Neurofilament light (NfL) chain levels predict clinical decline in Alzheimer's disease: A systematic review and meta-analysis

New cerebrospinal fluid biomarkers in Alzheimer’s disease

Spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis 4 (ALS4) are two forms of motor neuron disease characterized by clinically slow disease progression. Based on the current limited human studies, the contribution of central nervous neurodegeneration to these diseases and the rate of clinical progression is unclear. Neuronal proteins glial fibrillary acidic protein (GFAP), neurofilament light (NfL) chain, or Total-tau measured in either cerebrospinal fluid or blood could serve as sensitive markers of neurodegeneration. We studied 56 adult participants (32 SBMA, 7 ALS4, and 17 controls) who were enrolled at the National Institutes of Health, of whom 22 (10 SBMA, 7 ALS4, and 5 controls) underwent paired CSF and serum sampling, and of whom 6 participants were assessed longitudinally up to 24 months from initial visit. An additional 7 controls completed CSF sampling only. CSF GFAP, NfL chain, and Total-tau correlated with corresponding levels in serum (r = 0.74, r = 0.47, and r = 0.70, respectively). CSF GFAP was increased in patients with SBMA (median, 8840 pg/mL, interquartile range (IQR) 5780-10489) as compared to controls (median, 5315 pg/mL, IQR 1822-6657; P = 0.029) but not compared with ALS4 (median, 5015 pg/mL, IQR 3172-9803; P = 0.31). Patients with SBMA had increased concentrations of CSF NfL chain (median, 719 pg/mL, IQR 483-773) as compared to ALS4 (median, 307 pg/mL, IQR 187-629; P = 0.034) or controls (median, 395 pg/mL, IQR 307-497; P = 0.024). In contrast, serum concentrations of either biomarker did not differ significantly between SBMA, ALS4, or controls. Higher CSF GFAP and NfL chain levels were associated with lower SBMA Functional Rating Scale scores (r = -0.49 and r = -0.42, respectively). Over the course of 24 months, the average change in SBMA Functional Rating Scale was -0.83 points, while the changes in CSF GFAP and NfL chain were progressive (increased 1.4-fold and 1.3-fold, respectively). Our data suggest that SBMA patients have increased concentrations of CSF GFAP and NfL chain as compared to ALS4 and controls, and higher levels of these biomarkers are associated with disease severity. Importantly, these results indicate that SBMA is associated with progressive neurodegeneration and that either CSF GFAP or NfL chain may be useful for patient stratification and monitoring treatment effects in clinical trials.

A key question in designing MRI-based clinical trials is how the main magnetic field strength of the scanner affects the power to detect disease effects. In 110 subjects scanned longitudinally at both 3.0 and 1.5 T, including 24 patients with Alzheimer's Disease (AD) [74.8 +/- 9.2 years, MMSE: 22.6 +/- 2.0 at baseline], 51 individuals with mild cognitive impairment (MCI) [74.1 +/- 8.0 years, MMSE: 26.6 +/- 2.0], and 35 controls [75.9 +/- 4.6 years, MMSE: 29.3 +/- 0.8], we assessed whether higher-field MR imaging offers higher or lower power to detect longitudinal changes in the brain, using tensor-based morphometry (TBM) to reveal the location of progressive atrophy. As expected, at both field strengths, progressive atrophy was widespread in AD and more spatially restricted in MCI. Power analysis revealed that, to detect a 25% slowing of atrophy (with 80% power), 37 AD and 108 MCI subjects would be needed at 1.5 T versus 49 AD and 166 MCI subjects at 3 T; however, the increased power at 1.5 T was not statistically significant (alpha = 0.05) either for TBM, or for SIENA, a related method for computing volume loss rates. Analysis of cumulative distribution functions and false discovery rates showed that, at both field strengths, temporal lobe atrophy rates were correlated with interval decline in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), mini-mental status exam (MMSE), and Clinical Dementia Rating sum-of-boxes (CDR-SB) scores. Overall, 1.5 and 3 T scans did not significantly differ in their power to detect neurodegenerative changes over a year. Hum Brain Mapp, 2010. (c) 2009 Wiley-Liss, Inc.

Recent evidence suggests that blood-based biomarkers might be useful for Alzheimer's disease (AD). Among them, we intend to investigate whether neurofilament light (NfL) and multimer detection system-oligomeric Aβ (MDS-OAβ) values can be useful in screening, predicting, and monitoring disease progression and how the relationship between NfL and MDS-OAβ values changes. Eighty participants with probable AD dementia, 50 with mild cognitive impairment (MCI), and 19 with subjective cognitive decline (SCD) underwent baseline and follow-up evaluations of the Mini-Mental Status Examination (MMSE) and both plasma biomarkers. Baseline MDS-OAß (p = 0.016) and NfL (p = 0.002) plasma concentrations differed significantly among groups, but only NfL correlated with baseline MMSE scores (r = -0.278, p = 0.001). In follow-up, neither correlated with MMSE changes overall. However, in SCD and MCI participants (n = 32), baseline MDS-OAß correlated with follow-up MMSE scores (r = 0.532, p = 0.041). Linear regression revealed a relationship between baseline MDS-OAβ and follow-up MMSE scores. In SCD and MCI participants, plasma NfL changes correlated with MMSE changes (r = 0.564, p = 0.028). This study shows that only in participants with SCD and MCI, not including AD dementia, can MDS-OAß predict the longitudinal cognitive decline measured by follow-up MMSE. Changes of NfL, not MDS-OAß, parallel the changes of MMSE. Further studies with larger samples and longer durations could strengthen these results..

Plasma neurofilament light (NfL) is an intermediate filamentous protein involved in stabilizing axonal structure and promoting axon growth. Recent clinical studies have reported increased NfL levels in the plasma of Alzheimer's disease (AD) patients and patients with mild cognitive impairment (MCI). This study used meta-analysis to evaluate the potential of plasma NfL as a biomarker for patients with AD and MCI. PubMed, Embase, and Web of Science databases were systematically searched for studies of plasma NfL levels in AD and MCI, and a meta-analysis was employed to identify whether it was suited as a reliable biomarker and discrimination of healthy controls. A total of 24 published articles that included 2397 AD and 3242 MCI patients were analysed. The level of plasma NfL was significantly increased in patients with AD and MCI when compared with healthy control subjects (standard mean difference [SMD]: 14.33 [12.42-16.24], z = 14.71, p < 0.00001; SMD: 4.95 [3.82-6.80], z = 8.59, p < 0.00001) and higher in AD patients than MCI patients (SMD: 9.32 [8.07-10.57], z = 14.62, p < 0.00001). Meta-regression analysis showed a negative relationship between Mini-Mental State Examination (MMSE) scores and plasma NfL levels in MCI patients (slope = -0.399 [95% confidence interval (CI): -0.518 to -0.281], p < 0.05). The meta-analysis suggested that NfL levels increased in the plasma of patients with AD and MCI and were associated with cognitive decline. Results provide the clinical evidence to support plasma NfL as a cognitive biomarker for AD and MCI.

Use of an FDG-PET derived hypometabolic convergence index enrichment strategy to reduce sample sizes in Alzheimer's disease clinical trials: findings from the Alzheimer's Disease Neuroimaging Initiative (ADNI)

Serum neurofilament light level in the clinical diagnosis of Chinese patients with Alzheimer’s disease

Mild cognitive impairment and subjective cognitive impairment

Evaluation of what matters most in existing clinical outcomes assessments in Alzheimer's disease

The increasing burden of Alzheimer's disease (AD) emphasizes the need for effective diagnostic and therapeutic strategies. Despite available treatments targeting amyloid beta (Aβ) plaques, disease-modifying therapies remain elusive. Early detection of mild cognitive impairment (MCI) patients at risk for AD conversion is crucial, especially with anti-Aβ therapy. While plasma biomarkers hold promise in differentiating AD from MCI, evidence on predicting cognitive decline is lacking. This study's objectives were to evaluate whether plasma protein biomarkers could predict both cognitive decline in non-demented individuals and the conversion to AD in patients with MCI. This study was conducted as part of the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD), a prospective, community-based cohort. Participants were based on plasma biomarker availability and clinical diagnosis at baseline. The study included MCI (n = 50), MCI-to-AD (n = 21), and cognitively unimpaired (CU, n = 40) participants. Baseline plasma concentrations of six proteins-total tau (tTau), phosphorylated tau at residue 181 (pTau181), amyloid beta 42 (Aβ42), amyloid beta 40 (Aβ40), neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP)-along with three derivative ratios (pTau181/tTau, Aβ42/Aβ40, pTau181/Aβ42) were analyzed to predict cognitive decline over a six-year follow-up period. Baseline protein biomarkers were stratified into tertiles (low, intermediate, and high) and analyzed using a linear mixed model (LMM) to predict longitudinal cognitive changes. In addition, Kaplan-Meier analysis was performed to discern whether protein biomarkers could predict AD conversion in the MCI subgroup. This prospective cohort study revealed that plasma NFL may predict longitudinal declines in Mini-Mental State Examination (MMSE) scores. In participants categorized as amyloid positive, the NFL biomarker demonstrated predictive performance for both MMSE and total scores of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-TS) longitudinally. Additionally, as a baseline predictor, GFAP exhibited a significant association with cross-sectional cognitive impairment in the CERAD-TS measure, particularly in amyloid positive participants. Kaplan-Meier curve analysis indicated predictive performance of NFL, GFAP, tTau, and Aβ42/Aβ40 on MCI-to-AD conversion. This study suggests that plasma GFAP in non-demented participants may reflect baseline cross-sectional CERAD-TS scores, a measure of global cognitive function. Conversely, plasma NFL may predict longitudinal decline in MMSE and CERAD-TS scores in participants categorized as amyloid positive. Kaplan-Meier curve analysis suggests that NFL, GFAP, tTau, and Aβ42/Aβ40 are potentially robust predictors of future AD conversion.

Alzheimer's disease (AD) is a progressive, multifactorial, neurodegenerative disorder affecting >6 million Americans. Chronic, low-grade neuroinflammation, and insulin resistance may drive AD pathogenesis. We explored the neurophysiological and neuropsychological effects of NE3107, an oral, anti-inflammatory, insulin-sensitizing molecule, in AD. In this phase 2, open-label study, 23 patients with mild cognitive impairment or mild dementia received 20-mg oral NE3107 twice daily for 3 months. Primary endpoints assessed changes from baseline in neurophysiological health and oxidative stress (glutathione level) using advanced neuroimaging analyses. Secondary endpoints evaluated changes from baseline in neuropsychological health using cognitive assessments, including the 11-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment, Clinical Dementia Rating, Quick Dementia Rating Scale, Alzheimer's Disease Composite Score, and Global Rating of Change (GRC). Exploratory endpoints assessed changes from baseline in neuroinflammation biomarkers (tumor necrosis factor alpha, TNF-α) and AD (amyloid beta and phosphorylated tau [P-tau]). NE3107 was associated with clinician-rated improvements in cerebral blood flow and functional connectivity within the brain. In patients with MMSE ≥ 20 (mild cognitive impairment to mild AD; n = 17), NE3107 was associated with directional, but statistically nonsignificant, changes in brain glutathione levels, along with statistically significant improvements in ADAS-Cog11 (P = .017), Clinical Dementia Rating (P = .042), Quick Dementia Rating Scale (P = .002), Alzheimer's Disease Composite Score (P = .0094), and clinician-rated GRC (P < .001), as well as in cerebrospinal fluid P-tau levels (P = .034) and P-tau:amyloid beta 42 ratio (P = .04). Biomarker analyses also demonstrated directional, but statistically non-significant, changes in plasma TNF-α, consistent with the expected mechanism of NE3107. Importantly, we observed a statistically significant correlation (r = 0.59) between improvements in TNF-α levels and ADAS-Cog11 scores (P = .026) in patients with baseline MMSE ≥ 20. Our results indicate that in this study NE3107 was associated with what appear to be positive neurophysiological and neuropsychological findings, as well as evidence of improvement in biomarkers associated with neuroinflammation and AD in patients diagnosed with dementia. Our findings are consistent with previous preclinical and clinical observations and highlight a central role of neuroinflammation in AD pathogenesis.

An explanation on guiding principles of clinical research on mild cognitive impairment (protocol)

Comparative analysis of cerebrospinal fluid neurofilament medium, light and heavy chain in neurodegenerative diseases using an in-house assay for the detection of neurofilament medium chain

Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer's disease

Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer's disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer's disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer's disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer's disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer's disease.