CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis.

Background: Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed. Aim: To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine. Methods: Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs. Results: Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91). Conclusions: CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.

Timing of Biomarker Changes in Sporadic Alzheimer's Disease in Estimated Years from Symptom Onset.

OBJECTIVE: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). METHODS: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross-sectional data from the amyloid PET positive and negative groups. RESULTS: The amyloid PET positive sub-cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub-cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15-19 years before estimated symptom onset for CSF Aß42/Aß40, plasma Aß42/Aß40, CSF pT217/T217, and amyloid PET; 12-14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP-25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7-9 years before estimated symptom onset for CSF pT205/T205, CSF YKL-40, hippocampal volumes, and cognitive measures. INTERPRETATION: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951-965.

Chitinases as a potential diagnostic and prognostic biomarker for amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons, and there is currently a lack of reliable diagnostic biomarkers. This meta-analysis aimed to evaluate CHIT1, CHI3L1, and CHI3L2 levels in the cerebrospinal fluid (CSF) or blood and their diagnostic potential in ALS patients. A systematic, comprehensive search was performed of peer-reviewed English-language articles published before April 1, 2023, in PubMed, Scopus, Embase, Cochrane Library, and Web of Science. After a thorough screening, 13 primary articles were included, and their chitinases-related data were extracted for systematic review and meta-analysis. In ALS patients, the CSF CHIT1 levels were significantly elevated compared to controls with healthy control (HC) (SMD, 1.92; 95% CI, 0.78 - 3.06; P < 0.001). CHIT1 levels were elevated in the CSF of ALS patients compared to other neurodegenerative diseases (ONDS) control (SMD, 0.74; 95% CI, 0.22 - 1.27; P < 0.001) and exhibited an even more substantial increase when compared to ALS-mimicking diseases (AMDS) (SMD, 1.15; 95% CI, 0.35 - 1.94, P < 0.001). Similarly, the CSF CHI3L1 levels were significantly higher in ALS patients compared to HC (SMD, 3.16; 95% CI, 1.26 - 5.06, P < 0.001). CHI3L1 levels were elevated in the CSF of ALS patients compared to ONDS (SMD, 0.75; 95% CI, 0.32 - 1.19; P = 0.017) and exhibited a more pronounced increase when compared to AMDS (SMD, 1.92; 95% CI, 0.41 - 3.42; P < 0.001). The levels of CSF chitinases in the ALS patients showed a significant increase, supporting the role of CSF chitinases as diagnostic biomarkers for ALS.

An Association of Chitinase-3 Like-Protein-1 With Neuronal Deterioration in Multiple Sclerosis.

Elevated levels of Chitinase-3-like protein-1 (CHI3L1) in cerebrospinal fluid have previously been linked to inflammatory activity and disease progression in multiple sclerosis (MS) patients. This study aimed to investigate the presence of CHI3L1 in the brains of MS patients and in the cuprizone model in mice (CPZ), a model of toxic/metabolic demyelination and remyelination in different brain areas. In MS gray matter (GM), CHI3L1 was detected primarily in astrocytes and in a subset of pyramidal neurons. In neurons, CHI3L1 immunopositivity was associated with lipofuscin-like substance accumulation, a sign of cellular aging that can lead to cell death. The density of CHI3L1-positive neurons was found to be significantly higher in normal-appearing MS GM tissue compared to that of control subjects (p = .014). In MS white matter (WM), CHI3L1 was detected in astrocytes located within lesion areas, as well as in perivascular normal-appearing areas and in phagocytic cells from the initial phases of lesion development. In the CPZ model, the density of CHI3L1-positive cells was strongly associated with microglial activation in the WM and choroid plexus inflammation. Compared to controls, CHI3L1 immunopositivity in WM was increased from an early phase of CPZ exposure. In the GM, CHI3L1 immunopositivity increased later in the CPZ exposure phase, particularly in the deep GM region. These results indicate that CHI3L1 is associated with neuronal deterioration, pre-lesion pathology, along with inflammation in MS.

CSF CXCL13 and Chitinase 3-like-1 Levels Predict Disease Course in Relapsing Multiple Sclerosis.

Several biomarkers from multiple sclerosis (MS) patients' biological fluids have been considered to support diagnosis, predict disease course, and evaluate treatment response. In this study, we assessed the CSF concentration of selected molecules implicated in the MS pathological process. To investigate the diagnostic and prognostic significance of CSF concentration of target candidate biomarkers in both relapsing (RMS, n = 107) and progressive (PMS, n = 18) MS patients and in other inflammatory (OIND, n = 10) and non-inflammatory (ONIND, n = 15) neurological disorders. We measured the CSF concentration of APRIL, BAFF, CHI3L1, CCL-2, CXCL-8, CXCL-10, CXCL-12, CXCL-13 through a Luminex Assay. MS patients were prospectively evaluated, and clinical and radiological activity were recorded. CHI3L1 and CXCL13 CSF levels were significantly higher in both MS groups compared to control groups, while CCL2, BAFF, and APRIL concentrations were lower in RMS patients compared to PMS and OIND. Considering RMS patients with a single demyelinating event, higher concentrations of CHI3L1, CXCL10, CXCL12, and CXCL13 were recorded in patients who converted to clinically defined MS(CDMS). RMS patients in the CXCL13 and CHI3L1 high concentration group had a significantly higher risk of relapse (HR 12.61 and 4.57), MRI activity (HR 7.04 and 2.46), and of any evidence of disease activity (HR 12.13 and 2.90) during follow-up. CSF CXCL13 and CHI3L1 levels represent very good prognostic biomarkers in RMS patients, and therefore can be helpful in the treatment choice. Higher CSF concentrations of neuro-inflammatory biomarkers were associated with a higher risk of conversion to CDMS in patients with a first clinical demyelinating event. Differential CSF BAFF and APRIL levels between RMS and PMS suggest a different modulation of B-cells pathways in the different phases of the disease.

Dynamics of Selected Biomarkers in Cerebrospinal Fluid During Complex Endovascular Aortic Repair - A Pilot Study.

INTRODUCTION: Ischemic spinal cord injury (SCI) is a serious complication of complex aortic repair. Prophylactic cerebrospinal fluid (CSF) drainage, used to decrease lumbar cerebrospinal fluid (CSF) pressure, enables monitoring of CSF biomarkers that may aid in detecting impending SCI. We hypothesized that biomarkers, previously evaluated in traumatic SCI and brain injury, would be altered in CSF over time following complex endovascular aortic repair (cEVAR). OBJECTIVES: To examine if a chosen cohort of CSF biomarker correlates to SCI and warrants further research. METHODS: A prospective observational study on patients undergoing cEVAR with extensive aortic coverage. Vital parameters and CSF samples were collected on ten occasions during 72 hours post-surgery. A panel of ten biomarkers were analyzed (Neurofilament Light Polypeptide (NFL), Tau, Glial Fibrillary Acidic Protein (GFAP), Soluble Amyloid Precursos Protein (APP) α and ß, Amyloid ß 38, 40 and 42 (Aß38, 40 and 42), Chitinase-3-like protein 1 (CHI3LI or YKL-40), Heart-type fatty acid binding protein (H-FABP).). RESULTS: Nine patients (mean age 69, 7 males) were included. Median total aortic coverage was 68% [33, 98]. One patient died during the 30-day post-operative period. After an initial stable phase for the first few postoperative hours, most biomarkers showed an upward trend compared with baseline in all patients with >50% increase in value for NFL in 5/9 patients, in 7/9 patients for Tau and in 5/9 patients for GFAP. One patient developed spinal cord and supratentorial brain ischemia, confirmed with MRI. In this case, NF-L, GFAP and tau were markedly elevated compared with non-SCI patients (maximum increase compared with baseline in the SCI patient versus mean value of the maximal increase for all other patients: NF-L 367% vs 79%%, GFAP 95608% versus 3433%, tau 1020% vs 192%). CONCLUSION: This study suggests an increase in all ten studied CSF biomarkers after coverage of spinal arteries during endovascular aortic repair. However, the pilot study was not able to establish a specific correlation between spinal fluid biomarker elevation and clinical symptoms of SCI due to small sample size and event rate.

Changes in Cerebrospinal Fluid Balance of TNF and TNF Receptors in Naïve Multiple Sclerosis Patients: Early Involvement in Compartmentalised Intrathecal Inflammation.

An imbalance of TNF signalling in the inflammatory milieu generated by meningeal immune cell infiltrates in the subarachnoid space in multiple sclerosis (MS), and its animal model may lead to increased cortical pathology. In order to explore whether this feature may be present from the early stages of MS and may be associated with the clinical outcome, the protein levels of TNF, sTNF-R1 and sTNF-R2 were assayed in CSF collected from 122 treatment-naïve MS patients and 36 subjects with other neurological conditions at diagnosis. Potential correlations with other CSF cytokines/chemokines and with clinical and imaging parameters at diagnosis (T0) and after 2 years of follow-up (T24) were evaluated. Significantly increased levels of TNF (fold change: 7.739; p < 0.001), sTNF-R1 (fold change: 1.693; p < 0.001) and sTNF-R2 (fold change: 2.189; p < 0.001) were detected in CSF of MS patients compared to the control group at T0. Increased TNF levels in CSF were significantly (p < 0.01) associated with increased EDSS change (r = 0.43), relapses (r = 0.48) and the appearance of white matter lesions (r = 0.49). CSF levels of TNFR1 were associated with cortical lesion volume (r = 0.41) at T0, as well as with new cortical lesions (r = 0.56), whilst no correlation could be found between TNFR2 levels in CSF and clinical or MRI features. Combined correlation and pathway analysis (ingenuity) of the CSF protein pattern associated with TNF expression (encompassing elevated levels of BAFF, IFN-γ, IL-1ß, IL-10, IL-8, IL-16, CCL21, haptoglobin and fibrinogen) showed a particular relationship to the interaction between innate and adaptive immune response. The CSF sTNF-R1-associated pattern (encompassing high levels of CXCL13, TWEAK, LIGHT, IL-35, osteopontin, pentraxin-3, sCD163 and chitinase-3-L1) was mainly related to altered T cell and B cell signalling. Finally, the CSF TNFR2-associated pattern (encompassing high CSF levels of IFN-ß, IFN-λ2, sIL-6Rα) was linked to Th cell differentiation and regulatory cytokine signalling. In conclusion, dysregulation of TNF and TNF-R1/2 pathways associates with specific clinical/MRI profiles and can be identified at a very early stage in MS patients, at the time of diagnosis, contributing to the prediction of the disease outcome.

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis.

Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.

Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis.

OBJECTIVE: To determine whether neuronal and neuroaxonal injury, neuroinflammation, and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals. METHODS: Biomarkers of neuronal (total tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40), and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n = 34) or LGI1/CASPR2 (n = 11) AME and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scale (mRS) scores were evaluated in a subset (n = 20) of longitudinally followed patients. RESULTS: Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, whereas markers of neuronal injury and synaptic function were stable (total tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated patients from cognitively normal individuals (area under the receiver operating characteristic curve 0.99; 95% confidence interval 0.97, >0.99). Younger age (ρ = -0.56; p = 0.01), lower VILIP-1 (ρ = -0.60; p < 0.01) and SNAP-25 (ρ = -0.54; p = 0.01), and higher log10(YKL-40/SNAP-25) (ρ = 0.48; p = 0.04) associated with greater disease severity (higher mRS score) in prospectively followed patients. Higher YKL-40 (ρ = 0.60; p = 0.02) and neurogranin (ρ = 0.55; p = 0.03) at presentation were associated with higher mRS scores 12 months following hospital discharge. CONCLUSIONS: CSF biomarkers suggest that neuronal integrity is acutely maintained in AME, despite neuroaxonal compromise. Low levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell surface receptors and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.

Potential Role of CHI3L1+ Astrocytes in Progression in MS.

OBJECTIVE: Neurofilament light protein (NfL) and chitinase 3-like 1 (CHI3L1) are biomarkers for acute neuroaxonal damage and local inflammation, respectively. Thus, we set out to evaluate how these biomarkers were associated with clinical features of demyelinating diseases in parallel with the expression in brain autopsies from patients with similar disease stages, assuming their comparability. METHODS: NfL and CHI3L1 in CSF and serum CHI3L1 were assessed retrospectively in a cross-sectional cohort of controls (n = 17) and patients diagnosed with MS (n = 224), relapsing (n = 163) or progressive (n = 61); neuromyelitis optica (NMO, n = 7); and acute disseminated encephalomyelitis (ADEM, n = 15). Inflammatory activity was evaluated at the time of sampling, and CSF biomarker levels were related to the degree of inflammation in 22 brain autopsy tissues. RESULTS: During a clinical attack, the CSF NfL increased in MS, NMO, and ADEM, whereas CHI3L1 was only elevated in patients with NMO and ADEM and in outlier MS patients with extensive radiologic activity. Outside relapses, CHI3L1 levels only remained elevated in patients with progressive MS. CHI3L1 was detected in macrophages and astrocytes, predominantly in areas of active demyelination, and its expression by astrocytes in chronic lesions was independent of lymphocyte infiltrates and associated with active neurodegeneration. CONCLUSIONS: Both CSF NfL and CHI3L1 augment during acute inflammation in demyelinating diseases. In MS, CHI3L1 may be associated with low-grade nonlymphocytic inflammation and active neurodegeneration and therefore linked to progressive disease. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CSF NfL and CHI3L1 levels increase in inflammatory brain diseases during acute inflammation.

Chitinase 3-like 1 and neurofilament light chain in CSF and CNS atrophy in MS.

OBJECTIVE: To investigate cross-sectional associations of CSF levels of neurofilament light chain (NfL) and of the newly emerging marker chitinase 3-like protein 1 (CHI3L1) with brain and spinal cord atrophy, which are established MRI markers of disease activity in MS, to study CHI3L1 and NfL in relapsing (RMS) and progressive MS (PMS), and to assess the expression of CHI3L1 in different cell types. METHODS: In a single-center study, 131 patients with MS (42 RMS and 89 PMS) were assessed for NfL and CHI3L1 concentrations in CSF, MRI-based spinal cord and brain volumetry, MS subtype, age, disease duration, and disability. We included 42 matched healthy controls receiving MRI. CHI3L1 expression of human brain cell types was examined in 2 published single-cell RNA sequencing data sets. RESULTS: CHI3L1 was associated with spinal cord volume (B = -1.07, 95% CI -2.04 to -0.11, p = 0.029) but not with brain volumes. NfL was associated with brain gray matter (B = -7.3, 95% CI -12.0 to -2.7, p = 0.003) but not with spinal cord volume. CHI3L1 was suitable to differentiate between progressive or relapsing MS (p = 0.015, OR 1.0103, CI for OR 1.002-1.0187), and its gene expression was found in MS-associated microglia and macrophages and in astrocytes of MS brains. CONCLUSIONS: NfL and CHI3L1 in CSF were differentially related to brain and spinal cord atrophy. CSF CHI3L1 was associated with spinal cord volume loss and was less affected than NfL by disease duration and age, whereas CSF NfL was associated with brain gray matter atrophy. CSF NfL and CHI3L1 measurement provides complementary information regarding brain and spinal cord volumes. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CSF CHI3L1 is associated with spinal cord volume loss and that CSF NfL is associated with gray matter atrophy.

Radiologically isolated syndrome: targeting miRNAs as prognostic biomarkers.

Aim: Some clinical and biological characteristics have been described as prognostic factors for clinical conversion into clinically definite multiple sclerosis in radiologically isolated syndrome (RIS) population. The aim of this study was to assess signatures of circulating miRNAs in those patients according to their conversion status after 5 years of follow-up. Patients & methods: OpenArray plates assessing 216 miRNA candidates were run in 15 RIS patients, and their relative abundances were analyzed. Results: A specific profile of deregulated circulating miRNAs (miR-144-3p, miR-448 and miR-653-3p in cerebrospinal fluid and miR-142-3p, miR-338-3p, miR-363-3p, miR-374b-5p, miR-424-5p, miR-483-3p in plasma) differentiated individuals who remained as RIS after 5 years of follow-up. Conclusion: Circulating miRNAs might be used as prognostic biomarkers for RIS patients.

Cerebrospinal Fluid and Blood CX3CL1 as a Potential Biomarker in Early Diagnosis and Prognosis of Dementia.

BACKGROUND: A growing body of evidence highlights the crucial role of neuroinflammation and chemokine involvement in cognitive impairment pathophysiology. Fractalkine (CX3CL1) appears to be a relevant causative factor in the development of dementia, particularly at the early stages of the disease. However, limited data are available on the levels of CX3CL1 in the cerebrospinal fluid (CSF) and blood. Additionally, to date, its utility as a biomarker for MCI or AD has not been studied. OBJECTIVE: The aim of the present study was to evaluate the clinical utility of CX3CL1 in the early diagnosis of cognitive impairment. We also compared the diagnostic usefulness of CX3CL1 with other biomarkers associated with neuroinflammation. METHODS: A total of 60 patients with cognitive impairment, including 42 patients with AD and 18 subjects with MCI, as well as 20 cognitively healthy controls were enrolled in the study. CSF and blood concentrations of CX3CL1, CCL-2, and YKL-40 were measured by ELISA. RESULTS: Significantly higher CSF and blood concentrations of CX3CL1 were observed in MCI and AD patients compared to older individuals without cognitive impairment. The increase in the levels of CX3CL1 and YKL-40 in non-demented subjects was associated with MCI. The area under the ROC curve for CX3CL1 in MCI subjects was larger in comparison to classical AD markers. CONCLUSION: Presented results indicate a crucial role of CX3CL1 in the pathology of cognitive impairment and the potential usefulness of this protein in the early diagnosis of MCI and AD.

CSF chitinase 3-like-1 association with disability of primary progressive MS.

OBJECTIVE: To assess the role of CSF chitinase 3-like-1 (CHI3L1), chitinase 3-like-2 (CHI3L2), and neurofilament light chain (NfL) in predicting the course of primary progressive MS (PPMS). METHODS: We analyzed CSF CHI3L1, CHI3L2, and NfL levels in 25 patients with PPMS with disease duration ≤10 years and no disease-modifying therapy for ≥6 months from the prospective Understanding Primary Progressive Multiple Sclerosis cohort study. CSF samples taken at disease diagnosis were analyzed using commercial ELISAs and following the manufacturer's instructions. Data on Expanded Disability Status Scale (EDSS) scores, disability progression, and cognitive function according to the Brief Repeatable Neuropsychological Battery were also assessed throughout the 1-year study follow-up. RESULTS: Increasing CHI3L1 levels correlated with higher EDSS scores at baseline (ρ = 0.490, 95% CI 0.118-0.742, p = 0.013) and month 12 (ρ = 0.455, 95% CI 0.063-0.725, p = 0.026) and tended to be associated with a higher risk of disability progression according to EDSS scores (OR = 1.008, 95% CI 0.999-1.017, p = 0.089). Increasing CHI3L2 levels also tended to correlate with lower baseline EDSS scores (ρ = -0.366, 95% CI -0.676-0.054, p = 0.086). There was no correlation with regard to NfL levels. CONCLUSIONS: This analysis supports the association between CSF CHI3L1 levels and neurologic disability according to EDSS scores in patients with PPMS. Other chitinase-like proteins such as CHI3L2 may also be involved. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CSF CHI3L1 is associated with neurologic disability in patients with PPMS.

CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate the CSF levels of chitinase proteins during the presymptomatic and early symptomatic phases of amyotrophic lateral sclerosis (ALS). METHODS: CSF samples were obtained from 16 controls, 55 individuals at-risk for ALS (including 18 carrying a mutation in C9ORF72, 33 in SOD1), 12 ALS patients, and 7 phenoconverters (individuals diagnosed with ALS during follow-up). At-risk individuals and phenoconverters were enrolled through the Pre-fALS study, which includes individuals carrying an ALS-associated gene mutation without disease manifestations at initial assessment. Longitudinal CSF collections, where possible, took place every 3-12 months for ALS patients and every 1-2 years for others. CSF levels of chitotriosidase 1 (CHIT1), chitinase-3-like protein 1 (CHI3L1, YKL-40) and chitinase-3-like protein 2 (CHI3L2, YKL-39) were measured by ELISA, along with CHIT1 activity. Longitudinal changes in at-risk individuals and phenoconverters were fitted to linear mixed effects models. RESULTS: Slowly rising levels of CHIT1 were observed over time in the at-risk individuals (slope 0.059 log10 [CHIT1] per year, P < 0.001). Among phenoconverters, CHIT1 levels and activity rose more sharply (0.403 log10 [CHIT1] per year, P = 0.005; 0.260 log10 [CHIT1 activity] per year, P = 0.007). Individual levels of both CHI3L1 and CHI3L2 remained relatively stable over time in all participant groups. INTERPRETATION: The CHIT1 neuroinflammatory response is a feature of the late presymptomatic to early symptomatic phases of ALS. This study does not suggest a long prodrome of upregulated glial activity in ALS pathogenesis, but strengthens the place of CHIT1 as part of a panel of biomarkers to objectively assess the impact of immune-modulatory therapeutic interventions in ALS.

Cerebrospinal Fluid YKL-40 and Neurogranin in Familial Alzheimer's Disease: A Pilot Study.

BACKGROUND: YKL-40 and neurogranin are promising additional cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) which reflect different underlying disease mechanisms. OBJECTIVE: To compare the levels of CSF YKL-40 and neurogranin between asymptomatic carriers of familial AD (FAD) mutations (MC) and non-carriers (NC) from the same families. Another objective was to assess changes in YKL-40 and neurogranin, from the presymptomatic to clinical phase of FAD. METHODS: YKL-40 and neurogranin, as well as Aß42, total tau-protein, and phospho-tau, were measured in the CSF of 14 individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G), and PSEN1 (p.H163Y), as well as in 17 NC from the same families. Five of the MC developed mild cognitive impairment (MCI) during follow-up. RESULTS: In this pilot study, there was no difference in either CSF YKL-40 or neurogranin when comparing the presymptomatic MC to the NC. YKL-40 correlated positively with expected years to symptom onset and to age in both the MC and the NC, while neurogranin had no correlation to either variable in either of the groups. A subgroup of the participants underwent more than one CSF sampling in which half of the MC developed MCI during follow-up. The longitudinal data showed an increase in YKL-40 levels in the MC as the expected symptom onset approached. Neurogranin remained stable over time in both the MC and the NC. CONCLUSION: These findings support a positive correlation between progression from presymptomatic to symptomatic AD and levels of CSF YKL-40, but not neurogranin.

Determination of chitinase 3-like 1 in cerebrospinal fluid in multiple sclerosis and other neurological diseases.

OBJECTIVES: Chitinase 3-like 1 (CHI3L1) is an extracellular monomeric single-chain glycoprotein expressed by many types of cells. Its elevated levels were found in cerebrospinal fluid in central nervous system (CNS) inflammatory diseases patients. The aim of the study was 1) to validate the reference interval of cerebrospinal fluid (CSF) CHI3L1 in a control group; 2) to measure the CHI3L1 concentration in different diagnosis groups .including multiple sclerosis (MS); and 3) to correlate those values with other biomarkers of axonal damage or neuroinflammation in different grous. METHODS: The study included 132 CSF samples sent to the Department of Clinical Biochemistry, Institute of Laboratory Diagnostics, University Hospital Ostrava. Concentrations of CHI3L1, CXCL13 chemokine, neurofilament light chains, and phosphorylated neurofilament heavy chains were determined by enzyme-linked immunosorbent assays. IgG oligoclonal bands were detected by isoelectric focusing in agarose gels followed by immunofixation. IgM and FLC oligoclonal bands were analyzed by IEF followed by affinity immunoblotting. The group consisted of 42 patients with multiple sclerosis, 14 with clinically isolated syndrome, 11 with other central nervous system inflammatory diseases, 46 with non-inflammatory diseases of the central nervous system, 4 with inflammatory diseases of the peripheral nervous system, and 15 controls. RESULTS: The estimated reference values of CHI3L1 were 28.6-182.5 µg.L-1. Statistically significant differences of CSF CHI3L1 concentrations were found among diagnosis groups (p < 0.0001), after age adjustment (p = 0.002). There was a statistically significant relationship between CHI3L1 and NFL in the MS group (rs = 0.460; P = 0.002), and between CHI3L1 and pNFH in the MS group (rs = 0.691; P < 0.001). No statistically significant difference was found in the categorical comparison of CHI3L1 in the MS group and other diagnostic groups as well as when using the Mann-Whitney U test for CHI3L1 with additional parameters with and without oligoclonal bands present. CONCLUSIONS: CSF CHI3L1 values differ depending on diagnosis and correlate significantly with concentrations of the axonal damage markers CSF neurofilament light chains, and CSF phosphorylated neurofilament heavy chains, but not with CSF concentrations of the inflammatory marker CXCL13. Thus, CSF CHI3L1 could be another promising prognostic, albeit probably etiologically nonspecific, biomarker of MS.

Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis.

BACKGROUND: Disease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset. METHODS: We did the Huntington's disease Young Adult Study (HD-YAS) in the UK. We recruited young adults with preHD and controls matched for age, education, and sex to ensure each group had at least 60 participants with imaging data, accounting for scan fails. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. All participants underwent detailed neuropsychiatric and cognitive assessments, including tests from the Cambridge Neuropsychological Test Automated Battery and a battery assessing emotion, motivation, impulsivity and social cognition (EMOTICOM). Imaging (done for all participants without contraindications) included volumetric MRI, diffusion imaging, and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and CSF collection. We did a cross-sectional analysis using general least-squares linear models to assess group differences and associations with age and CAG length, relating to predicted years to clinical onset. Results were corrected for multiple comparisons using the false discovery rate (FDR), with FDR <0·05 deemed a significant result. FINDINGS: Data were obtained between Aug 2, 2017, and April 25, 2019. We recruited 64 young adults with preHD and 67 controls. Mean ages of participants were 29·0 years (SD 5·6) and 29·1 years (5·7) in the preHD and control groups, respectively. We noted no significant evidence of cognitive or psychiatric impairment in preHD participants 23·6 years (SD 5·8) from predicted onset (FDR 0·22-0·87 for cognitive measures, 0·31-0·91 for neuropsychiatric measures). The preHD cohort had slightly smaller putamen volumes (FDR=0·03), but this did not appear to be closely related to predicted years to onset (FDR=0·54). There were no group differences in other brain imaging measures (FDR >0·16). CSF neurofilament light protein (NfL), plasma NfL, and CSF YKL-40 were elevated in this far-from-onset preHD cohort compared with controls (FDR<0·0001, =0·01, and =0·03, respectively). CSF NfL elevations were more likely in individuals closer to expected clinical onset (FDR <0·0001). INTERPRETATION: We report normal brain function yet a rise in sensitive measures of neurodegeneration in a preHD cohort approximately 24 years from predicted clinical onset. CSF NfL appears to be a more sensitive measure than plasma NfL to monitor disease progression. This preHD cohort is one of the earliest yet studied, and our findings could be used to inform decisions about when to initiate a potential future intervention to delay or prevent further neurodegeneration while function is intact. FUNDING: Wellcome Trust, CHDI Foundation.

Biomarker profiling beyond amyloid and tau: cerebrospinal fluid markers, hippocampal atrophy, and memory change in cognitively unimpaired older adults.

Brain changes occurring in aging can be indexed by biomarkers. We used cluster analysis to identify subgroups of cognitively unimpaired individuals (n = 99, 64-93 years) with different profiles of the cerebrospinal fluid biomarkers beta amyloid 1-42 (Aß42), phosphorylated tau (P-tau), total tau, chitinase-3-like protein 1 (YKL-40), fatty acid binding protein 3 (FABP3), and neurofilament light (NFL). Hippocampal volume and memory were assessed across multiple follow-up examinations covering up to 6.8 years. Clustering revealed one group (39%) with more pathological concentrations of all biomarkers, which could further be divided into one group (20%) characterized by tauopathy and high FABP3 and one (19%) by brain ß-amyloidosis, high NFL, and slightly higher YKL-40. The clustering approach clearly outperformed classification based on Aß42 and P-tau alone in prediction of memory decline, with the individuals with most tauopathy and FABP3 showing more memory decline, but not more hippocampal volume change. The results demonstrate that older adults can be classified based on biomarkers beyond amyloid and tau, with improved prediction of memory decline.

Degree of genetic liability for Alzheimer's disease associated with specific proteomic profiles in cerebrospinal fluid.

Genetic factors play a major role in Alzheimer's disease (AD) pathology, but biological mechanisms through which these factors contribute to AD remain elusive. Using a cerebrospinal fluid (CSF) proteomic approach, we examined associations between polygenic risk scores for AD (PGRS) and CSF proteomic profiles in 250 individuals with normal cognition, mild cognitive impairment, and AD-type dementia from the Alzheimer's Disease Neuroimaging Initiative. Out of 412 proteins, 201 were associated with PGRS. Hierarchical clustering analysis on proteins associated with PGRS at different single-nucleotide polymorphism p-value inclusion thresholds identified 3 clusters: (1) a protein cluster correlated with highly significant single-nucleotide polymorphisms, associated with amyloid-beta pathology and complement cascades; (2) a protein cluster associated with PGRS additionally including variants contributing to modest risk, involved in neural injury; (3) a protein cluster that also included less strongly associated variants, enriched with cytokine-cytokine interactions and cell adhesion molecules. These findings suggest that CSF protein levels reflect varying degrees of genetic liability for AD and may serve as a tool to investigate biological mechanisms in AD.