Cerebrospinal Fluid Neurofilament Light Research Articles

Neurofilament light chain levels in cerebrospinal fluid as a sensitive biomarker for cerebral adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) has a poor prognosis when it progresses to the cerebral form (CALD). The aim of this study is to investigate whether cerebrospinal fluid (CSF) neurofilament light chain (cNfL) is a sensitive biomarker for detecting CALD and assessing response to hematopoietic stem cell transplantation (HSCT). We conducted a cross-sectional study of 41 male ALD patients. The cNfL levels in patients with the cerebral form of ALD (CALD) or the cerebello-brainstem form of ALD were compared with those in patients with adrenomyeloneuropathy (AMN). The correlation between cNfL levels and MRI-based Loes severity scores was investigated. A longitudinal analysis was performed on patients who underwent multiple CSF examinations. The cNfL levels in 22 patients with CALD were significantly higher than those in 14 patients with AMN (median, 5545 vs. 1490 pg/mL; p < 0.001). The cutoff cNfL level of 1930 pg/mL showed good sensitivity (95.5%) and specificity (85.7%) for distinguishing CALD from AMN. The cNfL levels were positively correlated with Loes scores (p < 0.001). The cNfL levels in three AMN patients who later converted to CALD increased above the cutoff level during the conversion period, while the cNfL levels in four patients who remained in AMN were consistently below the cutoff. In 10 ALD patients who underwent HSCT, their cNfL levels decreased 3-24 months after HSCT. Two patients whose cNfL increased after HSCT showed deterioration in cognitive functions. The cNfL level is useful for evaluating the disease activities of ALD and the response to HSCT.

CSF Aβ42 and tau biomarkers in cognitively unimpaired Aβ- middle-aged and older APOE ε4 carriers

This study aimed to determine the relationship between the apolipoprotein E (APOE) ε4 allele and cerebrospinal fluid (CSF) and neuroimaging biomarkers of Alzheimer’s disease, and cognition in cognitively unimpaired (CU) middle-aged adults (n = 82; Mage = 58.2), and in Aβ- CU older adults (n = 71; Mage = 71.8). Aβ- CU middle-aged ε4 carriers showed lower CSF Aβ42 levels, higher levels of CSF total tau (t-tau) and neurofilament light (NfL), and poorer cognitive performance compared to noncarriers (Cohen’s d: 0.30–0.56). In Aβ- CU older adults, ε4 carriers also had lower CSF Aβ42 levels and higher levels of CSF t-tau and p-tau181, compared to noncarriers (Cohen’s d: 0.65–0.74). In both Aβ- middle-aged and older adults, hippocampal and total brain volume were equivalent between ε4 carriers and noncarriers. In Aβ- CU middle-aged adults, APOE ε4 is associated with decreased levels of Aβ, increased tau and NfL, and poorer cognition. Similar relationships were observed in Aβ- CU older adults. These results have implications for understanding clinicopathological relationships between APOE ε4 and the emergence of cognitive and biomarker abnormalities in Aβ- adults.

Cerebrospinal fluid neurofilament light predicts longitudinal diagnostic change in patients with psychiatric and neurodegenerative disorders.

People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other. Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.

Cerebrospinal Fluid Neurofilament Light as a Marker of Neuro-axonal Injury in Normal Pressure Hydrocephalus (P10-6.001)

<h3>Objective:</h3> To compare Cerebrospinal fluid (CSF) Neurofilament-light chain (NfL) and NfL/amyloid beta₄₂ (Abeta42) ratio levels in normal pressure hydrocephalus (NPH) patients with healthy controls (HC), Alzheimer’s disease (AD), and Frontotemporal lobar degeneration (FTLD). <h3>Background:</h3> Levels of CSF NfL have been shown to be a marker of neuro-axonal injury and are elevated in neurodegenerative disease. One putative etiology of NPH involves axonal injury; however, low CSF Abeta42 has been reported in NPH. To control for the higher volume of CSF in NPH, the NfL/Abeta42 ratio was used. <h3>Design/Methods:</h3> 120 patients with CSF analysis: (a) 46 NPH: ventriculomegaly on MRI or CT, negative AD biomarkers, clinical symptoms of NPH, improvement in gait after tap test; (b) 39 FTLD: 5 behavioural-variant frontotemporal dementia, 14 corticobasal syndrome, 4 frontotemporal dementia with motor neuron disease, 12 progressive supranuclear palsy, 2 semantic-variant primary progressive aphasia (PPA), and 2 non-fluent PPA; (c) 29 AD; and (d) 6 HC. Levels of CSF NfL were measured using single molecule array (Simoa) technology while Abeta42 was measured using a sandwich ELISA method (Innotest). All statistical analyses were corrected for multiple comparisons and age. <h3>Results:</h3> Log transformed NfL levels in the NPH group were significantly higher than HC (p &lt; 0.05), but lower than FTLD and AD group (p &lt;0 .001). Log transformed CSF NfL/Abeta42 ratio was significantly higher in the NPH group compared to HC (p&lt;0.05); but no significant difference with FTLD and AD groups. <h3>Conclusions:</h3> Intermediate CSF NfL levels in NPH patients suggest that there is some neuro-axonal injury present - although less than in FTLD and AD. Further investigations are warranted to determine whether the NfL normalizes after shunting or the neuroaxonal injury is irreversible. NfL in NPH may help elucidate the pathophysiology of the disease. <b>Disclosure:</b> Ms. Davenport has nothing to disclose. Dr. Taghdiri has nothing to disclose. Anna Vasilevskaya has nothing to disclose. Ms. Anastassiadis has received research support from Fonds de Recherche du Québec - Santé (FRQS). Dr. Thapa has nothing to disclose. Dr. Dimal has nothing to disclose. Namita Multani, 14039 has nothing to disclose. Dr. Fasano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbott. Dr. Fasano has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbvie. Dr. Fasano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ipsen. Dr. Fasano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Medtronic. Dr. Fasano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Boston Scientific. Dr. Fasano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbott. Dr. Fasano has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medtronic. Dr. Fasano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sunovion. Dr. Fasano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ceregate. The institution of Dr. Fasano has received research support from Boston Scientific. The institution of Dr. Fasano has received research support from Medtronic. The institution of Dr. Fasano has received research support from Abbvie. Dr. Fasano has received publishing royalties from a publication relating to health care. Dr. Tang-Wai has nothing to disclose. Dr. Tartaglia has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. The institution of Dr. Tartaglia has received research support from NIH. The institution of Dr. Tartaglia has received research support from University of Toronto.

NfL as a Predictor of GdE Lesions in Patients With Relapsing Multiple Sclerosis Treated With Ozanimod in the Phase 2 RADIANCE Trial (P1-3.012)

NfL as a Predictor of GdE Lesions in Patients With Relapsing Multiple Sclerosis Treated With Ozanimod in the Phase 2 RADIANCE Trial (P1-3.012)

Comparison of neurofilament light and heavy chain in spinal muscular atrophy and amyotrophic lateral sclerosis: A pilot study.

Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) were two major motor neuron diseases with similar symptoms and poor outcomes. This study aimed to identify potential biomarkers in disease monitoring and differential diagnosis of adult SMA patients with sporadic ALS patients. This was a pilot study with ten adult SMA patients and ten ALS patients consecutively enrolled during hospitalization. Serum and cerebrospinal fluid (CSF) samples were collected for assessment of neurofilament light (NFL) and phosphorylated neurofilament heavy chain (pNFH). Serum creatine kinase (CK) and creatinine (Cr) were also compared between groups. The receiver operating characteristic (ROC) curves were used to identify differentiated values among ALS and SMA patients. Serum Cr, CSF NFL, and CSF pNFH levels of ALS patients were significantly higher than those of the adult SMA patients (p<.01). Serum CK and Cr were strongly correlated with baseline ALSFRS-R scores in SMA patients (p<.001). The ROC curves revealed an area under the curve (AUC) of 0.94 in serum Cr with a cut-off value of 44.5μmol/L (Sensitivity 90%, Specificity 90%). AUC from the ROC curve of CSF NFL and CSF pNFH were 1.0 and 0.84, with cut-off values of 1275 pg/mL and 0.395ng/mL, respectively (Sensitivity and Specificity of 100% and 100% in CSF NFL; Sensitivity and Specificity of 90% and 80% in CSF pNFH). CSF NFL and pNFH might be useful biomarkers for differential diagnosis of adult SMA and ALS.

Identification of plasma metabolites associated with modifiable risk factors and endophenotypes reflecting Alzheimer's disease pathology.

Modifiable factors can influence the risk for Alzheimer's disease (AD) and serve as targets for intervention; however, the biological mechanisms linking these factors to AD are unknown. This study aims to identify plasma metabolites associated with modifiable factors for AD, including MIND diet, physical activity, smoking, and caffeine intake, and test their association with AD endophenotypes to identify their potential roles in pathophysiological mechanisms. The association between each of the 757 plasma metabolites and four modifiable factors was tested in the wisconsin registry for Alzheimer's prevention cohort of initially cognitively unimpaired, asymptomatic middle-aged adults. After Bonferroni correction, the significant plasma metabolites were tested for association with each of the AD endophenotypes, including twelve cerebrospinal fluid (CSF) biomarkers, reflecting key pathophysiologiesfor AD, and four cognitive composite scores. Finally, causal mediation analyses were conducted to evaluate possible mediation effects. Analyses were performed using linear mixed-effects regression. A total of 27, 3, 23, and 24 metabolites were associated with MIND diet, physical activity, smoking, and caffeine intake, respectively. Potential mediation effects include beta-cryptoxanthin in the association between MIND diet and preclinical Alzheimer cognitive composite score, hippurate between MIND diet and immediate learning, glutamate between physical activity and CSF neurofilament light, and beta-cryptoxanthin between smoking and immediate learning. Our study identified several plasma metabolites that are associated with modifiable factors. These metabolites can be employed as biomarkers for tracking these factors, and they provide a potential biological pathway of how modifiable factors influence the human body and AD risk.

Cerebrospinal fluid biomarkers in SARS-CoV-2 patients with acute neurological syndromes.

Mechanisms underlying acute brain injury in SARS-CoV-2 patients remain poorly understood. A better characterization of such mechanisms remains essential to preventing long-term neurological sequelae. Our present aim was to study a panel of biomarkers of neuroinflammation and neurodegeneration in the cerebrospinal fluid (CSF) of NeuroCOVID patients. We retrospectively collected clinical and CSF biomarkers data from 24 NeuroCOVID adults seen at the University Hospital of Guadeloupe between March and June 2021. Among 24 NeuroCOVID patients, 71% had encephalopathy and 29% meningoencephalitis. A number of these patients also experienced de novo movement disorder (33%) or stroke (21%). The CSF analysis revealed intrathecal immunoglobulin synthesis in 54% of NeuroCOVID patients (two with a type 2 pattern and 11 with a type 3) and elevated neopterin levels in 75% of them (median 9.1nM, IQR 5.6-22.1). CSF neurofilament light chain (NfL) was also increased compared to a control group of non-COVID-19 patients with psychiatric illnesses (2905ng/L, IQR 1428-7124 versus 1222ng/L, IQR 1049-1566). Total-tau was elevated in the CSF of 24% of patients, whereas protein 14-3-3, generally undetectable, reached intermediate levels in two patients. Finally, CSF Aß1-42 was reduced in 52.4% of patients (median 536ng/L, IQR 432-904) with no change in the Aß1-42/Aß1-40 ratio (0.082, IQR 0.060-0.096). We showed an elevation of CSF biomarkers of neuroinflammation in NeuroCOVID patients and a rise of CSF NfL, evocative of neuronal damage. However, longitudinal studies are needed to determine whether NeuroCOVID could evolve into a chronic neurodegenerative condition.

Pre-analytical long-term stability of neopterin and neurofilament light in stored cerebrospinal fluid samples.

The aim of this study was to evaluate the impact of long-term sample storage on the concentrations of neopterin and neurofilament light (Nfl) in cerebrospinal fluid (CSF) samples. These are useful markers of neuroinflammation andneuronal damage and have been applied as biomarkers for several neurological diseases. However, different pre-analytical variables have potential to influence results. Twenty-one CSF samples donated by patients with HTLV-1-associated myelopathy (HAM) and stored for up to 11years at-80°C were retested after three-years for neopterin (n=10) and Nfl (n=11) by ELISA. There was a strong correlation between the paired results (r>0.98, p<0.0001). Neopterin concentrations (nmol/L) ranged from 12.4 to 64 initially and from 11.5 to 64.4 when retested, with means (SD) of 30 (18.4) 1st test and 33 (19.1) 2nd test. Nfl concentrations (pg/mL) ranged from 79.9 to 3,733 initially and from 86.3 to 3,332, when retested with means (SD) of 1,138 (1,272) 1st test and 1,009 (1,114) at re-test. Storing CSF samples at-80°C appears not to impact the quantification of neopterin and Nfl allowing confidence in the reporting of archived samples.

Fluid Biomarkers of Central Nervous System (CNS) Involvement in Myotonic Dystrophy Type 1 (DM1).

Myotonic dystrophy type 1 (DM1), commonly known as Steinert's disease (OMIM #160900), is the most common muscular dystrophy among adults, caused by an unstable expansion of a CTG trinucleotide repeat in the 3' untranslated region (UTR) of DMPK. Besides skeletal muscle, central nervous system (CNS) involvement is one of the core manifestations of DM1, whose relevant cognitive, behavioral, and affective symptoms deeply affect quality of life of DM1 patients, and that, together with muscle and heart, may profoundly influence the global disease burden and overall prognosis. Therefore, CNS should be also included among the main targets for future therapeutic developments in DM1, and, in this regard, identifying a cost-effective, easily accessible, and sensitive diagnostic and monitoring biomarker of CNS involvement in DM1 represents a relevant issue to be addressed. In this mini review, we will discuss all the papers so far published exploring the usefulness of both cerebrospinal fluid (CSF) and blood-based biomarkers of CNS involvement in DM1. Globally, the results of these studies are quite consistent on the value of CSF and blood Neurofilament Light Chain (NfL) as a biomarker of CNS involvement, with less robust results regarding levels of tau protein or amyloid-beta.

Neurofilament light level correlates with brain atrophy, and cognitive and motor performance.

The usefulness of neurofilament light (NfL) as a biomarker for small vessel disease has not been established. We examined the relationship between NfL, neuroimaging changes, and clinical findings in subjects with varying degrees of white matter hyperintensity (WMH). A subgroup of participants (n = 35) in the Helsinki Small Vessel Disease Study underwent an analysis of NfL in cerebrospinal fluid (CSF) as well as brain magnetic resonance imaging (MRI) and neuropsychological and motor performance assessments. WMH and structural brain volumes were obtained with automatic segmentation. CSF NfL did not correlate significantly with total WMH volume (r = 0.278, p = 0.105). However, strong correlations were observed between CSF NfL and volumes of cerebral grey matter (r = -0.569, p < 0.001), cerebral cortex (r = -0.563, p < 0.001), and hippocampi (r = -0.492, p = 0.003). CSF NfL also correlated with composite measures of global cognition (r = -0.403, p = 0.016), executive functions (r = -0.402, p = 0.017), memory (r = -0.463, p = 0.005), and processing speed (r = -0.386, p = 0.022). Regarding motor performance, CSF NfL was correlated with Timed Up and Go (TUG) test (r = 0.531, p = 0.001), and gait speed (r = -0.450, p = 0.007), but not with single-leg stance. After adjusting for age, associations with volumes in MRI, functional mobility (TUG), and gait speed remained significant, whereas associations with cognitive performance attenuated below the significance level despite medium to large effect sizes. NfL was strongly related to global gray matter and hippocampal atrophy, but not to WMH severity. NfL was also associated with motor performance. Our results suggest that NfL is independently associated with brain atrophy and functional mobility, but is not a reliable marker for cerebral small vessel disease.

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.

Disease activity 4.5 years after starting cladribine: experience in 264 patients with multiple sclerosis.

Cladribine is an effective immunotherapy for people with multiple sclerosis (pwMS). Whilst most pwMS do not require re-treatment following standard dosing (two treatment courses), disease activity re-emerges in others. The characteristics of pwMS developing re-emerging disease activity remain incompletely understood. To explore whether clinical and/or paraclinical baseline characteristics, including the degree of lymphocyte reduction, drug dose and lesions on magnetic resonance imaging (MRI) are associated with re-emerging disease activity. Service evaluation in pwMS undergoing subcutaneous cladribine (SClad) treatment. Demographics, clinical, laboratory and MRI data of pwMS receiving two courses of SClad were extracted from health records. To assess associations of predictor variables with re-emerging disease activity, a series of Cox proportional hazards models was fitted (one for each predictor variable). Of n = 264 pwMS 236 received two courses of SClad and were included in the analysis. Median follow-up was 4.5 years (3.9, 5.3) from the first, and 3.5 years (2.9, 4.3) from the last SClad administration. Re-emerging disease activity occurred in 57/236 pwMS (24%); 22/236 received further cladribine doses (SClad or cladribine tablets) at 36.7 months [median; interquartile range (IQR): 31.7, 42.1], and 22/236 other immunotherapies 18.9 months (13.0, 30.2) after their second course of SClad, respectively. Eligibility was based on MRI activity in 29, relapse in 5, both in 13, elevated cerebrospinal fluid neurofilament light chain level in 3, deterioration unrelated to relapse in 4 and other in 3. Only 36/57 of those eligible for additional immunotherapy had received a reduced dose of SClad for their second treatment course. Association was detected between re-emerging disease activity and (i) high baseline MRI activity and (ii) low second dose of SClad. Re-emerging disease activity was associated with baseline MRI activity and low dose second course of SClad.

Demographic and disease-related factors impact on cerebrospinal fluid neurofilament light chain levels in multiple sclerosis.

Neurofilament light (NfL) levels reflect inflammatory disease activity in multiple sclerosis (MS), but it is less clear if NfL also can serve as a biomarker for MS progression in treated patients without relapses and focal lesion accrual. In addition, it has not been well established if clinically effective treatment re-establishes an age and sex pattern for cerebrospinal fluid NfL (cNfL) as seen in controls, and to what degree levels are affected by disability level and magnetic resonance imaging (MRI) atrophy metrics. We included subjects for whom cNfL levels had been determined as per clinical routine or in clinical research, classified as healthy controls (HCs, n = 89), MS-free disease controls (DCs, n = 251), untreated MS patients (uMS; n = 296), relapse-free treated MS patients (tMS; n = 78), and ProTEct-MS clinical trial participants (pMS; n = 41). Using linear regression, we found a positive association between cNfL and age, as well as lower concentrations among women, in all groups, except for uMS patients. In contrast, disability level in the entire MS cohort, or T1 and T2 lesion volumes, brain parenchymal fraction, thalamic fraction, and cortical thickness in the pMS trial cohort, did not correlate with cNfL concentrations. Furthermore, the cNfL levels in tMS and pMS groups did not differ. In participants with MS lacking signs of inflammatory disease activity, disease modulatory therapy reinstates an age and sex cNfL pattern similar to that of control subjects. No significant association was found between cNfL levels and clinical worsening, disability level, or MRI metrics.

Plasma and cerebrospinal fluid neurofilament light concentrations reflect neuronal damage in systemic lupus Erythematosus

Neuronal damage in systemic lupus erythematosus (SLE) is common, but the extent and mechanisms are unclear. Neurofilament light (NfL) concentrations rise in plasma and cerebrospinal fluid (CSF) during neuronal damage in various neurological disorders. In this cross-sectional study, plasma and CSF concentrations of NfL were explored as a marker of neuronal damage in SLE. Seventy-two consecutive SLE out-patients and 26 healthy controls, all female, aged < 55 years, underwent magnetic resonance imaging (MRI) and neurocognitive testing. NfL concentrations in plasma from all individuals and in CSF from 32 patients were measured with single-molecule array technology. Patients were assessed by a rheumatologist and neurologist to define neuropsychiatric involvement (NPSLE) according to three attribution models: SLICC A, SLICC B and ACR. Plasma and CSF NfL concentrations correlated strongly (r = 0.72, p < 0.001). Both NPSLE and non-NPSLE patients in all attribution models had higher plasma NfL concentrations compared with healthy controls (log-NfL, pg/ml, mean (SD); healthy controls (0.71 (0.17)); SLICC A model: NPSLE (0.87 (0.13), p = 0.003), non-NPSLE (0.83 (0.18), p = 0.005); SLICC B model: NPSLE (0.87 (0.14), p = 0.001), non-NPSLE (0.83 (0.18), p = 0.008); ACR model: NPSLE (0.86 (0.16), p < 0.001), non-NPSLE (0.81 (0.17), p = 0.044)). Plasma and CSF NfL concentrations did not differ between NPSLE and non-NPSLE patients. Higher plasma NfL concentrations correlated with larger CSF volumes on MRI (r = 0.34, p = 0.005), and was associated with poorer cognitive performance in the domains of simple attention, psychomotor speed and verbal memory. SLICC/ACR-Damage Index ≥1 was independently associated with higher plasma NfL concentrations (β = 0.074, p = 0.038). Higher plasma creatinine concentrations, anti-dsDNA-positivity, low complement C3 levels, or a history of renal involvement were associated with higher plasma NfL concentrations (β = 0.003, p = 0.009; β = 0.072, p = 0.031; β = 0.077, p = 0.027; β = 0.069, p = 0.047, respectively). Higher plasma NfL concentrations in NPSLE and non-NPSLE patients may indicate a higher degree of neuronal damage in SLE in general, corresponding to cognitive impairment and organ damage development. Furthermore, our results may indicate a higher degree of neuronal breakdown in patients with active SLE, also without overt clinical symptoms. NfL may serve as an indicator of neuronal damage in SLE in further studies.

Preoperative Cerebrospinal Fluid and Plasma Markers of Inflammation and Neurodegeneration Predict Mortality Eight Years Later in an Observational Cohort Study of Postoperative delirium in an Older Elective Arthroplasty Populatio

AbstractBackgroundBetween 2012‐2014, an observational cohort study of postoperative delirium (POD) in an elective arthroplasty population recruited 315 individuals aged over 65, without a diagnosis of dementia. We are now conducting a follow‐up study to determine what effect POD has on cognition years later.MethodIn the baseline study, neuropsychological testing was undertaken preoperatively, cerebrospinal fluid (CSF) was sampled at the time of spinal anaesthesia and delirium was assessed daily on days 1‐3 postoperatively. Stored CSF (n = 270) was analysed for markers of inflammation and neurodegeneration. In 2020, all surviving participants were invited to take part in the follow‐up study.ResultThe average age of the cohort at baseline was 74.4 (5.8) years. Eight years later, 84% (n=264) of the observational study participants are still alive. Mortality rates in the intervening years are higher in those who developed POD (14/44, 32%) than those who did not (37/271, 14%), but is not statistically significant (p=0.13). Significant predictors of mortality in all participants included multi‐morbidity (p=0.007), age at surgery (p&lt;0.001), performance on Colour Trails 2, a test of executive function(p&lt;0.001); CSF glial fibrillary acidic protein (GFAP), a marker of inflammation (p=0.01); CSF neurofilament light (NFL), a marker of axonal degeneration (p=0.019); CSF interleukin‐8 (IL‐8), a marker of inflammation (p=0.007) and CSF triggering receptor expressed on myeloid cells 2 (sTREM2), a marker of age‐related neuroinflammation and tau‐related neurodegeneration (p=0.002).ConclusionThe majority of participants in this elective arthroplasty observational cohort are still alive eight years later. Older age at time of surgery, multimorbidity, lower neuropsychological performance and increased preoperative CSF measures of inflammation and neurodegeneration were associated with mortality in adults eight years following elective orthopaedic surgery.

Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from ‘phenocopy’ non‐progressors

AbstractBackgroundDistinguishing behavioural variant frontotemporal dementia (bvFTD) from non‐neurodegenerative ‘non‐progressor’, ‘phenocopy’ mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay.MethodCerebrospinal fluid (CSF) NfL, amyloid beta 1‐42 (AB42), total and phosphorylated tau (T‐tau, P‐tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow up information, patients were categorised as Progressors. Non‐Progressors were subtyped in to Phenocopy Non‐Progressors (non‐neurological/neurodegenerative final diagnosis), and Static Non‐Progressors (static deficits, not fully explained by non‐neurological/neurodegenerative causes).ResultForty‐three patients were included: 20 Progressors, 23 Non‐Progressors (15 Phenocopy, 8 Static), 20 controls. NfL concentrations were lower in Non‐Progressors (Non‐Progressors Mean, M=554pg/mL, 95%CI:[461, 675], Phenocopy Non‐Progressors M=459pg/mL, 95%CI:[385, 539], Static Non‐Progressors M=730pg/mL, 95%CI:[516, 940]), compared to bvFTD Progressors (M=2397pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non‐Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Static Non‐Progressors tended to have higher T‐tau and P‐tau levels compared to Phenocopy Non‐Progressors.ConclusionThis study demonstrated strong diagnostic utility of CSF NfL in distinguishing bvFTD from phenocopy non‐progressor variants, at baseline, with high accuracy, in a real‐world clinical setting. This has important clinical implications to improve outcomes for patients and clinicians facing this challenging clinical dilemma, as well as for healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non‐progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL.

The relationship between cerebrospinal fluid neurofilament light protein biomarker and cortical thinning across the spectrum of Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is an age‐related neurodegenerative disease pathologically characterized by beta‐amyloid plaque accumulation and tau‐protein neurofibrillary tangles in the brain. Recent research has sought to identify additional potential biomarkers for earlier detection and treatment of the disease, including one such protein named cerebrospinal fluid neurofilament light protein (CSF NfL). Despite CSF NfL’s essential contributions to forming the neuronal cytoskeleton and supporting neuroaxonal function, the roles of CSF NfL in longitudinal AD progression and AD‐related neurodegeneration remain to be elucidated. This study examined the relationships between baseline CSF NfL levels and cortical gray matter atrophy along the spectrum of AD on a longitudinal scale over the span of two years.MethodWe included 179 study subjects (mean age = 74.21; 90 Females) with 60 cognitively normal (CN) individuals, 63 patients with late mild cognitive impairment (LMCI), and 56 AD patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Baseline CSF NfL measures and demographic data were downloaded from the ADNI study. Structural magnetic resonance imaging (MRI) scans from three time points (baseline, year 1, year 2) were processed and analyzed using FreeSurfer longitudinal analysis pipelines to compute percent changes in gray matter thickness for Year 1 (Y1) and Year 2 (Y2) compared with baseline, respectively.ResultBaseline CSF NfL was positively associated with greater cortical thinning across all study subjects, which were more pronounced in Y2. This relationship between baseline CSF NfL and cortical thinning remained the same in the AD diagnosis group. For the LMCI diagnosis group, there was no clear trend between baseline CSF NfL measures and percent changes in cortical thickness. Interestingly, a positive association between baseline CSF NfL value and percent changes in cortical thickness was observed in the CN diagnosis group at Y1, especially in the left hemisphere.ConclusionCSF NfL may contribute to the disease progression potentially through cortical atrophy and has an ability to predict cortical thinning over the short period of time. Longitudinal follow‐up analyses are warranted to incorporate its trajectory into the A/T/N classification system.

Diagnostic utility of neurofilament markers for MND is limited in restricted disease phenotype and for differentiation from compressive myeloradiculopathies.

Misdiagnosis is frequent in early motor neuron disease (MND), typically compressive radiculopathy, or in patients with restricted MND phenotype. In this retrospective, single tertiary centre study, we measured levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (p-NfH) chain in cerebrospinal fluid (CSF) and of p-NfH in serum with commercially available ELISA kits and assessed their respective diagnostic performance as a marker of MND. The entire study population (n = 164) comprised 71 MND patients, 30 patients with compressive myelo- or radiculopathy, and 63 disease controls (DC). Among MND patients, we specified subgroups with only lower motoneuron involvement (MND-LMN, n = 15) and with confounding nerve roots or spinal cord compression (MND-C, n = 18), representing clinical diagnostic pitfalls. MND-LMN displayed significantly lower CSF NfL (p = 0.003) and p-NFH (p = 0.017), but not serum p-NfH (p = 0.347) levels compared to other MND patients (n = 56). The discriminative ability (area under the curve-AUC) of both CSF Nfs towards all MND patients was comparable to each other but significantly higher than that of p-NfH in serum (ps < 0.001). AUC of both CSF Nfs between MND-LMN and DC and also between MND-C and myelo-/radiculopathies were reduced, as compared to AUC between other MND and DC or myelo-/radiculopathies, respectively. Our results suggest that both Nfs in CSF represent a reliable diagnostic marker in a general MND population, fulfilling Awaji criteria. As for diagnostic pitfalls, and also for p-NfH in serum, their discriminative ability and, therefore, clinical utility appears to be limited.

The role of neurofilament light in genetic frontotemporal lobar degeneration.

Genetic frontotemporal lobar degeneration caused by autosomal dominant gene mutations provides an opportunity for targeted drug development in a highly complex and clinically heterogeneous dementia. These neurodegenerative disorders can affect adults in their middle years, progress quickly relative to other dementias, are uniformly fatal and have no approved disease-modifying treatments. Frontotemporal dementia, caused by mutations in the GRN gene which encodes the protein progranulin, is an active area of interventional drug trials that are testing multiple strategies to restore progranulin protein deficiency. These and other trials are also examining neurofilament light as a potential biomarker of disease activity and disease progression and as a therapeutic endpoint based on the assumption that cerebrospinal fluid and blood neurofilament light levels are a surrogate for neuroaxonal damage. Reports from genetic frontotemporal dementia longitudinal studies indicate that elevated concentrations of blood neurofilament light reflect disease severity and are associated with faster brain atrophy. To better inform patient stratification and treatment response in current and upcoming clinical trials, a more nuanced interpretation of neurofilament light as a biomarker of neurodegeneration is now required, one that takes into account its relationship to other pathophysiological and topographic biomarkers of disease progression from early presymptomatic to later clinically symptomatic stages.