–1.93, P = 0.155) compared to those with low NfL levels.ConclusionAs far as we know, this is the first meta-analysis evaluating the diagnosis and predictive value of blood NfL in MS. The present study indicates blood NfL may be a useful biomarker in diagnosing MS, distinguishing MS subtypes and predicting disease worsening in the future.

Combined Effects of Synaptic and Axonal Integrity on Longitudinal Gray Matter Atrophy in Cognitively Unimpaired Adults.

Synaptic dysfunction and degeneration is a predominant feature of brain aging, and synaptic preservation buffers against Alzheimer disease (AD) protein-related brain atrophy. We tested whether CSF synaptic protein concentrations similarly moderate the effects of axonal injury, indexed by CSF neurofilament light [NfL]), on brain atrophy in clinically normal adults. Clinically normal older adults enrolled in the observational Hillblom Aging Network study at the UCSF Memory and Aging Center completed baseline lumbar puncture and longitudinal brain MRI (mean scan [follow-up] = 2.6 [3.7 years]). CSF was assayed for synaptic proteins (synaptotagmin-1, synaptosomal-associated protein 25 [SNAP-25], neurogranin, growth-associated protein 43 [GAP-43]), axonal injury (NfL), and core AD biomarkers (ptau181/Aβ42 ratio; reflecting AD proteinopathy). Ten bilateral temporoparietal gray matter region of interest (ROIs) shown to be sensitive to clinical AD were summed to generate a composite temporoparietal ROI. Linear mixed-effects models tested statistical moderation of baseline synaptic proteins on baseline NfL-related temporoparietal trajectories, controlling for ptau181/Aβ42 ratios. Forty-six clinically normal older adults (mean age = 70 years; 43% female) were included. Synaptic proteins exhibited small to medium correlations with NfL (r range: 0.10-0.36). Higher baseline NfL, but not ptau181/Aβ42 ratios, predicted steeper temporoparietal atrophy (NfL × time: β = -0.08, p < 0.001; ptau181/Aβ42 × time: β = -0.02, p = 0.31). SNAP-25, neurogranin, and GAP-43 significantly moderated NfL-related atrophy trajectories (-0.07 ≤ β's ≥ -0.06, p's < 0.05) such that NfL was associated with temporoparietal atrophy at high (more abnormal) but not low (more normal) synaptic protein concentrations. At high NfL concentrations, atrophy trajectories were 1.5-4.5 times weaker when synaptic protein concentrations were low (β range: -0.21 to -0.07) than high (β range: -0.33 to -0.30). The association between baseline CSF NfL and longitudinal temporoparietal atrophy is accelerated by synaptic dysfunction and buffered by synaptic integrity. Beyond AD proteins, concurrent examination of in vivo axonal and synaptic biomarkers may improve detection of neural alterations that precede overt structural changes in AD-sensitive brain regions.

263 Neurofilament light chain is a predictor of outcome after aneurysmal subarach- noid haemorrhage

BackgroundThe best predictor of clinical outcome after aneurysmal subarachnoid haemorrhage (aSAH) is the World Federation of Neurological Surgeons (WFNS) score. Yet, this marker of early brain injury only explains 12% of the variance in outcome. Prolonged neurotoxicity via extracellular haemoglobin (Hb) may play a role. Neurofilament light chain (NFL) is released during neuronal damage. We hypothesize that CSF NFL predicts clinical outcome after aSAH and reflects Hb-induced neurotoxicity.MethodsCSF was collected via an external ventricular drain from 44 high-grade aSAH patients over 14 days post-ictus, and via lumbar puncture from 11 non-haemorrhagic, non-inflammatory neurologi- cal control patients. NFL and Hb were measured using enzyme-linked immunosorbent assay and ultra- performance liquid chromatography respectively. Clinical outcome after aSAH was assessed using the modified Rankin Score (mRS).ResultsNFL was higher in aSAH versus control CSF. High CSF NFL and high WFNS independently predicted worse mRS. CSF NFL was a stronger predictor than WFNS. Post-ictus, NFL and Hb CSF concentration gradually increased over two weeks. Maximum CSF NFL was correlated with maximum preceding CSF Hb, but not WFNS.ConclusionThe biomarker NFL is a predictor of clinical outcome after aSAH. NFL concentration likely reflects delayed Hb-induced neurotoxicity rather than early brain injury.pg1p07@soton.ac.uk

Plasma neurofilament light chain protein as a predictor of days in delirium and deep sedation, mortality and length of stay in critically ill patients.

SummaryBackgroundDelirium predicts poor outcomes, however identifying patients with the worst outcomes is challenging. Plasma neurofilament light protein (NfL) is a sensitive indicator of neuronal damage. We undertook an exploratory observational study to determine the association between plasma NfL and delirium in the critically ill.MethodsMoDUS was a randomised placebo-controlled delirium trial of simvastatin done in an UK adult general ICU. We measured NfL levels in plasma samples using a Single molecule array (Simoa) platform. We explored associations between patient's plasma NfL levels and number of delirium days, and clinical outcomes. The control group for baseline NfL were preoperative patients undergoing major surgery.FindingsThe majority of critically ill patients already had a high NfL level on admission. Patients with higher plasma NfL levels at days one and three spent more days in delirium or deep sedation. Patients with zero or one day in delirium or deep sedation had day one mean concentrations of 37.8 pg/ml (SD 32.6) compared with 96.5 pg/ml (SD 106.1)) for patients with two days or more, p-value 0.002 linear mixed effects model.Survivors discharged before 14 days had lower mean plasma NfL concentrations compared to those with longer hospital stays and/or who died within six months. The area under ROC curve for predicting death within six months using day one NfL was 0.81 (0.7,0.9).InterpretationMeasurement of plasma NfL within three days of admission may be useful to identify those patients with worse clinical outcomes, and as an enrichment strategy for future delirium interventional trials in the critically ill.FundingAlzheimer's Society UK, UK Dementia Research Institute.

Relationship Between Plasma Neurofilament Light Chain, Gut Microbiota, and Dementia: A Cross-Sectional Study.

Previous studies have demonstrated associations between gut microbiota, microbial metabolites, and cognitive decline. However, relationships between these factors and neurofilament light chain (NfL; a disease-nonspecific biomarker of neural damage) remain controversial. To evaluate the associations between plasma NfL, gut microbiota, and cognitive function. We performed a cross-sectional sub-analysis of data from our prospective cohort study that was designed to investigate the relationship between gut microbiota and cognitive function. Patients who visited our memory clinic were enrolled and demographics, dementia-related risk factors, cognitive function, brain imaging, gut microbiomes, and microbial metabolites were assessed. We evaluated the relationships between the gut microbiome, microbial metabolites, and plasma NfL. Moreover, the relationships between plasma NfL and cognitive function were assessed using multivariable logistic regression analyses. We analyzed 128 participants (women: 59%, mean age: 74 years). Participants with high (above the median) plasma NfL concentrations tended to be older, women, and hypertensive and have a history of stroke, chronic kidney disease, and dementia. Plasma NfL was also associated with cerebral small vessel disease. However, plasma NfL levels were not significantly correlated with gut microbial metabolites. Multivariable analyses revealed that a higher plasma NfL concentration was independently associated with the presence of dementia (odds ratio: 9.94, 95% confidence interval: 2.75-48.2, p < 0.001). High plasma NfL concentration was independently associated with the presence of dementia as previously reported. However, plasma NfL levels were not significantly correlated with gut microbial metabolites in this preliminary study.

Examination of Neurofilament Light Chain Serum Concentrations, Physical Activity, and Cognitive Decline in Older Adults

Little is known about the association of serum neurofilament light chain (NfL) concentrations and physical activity with the rate of cognitive decline in older adults. To examine the association of physical activity and NfL concentrations with cognitive decline in older adults over time. This cohort study used data from the Chicago Health and Aging Project (CHAP), a population-based cohort study that recruited participants through door-to-door census in 4 Chicago-area communities and collected data between 1993 and 2012 in cycles of 3 years. Participants in CHAP who had 2 or more cognitive function assessments and at least 1 blood sample collected for NfL measurement were selected for inclusion in the current study. Data were analyzed from January to December 2021. Self-reported physical activity (minutes per week) and serum NfL concentration (pg/mL). Associations of baseline physical activity and NfL concentrations with changes in global cognitive function over time as evaluated using the East Boston Memory Test for episodic memory, the Symbol Digit Modalities Test for perceptual speed, and the Mini-Mental State Examination. Mixed-effects regression analyses were conducted to examine associations at baseline and longitudinally. The study sample included 1158 participants (695 [60%] African American; 728 [63%] female), with a mean (SD) age of 77.4 (6.0) years and a mean educational level of 12.6 (3.5) years. Among participants with high NfL concentrations (>25 pg/mL), those who engaged in medium physical activity (<150 minutes per week) had a 12% slower rate of global cognitive decline (SD units, or β, -0.065; 95% CI, -0.099 to -0.032) and participants who engaged in high physical activity (≥150 minutes per week) had a 36% slower rate of decline (β, -0.048; 95% CI, -0.080 to -0.016) than did participants with low physical activity (no reported participation) (β, -0.075; 95% CI, -0.108 to -0.041). For participants with low NfL concentrations (≤25 pg/mL), those who took part in medium physical activity had 43% slower global cognitive decline (β, -0.025; 95% CI, -0.043 to -0.007) and individuals who participated in high physical activity had 30% slower decline (β, -0.031; 95% CI, -0.048 to -0.014) than did those who participated in low physical activity (β, -0.046; 95% CI, -0.066 to -0.025). The findings suggest that physical activity is associated with diminished cognitive decline among older adults with increased serum NfL concentrations. The results support the potential use of blood biomarkers in measuring the benefits of health behaviors, such as physical activity, and early intervention for older adults at risk for cognitive decline.

Interactions Between Weight Loss and Plasma Neurodegenerative Markers for Determining Cognitive Decline Among Community-Dwelling Older Adults.

This study aimed to investigate the interaction between weight loss (WL) and plasma amyloid-β 42/40 (Aβ 42/40), neurofilament light chain (NfL), progranulin, and their association with cognitive decline over time among older adults. This 5-year observational approach included 470 participants from the Multidomain Alzheimer Preventive Trial, mean age 76.8 years (SD = 4.5), 59.4% women. WL was defined as ≥5% decrease over the first year. Biomarkers were measured at 12 months. Cognitive function was assessed yearly from 12 months onward by Mini-Mental State Examination (MMSE); Clinical Dementia Rating sum of boxes (CDR-SB); a composite score based on Category Naming Test; Digit Symbol Substitution Test; 10 MMSE orientation items (MMSEO) and free and total recall of the Free and Cued Selective Reminding test; and these tests individually. Twenty-seven participants (5.7%) presented WL. In adjusted analyses, combined WL + lower Aβ 42/40 (≤0.103, lowest quartile) was related with more pronounced 4-year cognitive decline according to CDR-SB (p < .0001) and MMSEO (p = .021), compared with non-WL + higher Aβ 42/40. WL + higher NfL (>94.55 pg/mL, highest quartile) or progranulin (>38.4 ng/mL, 3 higher quartiles) were related with higher cognitive decline according to CDR-SB, MMSE, MMSEO, and composite score (all p < .03), compared with non-WL + lower NfL or higher progranulin. Regrouping progranulin quartiles (Q1-Q3 vs Q4) revealed higher cognitive decline among the WL + lower progranulin group compared with non-WL + lower progranulin. In conclusion, 1-year WL was associated with subsequent higher 4-year cognitive decline among older adults presenting low Aβ 42/40 or high NfL. Future studies combining plasma biomarker assessments and body weight surveillance may be useful for identifying people at risk of cognitive impairment. Clinical trial number: NCT00672685.

Cerebrospinal fluid neurofilament light chain levels in CLN2 disease patients treated with enzyme replacement therapy normalise after two years on treatment

Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is caused by a deficiency of tripeptidyl-peptidase-1. In 2017, the first CLN2 enzyme replacement therapy (ERT) cerliponase alfa (Brineura) was approved by the FDA and EMA. The CLN2 disease clinical rating scale (CLN2 CRS) was developed to monitor loss of motor function, language and vision as well as frequency of generalised tonic clonic seizures. Using CLN2 CRS in an open label clinical trial it was shown that Brineura slowed down the progression of CLN2 symptoms. Neurofilament light chain (NfL) is a protein highly expressed in myelinated axons. An increase of cerebrospinal fluid (CSF) and blood NfL is found in a variety of neuroinflammatory, neurodegenerative, traumatic, and cerebrovascular diseases. We analysed CSF NfL in CLN2 patients treated with Brineura to establish whether it can be used as a possible biomarker of response to therapy. Newly diagnosed patients had CSF samples collected and analysed at first treatment dose and up to 12 weeks post-treatment to look at acute changes. Patients on a compassionate use programme who were already receiving ERT for approximately 1yr had CSF samples collected and NfL analysed over the following 1.3 years (2.3 years post-initiation of ERT) to look at long-term changes. All newly diagnosed patients we investigated with classical late infantile phenotype had high NfL levels >2000 pg/ml at start of treatment. No significant change was observed in NfL up to 12 weeks post-treatment. After one year of ERT, two out of six patients still had high NfL levels, but all patients showed a continued decrease, and all had low NfL levels after two years on ERT. NfL levels appear to correspond and predict improved clinical status of patients on ERT and could be useful as a biomarker to monitor neurodegeneration and verify disease modification in CLN2 patients on ERT.

CSF Neurofilament Light Chain Concentrations Predict Outcome in Bacterial Meningitis.

Background and ObjectivesNeurofilament light chain (NfL) is a biomarker for neuroaxonal damage and has been found to be elevated proportionally to the degree of neuronal damage in neurologic diseases. The objective of this study was to determine the prognostic accuracy of NfL concentrations on unfavorable outcome in adults with community-acquired bacterial meningitis.MethodsWe measured NfL concentration CSF samples from a prospective cohort study of adults with community-acquired bacterial meningitis in The Netherlands and determined associations between NfL CSF concentrations, clinical characteristics, and outcome in multivariate analyses. We identified independent predictors of an unfavorable outcome (Glasgow Outcome Scale scores 1–4) by logistic regression.ResultsCSF NfL concentrations were evaluated in 429 episodes of 425 patients with community-acquired bacterial meningitis. The median age of 429 episodes was 62 years (interquartile range, 50–69 years). Of note, 290 of 422 (68%) episodes presented with an altered mental status (Glasgow Coma Scale score < 14). Most common causative pathogens were Streptococcus pneumoniae (73%), Neisseria meningitidis (7%), and Listeria monocytogenes (5%). The overall case fatality rate was 62 of 429 (15%), and unfavorable outcome occurred in 57 (37%) of 429 episodes. In multivariate analysis, predictors of unfavorable outcome were older age (OR 1.03, 95% CI 1.01–1.05), cranial nerve palsy (OR 4, 95% CI 1.6–10.3), high serum C-reactive protein concentration (OR 1.3, 95% CI 1.01–1.05), and high CSF NfL concentration (OR 1.5, 95% CI 1.07–2.00). CSF NfL concentrations were higher in patients presenting with focal cerebral deficits (717 pg/mL [416–1,401] vs 412 pg/mL [278–731]; p < 0.001). The area under the curve (AUC) for predicting unfavorable outcome in bacterial meningitis of CSF NfL concentration was 0.69 (95% CI, 0.64–0.74).DiscussionCSF NfL concentration is independently associated with unfavorable outcome in adults with community-acquired bacterial meningitis, suggesting that CSF NfL concentration may be a useful biomarker for prognostic assessment in bacterial meningitis.Classification of EvidenceCan the level of NfL in CSF (the index test) predict unfavorable outcome in patients with bacterial meningitis, in a cohort of bacterial meningitis patients with a favorable and unfavorable outcome? This study provides Class II evidence that NfL level in CSF is a moderate predictor, with the AUC for predicting unfavorable outcome in bacterial meningitis being 0.69 (95% CI, 0.64–0.74).

Clinical value of CSF tau, p‐tau181, neurogranin and neurofilaments in familial frontotemporal lobar degeneration

AbstractBackgroundBlood neurofilament light chain (NfL) is a robust predictor of phenoconversion in familial frontotemporal lobar degeneration (fFTLD). The comparative value of CSF NfL and other CSF markers of degeneration in fFTLD remains unexplored.MethodFLTD‐causing mutation carriers were recruited through ALLFTD (n = 113, 56.6% female, mean age 48.1 ± 13 years; 29 C9orf72, 16 GRN, 34 MAPT, 34 mutation non‐carriers) and prospectively evaluated for 3 years. Baseline CSF was analyzed for NfL, phosphorylated neurofilament heavy chain (p‐NfH), tau, phosphorylated tau181 (p‐tau) and neurogranin using fit‐for‐purpose immunoassays. Mixed effect linear models, with random slopes, corrected for age, sex, genotype and total intracranial volume related CSF biomarkers to longitudinal clinical variables.ResultNfL (β = 0.64, p &lt; 0.001), p‐NfH (β = 0.68, p &lt; 0.001) and tau (β = 0.46, p &lt; 0.001) correlated with age. There were no differences in biomarker concentrations by phenotype or severity, except for higher NfL and p‐NfH in full phenotype, compared to prodromal disease and asymptomatic carriers. Low neurogranin (β = ‐0.39, p &lt; 0.001), low p‐tau (β = ‐0.33, p &lt; 0.001) and high NfL (β = 0.42, p &lt; 0.001) correlated with worse baseline disease severity measured by the CDR® Dementia Staging Instrument plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center FTLD module sum of boxes (CDR®+NACC‐FTLDsb), and with other measures of global cognition, instrumental and daily function, and frontal and temporal brain volumes. Regardless of genotype, the predicted annualized rate of CDR®+NACC‐FTLDsb score worsenings per higher baseline CSF biomarker Log pg/mL were tau: 3.0 ± 0.2, NfL: 2.8 ± 0.2 and p‐NfH: 2.8 ± 0.2. High tau, NfL and p‐NfH also predicted worsening in other measures of global cognition and instrumental and daily function. Neurogranin and p‐tau did not predict clinical decline.ConclusionCSF tau, p‐tau, neurogranin, NfL and p‐NfH reflect important aspects of disease severity in fFTLD. In contrast to Alzheimer’s disease, low p‐tau and neurogranin are inversely related to clinical severity, which suggests a distinctive pathophysiological process and has implications for therapeutic development. CSF NfL, p‐NfH and tau have strong prognostic value in fFTLD.

Prodromal frontotemporal dementia: clinical features and predictors of progression

BackgroundThe prodromal phase of frontotemporal dementia (FTD) is still not well characterized, and conversion rates to dementia and predictors of progression at 1-year follow-up are currently unknown.MethodsIn this retrospective study, disease severity was assessed using the global CDR plus NACC FTLD. Prodromal FTD was defined to reflect mild cognitive or behavioural impairment with relatively preserved functional independence (global CDR plus NACC = 0.5) as well as mild, moderate and severe dementia (classified as global CDR plus NACC = 1, 2, 3, respectively). Disease progression at 1-year follow-up and serum NfL measurements were acquired in a subgroup of patients.ResultsOf 563 participants, 138 were classified as prodromal FTD, 130 as mild, 175 as moderate and 120 as severe FTD. In the prodromal and mild phases, we observed an early increase in serum NfL levels followed by behavioural disturbances and deficits in executive functions. Negative symptoms, such as apathy, inflexibility and loss of insight, predominated in the prodromal phase. Serum NfL levels were significantly increased in the prodromal phase compared with healthy controls (average difference 14.5, 95% CI 2.9 to 26.1 pg/mL), but lower than in patients with mild FTD (average difference -15.5, 95% CI -28.4 to -2.7 pg/mL). At 1-year follow-up, 51.2% of patients in the prodromal phase had converted to dementia. Serum NfL measurements at baseline were the strongest predictors of disease progression at 1-year follow-up (OR 1.07, 95% CI 1.03 to 1.11, p < 0.001).ConclusionsProdromal FTD is a mutable stage with high rate of progression to fully symptomatic disease at 1-year follow-up. High serum NfL levels may support prodromal FTD diagnosis and represent a helpful marker to assess disease progression.

Role of Blood Neurofilaments in the Prognosis of Amyotrophic Lateral Sclerosis: A Meta-Analysis.

Background: Neurofilaments in cerebrospinal fluid (CSF) and in blood are considered promising biomarkers of amyotrophic lateral sclerosis (ALS) because their levels can be significantly increased in patients with ALS. However, the roles of neurofilaments, especially blood neurofilaments, in the prognosis of ALS are inconsistent. We performed a meta-analysis to explore the prognostic roles of blood neurofilaments in ALS patients.Methods: We searched all relevant studies on the relationship between blood neurofilament levels and the prognosis of ALS patients in PubMed, Embase, Scopus, and Web of Science before February 2, 2021. The quality of the included articles was assessed using the Quality in Prognosis Studies (QUIPS) scale, and R (version 4.02) was used for statistical analysis.Results: Fourteen articles were selected, covering 1,619 ALS patients. The results showed that higher blood neurofilament light chain (NfL) levels in ALS patients were associated with a higher risk of death [medium vs. low NfL level: HR = 2.43, 95% CI (1.34–4.39), p < 0.01; high vs. low NfL level: HR = 4.51, 95% CI (2.45–8.32), p < 0.01]. There was a positive correlation between blood phosphorylated neurofilament heavy chain (pNfH) levels and risk of death in ALS patients [HR = 1.87, 95% CI (1.35–2.59), p < 0.01]. The levels of NfL and pNfH in blood positively correlated with disease progression rate (DPR) of ALS patients [NfL: summary r = 0.53, 95% CI (0.45–0.60), p < 0.01; pNfH: summary r = 0.51, 95% CI (0.24–0.71), p < 0.01].Conclusion: The blood neurofilament levels can predict the prognosis of ALS patients; specifically, higher levels of blood neurofilaments are associated with a greater risk of death.

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency

Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03). In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible. ClinicalTrials.gov Identifier: NCT02149160.

Neurofilament Light Chain as a Biomarker for Cognitive Decline in Parkinson Disease

Neurofilament light chain protein (NfL) is a promising biomarker of neurodegeneration. To determine whether plasma and CSF NfL (1) associate with motor or cognitive status in Parkinson's disease (PD) and (2) predict future motor or cognitive decline in PD. Six hundred and fifteen participants with neurodegenerative diseases, including 152 PD and 200 healthy control participants, provided a plasma and/or cerebrospinal fluid (CSF) NfL sample. Diagnostic groups were compared using the Kruskal-Wallis rank test. Within PD, cross-sectional associations between NfL and Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) and Mattis Dementia Rating Scale (DRS-2) scores were assessed by linear regression; longitudinal analyses were performed using linear mixed-effects models and Cox regression. Plasma and CSF NfL levels correlated substantially (Spearman r=0.64, P < 0.001); NfL was highest in neurocognitive disorders. PD participants with high plasma NfL were more likely to develop incident cognitive impairment (HR 5.34, P=0.005). Plasma NfL is a useful prognostic biomarker for PD, predicting clinical conversion to mild cognitive impairment or dementia. © 2021 International Parkinson and Movement Disorder Society.

Serum neurofilament light chain or glial fibrillary acidic protein in the diagnosis and prognosis of brain metastases.

Brain metastases (BM) remains the most cumbersome disease burden in patients with lung cancer. This study aimed to investigate whether serum brain injury biomarkers can indicate BM, to further establish related diagnostic models, or to predict prognosis of BM. This was a prospective study of patients diagnosed with lung cancer with BM (BM group), with lung cancer without BM (NBM group), and healthy participants (control group). Serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were detected at baseline. We identified and integrated the risk factors of BM to establish diagnostic models. A total of 158 patients were included (n = 37, 57, and 64 in the BM, NBM, and control groups, respectively). Serum biomarker levels were significantly higher in the NBM group than in the control group. Higher serum NfL and GFAP concentrations were associated with BM (odds ratios, 3.06 and 1.79, respectively). NfL (area under curve [AUC] = 0.77, p < 0.001) and GFAP (AUC = 0.64, p = 0.02) had diagnostic value for BM. The final diagnostic model included NfL level, age, Karnofsky Performance Status. The model had an AUC value of 0.83 (95% confidence interval [CI] 0.75-0.92). High NfL concentration was correlated with poor overall survival of patients with BM (hazard ratio, 3.31; 95% CI 1.22-9.04; p = 0.019). Serum NfL and GFAP could be potential diagnostic biomarkers for BM in patients with lung cancer. We established a model that can provide individual diagnoses of BM. Higher NfL level may be associated with poor prognosis of patients with BM.

Neurofilament light chain as novel blood biomarker of disturbed neuroaxonal integrity in patients with ketamine dependence

Objectives Chronic and heavy ketamine use has been associated with persistent neurocognitive impairment and structural brain abnormalities. Blood levels of neurofilament light chain (NFL) was recently proposed as a measure of axonal integrity in several neuropsychiatric disorders. We aimed to characterise the axonal neurotoxicity of chronic ketamine use and its relationship to relevant clinical outcomes. Methods We enrolled 65 treatment-seeking ketamine-dependent patients (55 males and 10 females) and 60 healthy controls (51 males and 9 females). Blood NFL levels measured by single molecule array (SiMoA) immunoassay. We compared NFL levels between groups and used regression analyses to identify clinical variables related to NFL levels. Results Ketamine-dependent patients had significantly higher NFL levels compared to controls (p < 0.001). A multivariate regression showed that age (p < 0.05) and lifetime history of major depressive disorder (MDD) (p < 0.01) predicted high NFL blood levels in patients. Subsequent group comparisons showed that specifically ketamine-dependent patients with a lifetime history of MDD had significantly increased NFL levels than those without (p < 0.05). Conclusions These results suggest substantial neuroaxonal alterations following chronic and heavy ketamine use. The pronounced increase of NFL levels in the MDD subgroup warrants further investigation of a potential neuroaxonal vulnerability of depressed patients to ketamine.