Neurofilament Light Chain Concentrations Research Articles

Comparison of Serum and Cerebrospinal Fluid Neurofilament Light Chain Concentrations Measured by Ella™ and Lumipulse™ in Patients with Cognitive Impairment.

Neurofilament light chain proteins (NfLs) are considered a promising biomarker of neuroaxonal damage in several neurological diseases. Their measurement in the serum and cerebrospinal fluid (CSF) of patients with dementia may be especially useful. Our aim was to compare the NfL measurement performance of two advanced technologies, specifically the Ella™ microfluidic platform and the Lumipulse™ fully automated system, in patients with cognitive disorders. Thirty subjects with neurodegenerative cognitive disorders (10 with Alzheimer's Disease, 10 with Frontotemporal Dementia, and 10 with non-progressive Mild Cognitive Impairment) seen at the Cognitive Neurology Clinic of Modena University Hospital (Italy) underwent CSF and serum NfL measurement with both the Ella™ microfluidic platform (Bio-Techne, Minneapolis, MN, USA)) and the Lumipulse™ fully automated system for the CLEIA (Fujirebio Inc., Ghent, Belgium). Correlation and regression analyses were applied to assess the association between NfL concentrations obtained with the two assays in CSF and serum. The Passing-Bablok regression method was employed to evaluate the agreement between the assays. There were high correlations between the two assays (r = 0.976, 95% CI. 0.950-0.989 for CSF vs. r = 0.923, 95% CI 0.842-0.964 for serum). A Passing-Bablok regression model was estimated to explain the relationship between the two assays, allowing us to switch from one to the other when only one assay was available. We found a good degree of correlation between the two methods in patients with neurocognitive disorders. We also established a method that will allow comparisons between results obtained with either technique, allowing for meta-analyses and larger sample sizes.

Elevated plasma and CSF neurofilament light chain concentrations are stabilized in response to mutant huntingtin lowering in the brains of Huntington’s disease mice

BackgroundTherapeutic approaches aimed at lowering toxic mutant huntingtin (mHTT) levels in the brain can reverse disease phenotypes in animal models of Huntington's disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with progression of HD. However, it remains unknown whether NfL in biofluids could serve as a response biomarker for assessing the efficacy of disease-modifying therapies for HD.MethodsLongitudinal plasma and cross-sectional CSF samples were collected from the YAC128 transgenic mouse model of HD and wild-type (WT) littermate control mice throughout the natural history of disease. Additionally, biofluids were collected from YAC128 mice following intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting the mutant HTT transgene (HTT ASO), at ages both before and after the onset of disease phenotypes. NfL concentrations in plasma and CSF were quantified using ultrasensitive single-molecule array technology.ResultsPlasma and CSF NfL concentrations were significantly elevated in YAC128 compared to WT littermate control mice from 9 months of age. Treatment of YAC128 mice with either 15 or 50 µg HTT ASO resulted in a dose-dependent, allele-selective reduction of mHTT throughout the brain at a 3-month interval, which was sustained with high-dose HTT ASO treatment for up to 6 months. Lowering of brain mHTT prior to the onset of regional brain atrophy and HD-like motor deficits in this model had minimal effect on plasma NfL at either dose, but led to a dose-dependent reduction of CSF NfL. In contrast, initiating mHTT lowering in the brain after the onset of neuropathological and behavioural phenotypes in YAC128 mice resulted in a dose-dependent stabilization of NfL increases in both plasma and CSF.ConclusionsOur data provide evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may serve as a promising exploratory response biomarker for HD.

Uncovering neural substrates across Alzheimer's disease stages using contrastive variational autoencoder.

Alzheimer's disease is the most common major neurocognitive disorder. Although currently, no cure exists, understanding the neurobiological substrate underlying Alzheimer's disease progression will facilitate early diagnosis and treatment, slow disease progression, and improve prognosis. In this study, we aimed to understand the morphological changes underlying Alzheimer's disease progression using structural magnetic resonance imaging data from cognitively normal individuals, individuals with mild cognitive impairment, and Alzheimer's disease via a contrastive variational autoencoder model. We used contrastive variational autoencoder to generate synthetic data to boost the downstream classification performance. Due to the ability to parse out the nonclinical factors such as age and gender, contrastive variational autoencoder facilitated a purer comparison between different Alzheimer's disease stages to identify the pathological changes specific to Alzheimer's disease progression. We showed that brain morphological changes across Alzheimer's disease stages were significantly associated with individuals' neurofilament light chain concentration, a potential biomarker for Alzheimer's disease, highlighting the biological plausibility of our results.

Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Does serum neurofilament light chain measurement influence therapeutic decisions in multiple sclerosis?

BackgroundThe assessment of serum neurofilament light chain (sNfL) concentration in multiple sclerosis (MS) is a useful tool for predicting clinical outcomes and assessing treatment response. However, its use in clinical practice is still limited. We aimed to assess how measurement of sNfL influences neurologists’ treatment decisions in MS. MethodsWe conducted a cross-sectional, web-based study in collaboration with the Spanish Society of Neurology. Neurologists involved in MS care were presented with different simulated case scenarios of patients experiencing either their first demyelinating MS event or a relapsing-remitting MS. The primary outcome was therapeutic inertia (TI), defined as the absence of treatment initiation or intensification despite elevated sNfL levels. Nine cases were included to estimate the TI score (range 0–9, where higher values represented a higher degree of TI). ResultsA total of 116 participants were studied. Mean age (standard deviation-SD) was 41.9 (10.1) years, 53.4 % male. Seventy-eight (67.2 %) were neurologists fully dedicated to the care of demyelinating disorders. Mean (SD) TI score was 3.65 (1.01). Overall, 92.2 % of participants (n = 107) presented TI in at least 2/9 case scenarios. The lack of full dedication to MS care (p = 0.014), preference for taking risks (p = 0.008), and low willingness to adopt evidence-based innovations (p = 0.009) were associated with higher TI scores in the multivariate analysis after adjustment for confounders. ConclusionTI was a common phenomenon among neurologists managing MS patients when faced with the decision to initiate or escalate treatment based on elevated sNfL levels. Identifying factors associated with this phenomenon may help optimize treatment decisions in MS care.

Associations Between Blood-Based Biomarkers and Cognitive and Functional Trajectories Among Participants of the MEMENTO Cohort.

Elevated levels of Alzheimer disease (AD) blood-based biomarkers are associated with accelerated cognitive decline. However, their distinct relationships with specific cognitive and functional domains require further investigation. We aimed at estimating the associations between AD blood-based biomarkers and the trajectories of distinct cognitive and functional domains over a 5-year follow-up period. We conducted a clinic-based prospective study using data from the MEMENTO study, a nationwide French cohort. We selected dementia-free individuals at baseline aged 60 years or older. Baseline measurements of β-amyloid (Aβ) 40 and 42, phosphorylated tau (p-tau181), and neurofilament light chain (NfL) concentrations were obtained using the Simoa HD-X analyzer. Mini-Mental State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT), animal fluency, Trail Making Tests A and B, Short Physical Performance Battery (SPPB), and Instrumental Activities of Daily Living were administered annually for up to 5 years. We used linear mixed models, adjusted for potential confounders, to model AD biomarkers' relation with cognitive and functional decline. A total of 1,938 participants were included in this study, with a mean (SD) baseline age of 72.8 (6.6) years, and 62% were women. Higher baseline p-tau181 and NfL were associated with significantly faster decline in most cognitive, physical, and functional outcomes (+1 SD p-tau181: βMMSE = -0.055, 95% CI -0.067 to -0.043, βFCSRT = -0.034, 95% CI -0.043 to -0.025, βfluency = -0.029, 95% CI -0.038 to -0.020, βSPPB = -0.040, 95% CI -0.057 to -0.022, and β4IADL = -0.115, 95% CI 0.091-0.140. +1 SD NfL: βMMSE = -0.039, 95% CI -0.053 to -0.025, βFCSRT = -0.022, 95% CI -0.032 to -0.012, βfluency = -0.014, 95% CI -0.024 to -0.004, and β4IADL = 0.077, 95% CI 0.048-0.105). A multiplicative association of p-tau181 and NfL with worsening cognitive and functional trajectories was evidenced. Lower Aβ42/40 ratio was only associated with slightly faster cognitive decline in FCSRT and semantic fluency (+1 SD: β = 0.011, 95% CI 0.002-0.020, and β = 0.011, 95% CI 0.003-0.020, respectively). These associations were not modified by APOE ε4, sex, nor education level. In a memory clinic sample, p-tau181 and NfL, both independently and jointly, are linked to more pronounced cognitive, physical and functional declines. Blood-based biomarker measurement in AD research may provide useful insights regarding biological processes underlying cognitive, physical, and functional declines in at-risk individuals.

Pumping up the Fight against Multiple Sclerosis: The Effects of High-Intensity Resistance Training on Functional Capacity, Muscle Mass, and Axonal Damage.

Resistance training (RT) has been recognized as a beneficial non-pharmacological intervention for multiple sclerosis (MS) patients, but its impact on neurodegeneration is not fully understood. This study aimed to investigate the effects of high-intensity RT on muscle mass, strength, functional capacity, and axonal damage in MS patients. Eleven relapsing-remitting MS patients volunteered in this within-subject counterbalanced intervention study. Serum neurofilament light-chain (NfL) concentration, vastus lateralis thickness (VL), timed up-and-go test (TUG), sit-to-stand test (60STS), and maximal voluntary isometric contraction (MVIC) were measured before and after intervention. Participants performed 18 sessions of high-intensity RT (70-80% 1-RM) over 6 weeks. Significant (p < 0.05) differences were observed post-intervention for VL (ES = 2.15), TUG (ES = 1.98), 60STS (ES = 1.70), MVIC (ES = 1.78), and NfL (ES = 1.43). Although moderate correlations between changes in VL (R = 0.434), TUG (R = -0.536), and MVIC (R = 0.477) and changes in NfL were observed, only the correlation between VL and MVIC changes was significant (R = 0.684, p = 0.029). A 6-week RT program significantly increased muscle mass, functional capacity, and neuromuscular function while also decreasing serum NfL in MS patients. These results suggest the effectiveness of RT as a non-pharmacological approach to mitigate neurodegeneration while improving functional capacity in MS patients.

Neurofilament light chain concentration does not correlate with disease status in Labrador Retrievers affected with idiopathic laryngeal paralysis.

The aim of this study was to investigate whether plasma neurofilament light chain (pNfL) concentration was altered in Labrador Retrievers with idiopathic laryngeal paralysis (ILP) compared to a control population. A secondary aim was to investigate relationships between age, height, weight, and body mass index in the populations studied. 123 dogs: 62 purebred Labrador Retrievers with ILP (ILP Cases) and 61 age-matched healthy medium- to large-breed dogs (Controls). Dogs, recruited from August 1, 2016, to March 1, 2022, were categorized as case or control based on a combination of physical exam, neurologic exam, and history. Blood plasma was collected, and pNfL concentration was measured. pNfL concentrations were compared between ILP Cases and Controls. Covariables including age, height, and weight were collected. Relationships between pNfL and covariables were analyzed within and between groups. In dogs where 2 plasma samples were available from differing time points, pNfL concentrations were measured to evaluate alterations over time. No significant difference in pNfL concentration was found between ILP Cases and Control (P = .36). pNfL concentrations had moderate negative correlations with weight and height in the Control group; other variables did not correlate with pNfL concentrations in ILP Case or Control groups. pNfL concentrations do not correlate with ILP disease status or duration in Labrador Retrievers. There is no evidence that pNfL levels are altered due to ILP disease duration or progression when compared with healthy controls. When evaluating pNfL concentrations in the dog, weight and height should be considered.

Neurofilament Light Chain Concentration in Cerebrospinal Fluid in Children with Acute Nontraumatic Neurological Disorders.

(1) Introduction: This pilot study aimed to analyze neurofilament light chain levels in cerebrospinal fluid (cNfL) in a cohort of children with different acute nontraumatic neurological conditions. (2) Methods: This prospective observational cohort study consisted of 35 children aged 3 months to 17 years and was performed from November 2017 to December 2019. Patients' clinical data were reviewed, and patients were assigned to the following groups: n = 10 (28.6%) meningitis, 5 (14.3%) Bell's palsy, 7 (20.0%) febrile non-CNS infection, 3 (8.6%) complex febrile seizure, 4 (11.4%) idiopathic intracranial hypertension, and 6 (17.1%) others. cNfL levels were measured using a sensitive single-molecule array assay. (3) Results: The cNfL levels [median (range)] in children with meningitis were 120.5 pg/mL (58.1-205.4), in Bell's palsy 88.6 pg/mL (48.8-144.5), in febrile non-CNS infection 103.9 pg/mL (60.1-210.8), in complex febrile seizure 56 pg/mL (53.2-58.3), and in idiopathic intracranial hypertension 97.1 pg/mL (60.1-124.6). Within the meningitis group, children with Lyme neuroborreliosis (LNB) had significantly higher cNfL concentrations (median 147.9 pg/mL; range 87.8-205.4 pg/mL) than children with enterovirus meningitis (72.5 pg/mL; 58.1-95.6 pg/mL; p = 0.048) and non-significantly higher cNfL levels when compared to Bell's palsy (88.6 pg/mL; 48.8-144.5 pg/mL; p = 0.082). There was no correlation between cNfL levels and age. (4) Conclusions: Although the number of patients in this pilot study cohort is limited, higher cNfL levels in children with LNB compared to those with viral meningitis (significant) and Bell's palsy (trend) may indicate the potential of cNfL as a biomarker in the differential diagnosis of pediatric meningitis and facial palsy.

Neurofilament light-chain (NfL) and 18 kDa translocator protein in early psychosis and its putative high-risk

Evidence of elevated peripheral Neurofilament light-chain (NfL) as a biomarker of neuronal injury can be utilized to reveal nonspecific axonal damage, which could reflect altered neuroimmune function. To date, only a few studies have investigated NfL as a fluid biomarker in schizophrenia primarily, though none in its putative prodrome (Clinical High-Risk, CHR) or in untreated first-episode psychosis (FEP). Further, it is unknown whether peripheral NfL is associated with 18 kDa translocator protein (TSPO), a validated neuroimmune marker. In this secondary study, we investigated for the first time (1) serum NfL in early stages of psychosis including CHR and FEP as compared to healthy controls, and (2) examined its association with brain TSPO, using [18F]FEPPA positron emission tomography (PET). Further, in the exploratory analyses, we aimed to assess associations between serum NfL and symptom severity in patient group and cognitive impairment in the combined cohort. A large cohort of 84 participants including 27 FEP (24 antipsychotic-naive), 41 CHR (34 antipsychotic-naive) and 16 healthy controls underwent structural brain MRI and [18F]FEPPA PET scan and their blood samples were obtained and assessed for serum NfL concentrations. We found no significant differences in serum NfL levels across clinical groups, controlling for age. We also found no significant association between NfL levels and brain TSPO in the entire cohort. We observed a negative association between serum NfL and negative symptom severity in CHR. Our findings suggest that neither active neuroaxonal deterioration as measured with NfL nor associated neuroimmune activation (TSPO) is clearly identifiable in an early mostly untreated psychosis sample including its putative high-risk.

Temporal serum neurofilament light chain concentrations in sheep inoculated with the agent of classical scrapie.

Neurofilament light chain (Nf-L) has been used to detect neuroaxonal damage in the brain caused by physical injury or disease. The purpose of this study was to determine if serum Nf-L could be used as a biomarker for pre-symptomatic detection of scrapie in sheep. Four sheep with prion protein genotype AVQQ were intranasally inoculated with the classical scrapie strain x124. Blood was collected every 4 weeks until 44 weeks post-inoculation, at which point weekly collection commenced. Serum was analyzed using single molecule array (Quanterix SR-X) to evaluate Nf-L concentrations. Scrapie was confirmed in each sheep by testing homogenized brainstem at the level of the obex with a commercially available enzyme immunoassay. Increased serum Nf-L concentrations were identified above the determined cutoff during the last tenth of the respective incubation period for each sheep. Throughout the time course study, PrPSc accumulation was not detected antemortem by immunohistochemistry in rectal tissue at any timepoint for any sheep. RT-QuIC results were inconsistently positive throughout the timepoints tested for each sheep; however, each sheep had at least one timepoint detected positive. When assessing serum Nf-L utility using receiver operator characteristic curves against different clinical parameters, such as asymptomatic and symptomatic (pruritus or neurologic signs), results showed that Nf-L was most useful at being an indicator of disease only late in disease progression when neurologic signs were present. Serum Nf-L concentrations in the cohort of sheep increased as disease progressed; however, serum Nf-L did not increase during the presymptomatic window. The levels increased substantially throughout the final 10% of the animals' scrapie incubation period when other clinical signs were present. Serum Nf-L is not a reliable biomarker for pre-clinical detection of scrapie.

Comparing the effects of augmented virtual reality treadmill training versus conventional treadmill training in patients with stage II-III Parkinson's disease: the VIRTREAD-PD randomized controlled trial protocol.

Intensive treadmill training (TT) has been documented to improve gait parameters and functional independence in Parkinson's Disease (PD), but the optimal intervention protocol and the criteria for tailoring the intervention to patients' performances are lacking. TT may be integrated with augmented virtual reality (AVR), however, evidence of the effectiveness of this combined treatment is still limited. Moreover, prognostic biomarkers of rehabilitation, potentially useful to customize the treatment, are currently missing. The primary aim of this study is to compare the effects on gait performances of TT + AVR versus TT alone in II-III stage PD patients with gait disturbance. Secondary aims are to assess the effects on balance, gait parameters and other motor and non-motor symptoms, and patient's satisfaction and adherence to the treatment. As an exploratory aim, the study attempts to identify biomarkers of neuroplasticity detecting changes in Neurofilament Light Chain concentration T0-T1 and to identify prognostic biomarkers associated to blood-derived Extracellular Vesicles. Single-center, randomized controlled single-blind trial comparing TT + AVR vs. TT in II-III stage PD patients with gait disturbances. Assessment will be performed at baseline (T0), end of training (T1), 3 (T2) and 6 months (T3, phone interview) from T1. The primary outcome is difference in gait performance assessed with the Tinetti Performance-Oriented Mobility Assessment gait scale at T1. Secondary outcomes are differences in gait performance at T2, in balance and spatial-temporal gait parameters at T1 and T2, patients' satisfaction and adherence. Changes in falls, functional mobility, functional autonomy, cognition, mood, and quality of life will be also assessed at different timepoints. The G*Power software was used to estimate a sample size of 20 subjects per group (power 0.95, α < 0.05), raised to 24 per group to compensate for potential drop-outs. Both interventions will be customized and progressive, based on the participant's performance, according to a predefined protocol. This study will provide data on the possible superiority of AVR-associated TT over conventional TT in improving gait and other motor and non-motor symptoms in persons with PD and gait disturbances. Results of the exploratory analysis could add information in the field of biomarker research in PD rehabilitation.

Neurofilament light chain concentration mediates the association between regional medial temporal lobe structure and memory in adults with Down syndrome.

Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimer's disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS. T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory. Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory. The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS.

Significant dose‐dependent reduction in neurofilament light chain concentration in plasma with oral tau aggregation inhibitor hydromethylthionine mesylate

AbstractBackgroundHydromethylthionine mesylate (HMTM) is a potent oral tau aggregation inhibitor. Recent results from Study TRx‐237‐039 (LUCIDITY) suggest strong effects on cognitive and functional decline and progression of brain atrophy. We investigated the effect of HMTM on change in the plasma biomarker neurofilament light chain (NfL) in LUCIDITY. NfL is a clinically accessible and established biomarker for neurodegeneration that is known to be correlated with measures of clinical decline and brain atrophy in AD and MCI due to AD (MCI‐AD).MethodLUCIDITY is a double‐blind randomised controlled Phase 3 clinical trial comparing change over 12 months in cognitive, functional and brain atrophy outcomes at HMTM doses of 16 mg/day, 8 mg/day and methylthioninium chloride (MTC) at a dose of 4 mg twice weekly as a control in a 4:1:4 randomisation, with a subsequent 12 month blinded open‐label extension phase in which all participants received 16 mg/day.ResultBaseline and 12‐month NfL plasma levels were available as randomised in 161/185 participants receiving HMTM 16 mg/day, 38/48 receiving HMTM 8 mg/day and 136/185 receiving MTC 8 mg/week. The corresponding prespecified analysis model showed a 93% reduction in the change in NfL levels relative to control for HMTM 16 mg/day overall (p = 0.0278). Reduction in NfL change in the MCI‐AD subgroup was significant also at HMTM 8 mg/day (p = 0.0242). In the AD subgroup, there were directional dose‐dependent trends that did not reach statistical significance. Change in NfL level at 12 months was significantly correlated with change in ADAS‐cog11 (p = 0.0038) and whole brain volume (p = 0.0359) over 24 months.ConclusionThese results demonstrate that the orally administered tau aggregation‐inhibitor, HMTM, is able to produce a significant dose‐dependent reduction in neurodegeneration in AD as measured by change in plasma NfL levels.

Plasma biomarkers in relation to spatial distribution of Alzheimer’s disease neuropathology

AbstractBackgroundThe clinical utility of plasma biomarkers will in part be based on the information they convey regarding the distribution of neuropathology, especially beyond the information provided by demographics. We examined the associations of plasma biomarkers with cerebral amyloid and tau pathology determined by positron emission tomography (PET).MethodIn the Baltimore Longitudinal Study of Aging, plasma Aß42/Aß40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) concentrations were measured using Quanterix Simoa assays. Plasma concentrations of phosphorylated tau at threonine 181 (p‐tau181) and at 231 (p‐tau231) were measured using in‐house Simoa assays at University of Gothenburg. Using voxelwise linear regression models, we investigated cross‐sectional associations of plasma biomarkers with brain fibrillar amyloid and phosphorylated tau pathology as measured by PET with 11C‐Pittsburgh compound B (PiB) conducted on a GE Advance scanner (N = 189) and 18F‐flortaucipir (FTP) conducted on a Siemens High Resolution Research Tomograph (N = 107), respectively. In addition to unadjusted analyses, we conducted analyses adjusting for age, sex, and race. Results were corrected for multiple comparisons using permutation test‐based threshold‐free cluster enhancement (TFCE).ResultLower plasma Aß42/Aß40 was associated with higher PiB distribution volume ratio (DVR) in the unadjusted model, but not in the adjusted model (Figure 1). The remaining plasma biomarkers exhibited statistically significant positive associations with PiB DVR in both unadjusted and adjusted models. The plasma biomarker with the strongest and most widespread association with PiB DVR was p‐tau231 (Figure 2). Both p‐tau biomarkers exhibited statistically significant associations with FTP standardized uptake value ratio (SUVR) in both unadjusted and adjusted models. Aß42/Aß40, GFAP, and NfL did not exhibit statistically significant associations with FTP SUVR. Associations of p‐tau biomarkers with PiB DVR were stronger and more widespread than with FTP SUVR. We did not find any statistically significant associations when we repeated the analyses separately by binary PiB group.ConclusionPlasma biomarkers convey information beyond age, sex, and race in relation to the cerebral distribution of amyloid, and to a lesser extent, tau. The smaller sample size of our FTP PET study might in part explain the weaker associations we observed with FTP SUVR compared to PiB DVR.

Plasma amyloid‐β, total tau, and neurofilament light chain across the Alzheimer clinical spectrum: a population‐based study

AbstractBackgroundPlasma biomarkers have emerged as a promising approach for defining mild cognitive impairment (MCI) and Alzheimer’s disease (AD). We aimed to characterize Alzheimer’s plasma biomarkers across the clinical continuum of AD, and to assess their ability to differentiate between MCI, AD, and normal cognition.MethodThis population‐based study engaged 1446 rural‐dwelling older adults (age≥60 years, 61.0% women) derived from Multimodal Interventions to Delay Dementia and Disability in Rural China study; of these, 902 were defined with normal cognition, 402 with MCI, and 142 with AD according to the international criteria. Plasma amyloid‐beta (Aβ), total‐tau (t‐tau), and neurofilament light chain (NfL) concentrations were analysed using Simoa platform. Data were analysed using the logistic and general linear models, and receiver operating characteristic (ROC) analysis.ResultPlasma concentrations of Aβ40, Aβ42, t‐tau, and NfL were significantly increased with age (P&lt;0.01). Women had higher plasma Aβ2 (age‐adjusted β = 0.62; 95%CI = 0.30‐0.94), Aβ42/Aβ40 ratio (0.19; 0.01‐0.36) and lower NfL concentrations (‐0.11; ‐0.16‐ ‐0.06). Plasma Aβ42 (age‐ and sex‐adjusted β = ‐0.73; ‐1.15‐ ‐0.31) and Aβ42/Aβ40 ratio (‐0.51; ‐0.74‐ ‐0.29) were lower in APOE ε4 carriers than that in non‐carriers. Plasma Aβ40 and Aβ42/Aβ40 ratio showed an increased and decreased trend, respectively, across AD clinical spectrum. Plasma t‐tau and t‐tau/Aβ42 ratio were higher in people with AD than those with MCI or normal cognition. Plasma NfL was increased across the AD clinical continuum and outperformed other Alzheimer’s biomarkers in differentiating AD from normal cognition (area under the ROC curve [AUC] = 0.75). However, all of these plasma biomarkers performed poorly to distinguish MCI from normal cognition (AUC&lt;0.60). When adding plasma NfL to the basic model that included age, sex, education, and APOE genotype, the AUC was 0.87 for differentiating between AD and normal cognition, 0.79 between AD and MCI, and 0.64 between MCI and normal cognition.ConclusionAge, sex, and APOE genotype should be considered in clinical interpretation of Alzheimer’s plasma biomarkers. Plasma Aβ, t‐tau, and NfL concentrations differ across the cognitive continuum, but plasma NfL, which starts to elevate in the early stages of AD development, appears to be superior than plasma Aβ and t‐tau for defining cognitive continuum in old age.

Associations between blood‐based biomarkers and cognitive decline among participants at risk of Alzheimer’s disease: the Memento cohort

AbstractBackgroundBlood‐based biomarkers for Alzheimer’s disease (AD) pathology and neurodegeneration are promising biomarkers due to their lower cost, accessibility, and minimally invasive nature. Higher levels of AD blood‐based biomarkers have been shown to be associated with the risk of AD and cognitive decline. Yet, the specific cognitive domains involved need to be further investigated. We thus aimed at estimating the association between levels of baseline AD blood‐based biomarkers with cognitive trajectories over 5 years of follow‐up across different domains in a large clinical based cohort.MethodWe selected the 2060 dementia‐free individuals aged 60 years and older included in the Memento study, a French nationwide cohort, following patients from 28 memory clinics with either isolated cognitive complaints or mild cognitive impairment. Amyloid‐β 40 and 42, P‐tau181, and Neurofilament Light Chain (NfL) concentrations were measured at baseline using Simoa HD‐X analyzer. Global cognition, episodic memory, semantic memory, and executive functioning were assessed every year up to 5 years using the Mini Mental State Examination, the Free and Cued Reminding test, the Animal fluency test, and the Trail Making Test B respectively. Linear mixed models adjusted for sex, education level, APOE‐ε4 status, and practice effect, with age as time scale and quadratic slopes were performed to examine how AD blood‐based biomarkers relate to longitudinal cognitive trajectories by domain.ResultMean age was 72.8 years, 62% were women, 28% were APOE‐ε4 carriers, and 58% had a Clinical Dementia Rating score of 0.5. Higher baseline plasma P‐tau181 was associated with significantly faster nonlinear cognitive decline in all four cognitive domains (p&lt;0.001). On the opposite, baseline plasma Aβ42/40 ratio and NfL were not associated with cognitive decline whatever the domain. Associations between AD blood‐based biomarkers and faster cognitive decline were not modified by APOE‐ε4, sex, nor education level (p value for interaction &gt; 0.05).ConclusionIn a memory clinic population, plasma P‐tau181 is a marker of future cognitive decline. This marker is a good candidate for additional studies assessing biomarkers relevant for the identification of individuals who may benefit from treatment early in the disease course.

Renal function, Alzheimer’s plasma biomarker, and cognitive phenotypes among rural older adults in China: a population‐based study

AbstractBackgroundEmerging evidence has linked impaired renal function with dementia, but the neuropathological mechanisms underlying the association remains poorly understood. We sought to examine the relationships of renal function, Alzheimer’s plasma biomarker, and cognitive phenotypes among rural Chinese older adults.MethodThis population‐based cross‐sectional study included 5715 participants (age ≥60 years; 57.15% women; 40.49% illiteracy) in the Multimodal Interventions to Delay Dementia and Disability in Rural China (MIND‐China). We calculated the estimate glomerular filtration rate (eGFR) using serum creatinine and the simplified modification of diet in renal disease equation specifically for individuals from China, and impaired renal function was defined as eGFR &lt;60 mL/min/1.73 m2. Dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) were diagnosed following the international criteria. Plasma amyloid‐β (Aβ) 40, Aβ42, total tau, and neurofilament light chain (NfL) concentrations were measured using the SIMOA platform in a subsample (n = 1446). Data were analyzed using logistic, the general linear regression, and mediation models.ResultOf the 5715 participants, 283 (4.95%) were detected with renal function impairment, and 326 (5.70%) were diagnosed with dementia (195 with AD and 10 with VaD). The multivariable‐adjusted odds ratios of eGFR &lt;60 mL/min/1.73 m2 (vs. &gt;90mL/min/1.73 m2) were 2.43 (95% confidence interval [CI] 1.56‐3.72) for all‐cause dementia, 2.74 (1.64‐4.49) for AD, and 1.30 (0.50‐2.98) for VaD. In the plasma biomarkers subsample, controlling for demographic factors, impaired renal function was significantly associated with higher levels of plasma Aβ40 (demographic‐adjusted β‐coefficient = 59.06; 95%CI 46.93‐71.19), Aβ42 (3.41; 2.62‐4.20), NfL (14.57; 9.08‐20.05), and total tau (0.74; 0.48‐1.01), and the observed associations remained significant even in the multivariable‐adjusted model (P&lt;0.001). The mediation analysis showed that total tau mediated 12.77% of the association between impaired renal function and AD.ConclusionImpaired renal function is associated with an increased risk of dementia and AD. Plasma total tau may partly underlie the association of renal function with Alzheimer’s dementia.

Plasma Amyloid-β, Total Tau, and Neurofilament Light Chain Across the Alzheimer's Disease Clinical Spectrum: A Population-Based Study.

Plasma biomarkers have emerged as a promising approach for characterizing pathophysiology in mild cognitive impairment (MCI) and Alzheimer's disease (AD). We aimed to characterize plasma biomarkers for AD and neurodegeneration across the AD clinical continuum, and to assess their ability to differentiate between AD, MCI, and normal cognition. This population-based study engaged 1,446 rural-dwelling older adults (age ≥60 years, 61.0% women) derived from MIND-China; of these, 402 were defined with MCI and 142 with AD. Plasma amyloid-β (Aβ), total tau (t-tau), and neurofilament light chain (NfL) concentrations were analyzed using the Simoa platform. Data were analyzed using linear and logistic regression models, and receiver operating characteristic (ROC) analysis. Across the AD clinical spectrum, plasma Aβ40 and NfL increased, whereas Aβ42/Aβ40 ratio decreased. Plasma t-tau was higher in people with AD dementia than those with MCI or normal cognition. Plasma NfL outperformed other biomarkers in differentiating AD from normal cognition (area under the ROC curve [AUC] = 0.75), but all plasma biomarkers performed poorly to distinguish MCI from normal cognition (AUC <0.60). Plasma NfL in combination with age, sex, education, and APOE genotype yielded the AUC of 0.87 for differentiating between AD and normal cognition, 0.79 between AD and MCI, and 0.64 between MCI and normal cognition. In this Chinese population, AD plasma biomarkers vary by age, sex, and APOE genotype. Plasma Aβ, t-tau, and NfL differ across the AD clinical spectrum, and plasma NfL appears to be superior to plasma Aβ and t-tau for defining the clinical spectrum.

Tofersen: Silver Lining or Hyperbole??

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of anterior horn cells with a dismal prognosis. Over a century since its description, we still do not have a cure for this disorder. Edaravone, Riluzole, and combination of phenylbutyrate and taurursodiol are a handful of FDA-approved drugs that only delay the progression of the disease by a few months. Tofersen, an antisense oligonucleotide, in SOD1 related ALS, has joined the bandwagon of FDA-approved drugs for ALS recently. It is a gene therapy that has been found to lower SOD1 concentrations and neurofilament light chain concentrations in blood and CSF, a known biomarker of ALS, leading to the accelerated approval of the drug. Although it did not show any statistically significant clinical improvement. In this article, we discuss the development and approval process of the first gene-based therapy, Tofersen, for ALS.