Cerebrospinal Fluid YKL-40 Research Articles

Pharmacodynamic effects of semorinemab on plasma and CSF biomarkers of Alzheimer's disease pathophysiology.

Semorinemab, an anti-tau monoclonal antibody, was assessed in two Phase II trials for Alzheimer's disease (AD). Plasma and cerebrospinal fluid (CSF) biomarkers provided insights into the drug's potential mechanism of action. Qualified assays were used to measure biomarkers of tau, amyloidosis, glial activity, neuroinflammation, synaptic function, and neurodegeneration from participant samples in Tauriel (NCT03289143) and Lauriet (NCT03828747) Phase II trials. Plasma phosphorylated Tau 181 (pTau181) and CSF chitinase-3-like protein 1 (YKL-40) increased following semorinemab treatment in both studies. In Lauriet, increasing plasma glial fibrillary protein (GFAP) concentrations stabilized with semorinemab, while this was not observed in Tauriel. Other AD pathophysiology biomarkers showed no consistent response to semorinemab. Increases in CSF YKL-40 suggest that semorinemab may stimulate microglia activation in the presence of AD-associated Tau pathology, but not in healthy controls. Stabilization of plasma GFAP in Lauriet indicates a possible impact on reactive gliosis in mild-to-moderate AD. Tauriel ClinicalTrials.gov Identifier: NCT03289143. Lauriet ClinicalTrials.gov Identifier: NCT03828747. Phase 1 ClinicalTrials.gov Identifier: NCT02820896. AD pathophysiology biomarkers were measured to assess the mechanism of action. Semorinemab increased CSF YKL-40 in participants with AD but not in healthy controls. Semorinemab possibly stabilized plasma GFAP in the Lauriet trial. Semorinemab treatment may activate microglia and moderate reactive gliosis.

Sex/gender effects of glial reactivity on preclinical Alzheimer's disease pathology.

Glial reactivity may contribute to sex/gender differences in Alzheimer's disease (AD) pathophysiology. Here, we investigated the differential effect of cerebrospinal fluid (CSF) glial markers on AD pathology and neurodegeneration by sex/gender among cognitively unimpaired older adults at increased risk of developing AD. We included 397 participants from the ALFA+ cohort with CSF Aβ42/40, p-tau181, sTREM2, YKL40, and GFAP, magnetic resonance imaging-based hippocampal volume (n = 299), and amyloid burden (centiloids) measured with [18F] flutemetamol positron emission tomography (n = 341). We ran multiple linear regression models to assess the association between glial markers, AD pathology and hippocampal volumes and their interaction with sex/gender, usingFalse Discovery Rateto correctfor multiple comparisons. Glial markers significantly contributed to explain amyloid burden, tau pathology, and hippocampal volumes, beyond age and/or primary AD pathology in a sex/gender-specific manner. Compared to men, women showed increased amyloid burden (centiloids) and CSF p-tau181 with increasing levels of sTREM2 and YKL40, and YKL40 and GFAP, respectively. Compared to women, men with greater tau burden showed lower hippocampal volumes as CSF YKL40 levels increased. Overall, our findings suggest that glial reactivity may contribute to sex/gender differences in AD progression, mostly, downstream amyloid. Further research identifying sex/gender-specific temporal dynamics in AD development is warranted to inform clinical trials.

Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study.

We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array. We identified Bonferroni-significant differential methylation associated with CSF YKL-40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL-40 levels correlating with plasma YKL-40 levels. A co-localization analysis showed shared genetic variants underlying YKL-40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co-methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development. We conducted the most comprehensive epigenome-wide association study (EWAS) of AD-relevant CSF biomarkers to date. Future work should explore the relationship between YKL-40 genotype, DNA methylation, and protein levels in the brain. Blood DNA methylation was assessed in the EMIF-AD MBD study. Epigenome-wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)-relevant cerebrospinal fluid (CSF) biomarker measures. Five Bonferroni-significant loci were associated with YKL-40 levels and seven with neurofilament light chain (NfL). DNA methylation in YKL-40 co-localized with previously reported genetic variation. DNA methylation potentially mediates the effect ofsingle-nucleotide polymorphisms (SNPs) in YKL-40 on CSF protein levels.

CSF glial biomarkers are associated with cognition in individuals at risk of Alzheimer's disease.

We examined whether baseline glial markers soluble triggering receptor expressed on myeloid cell 2 (sTREM2), chitinase 3-like protein 1 (YKL-40), and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF), and plasma GFAP are associated with cognitive change in cognitively unimpaired (CU) individuals at risk of Alzheimer's disease (AD). A total of 353 CU (mean age 60.9 years) participants were included (mean follow-up time 3.28 years). Linear regression models with cognition as outcome were used. We also tested whether amyloid beta (Aβ) status modified these associations. Higher baseline CSF sTREM2 was associated with a positive global cognition (Preclinical Alzheimer's Cognitive Composite) rate of change, and better memory and executive outcomes, independently of AD pathology. Higher baseline plasma GFAP was associated with a decline on attention rate of change. Stratified analyses by Aβ status showed that CSF sTREM2 and YKL-40 were positively associated with executive functioning in amyloid negative (Aβ-) individuals. Our results suggest that a TREM2-mediated microglial response may be associated with better longitudinal cognitive performance. Higher cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cell 2 (sTREM2) relates to better longitudinal cognitive performance. The association between CSF sTREM2 and cognition is independent of Alzheimer's disease (AD) pathology. Targeting microglial reactivity may be a therapeutic strategyfor AD prevention.

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

A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). 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. 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 Aβ42/Aβ40, plasma Aβ42/Aβ40, 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. 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.

Longitudinal cerebrospinal fluid measurements show glial hypo- and hyperactivation in predementia Alzheimer’s disease

BackgroundBrain innate immune activation is associated with Alzheimer’s disease (AD), but degrees of activation may vary between disease stages. Thus, brain innate immune activation must be assessed in longitudinal clinical studies that include biomarker negative healthy controls and cases with established AD pathology. Here, we employ longitudinally sampled cerebrospinal fluid (CSF) core AD, immune activation and glial biomarkers to investigate early (predementia stage) innate immune activation levels and biomarker profiles.MethodsWe included non-demented cases from a longitudinal observational cohort study, with CSF samples available at baseline (n = 535) and follow-up (n = 213), between 1 and 6 years from baseline (mean 2.8 years). We measured Aβ42/40 ratio, p-tau181, and total-tau to determine Ab (A+), tau-tangle pathology (T+), and neurodegeneration (N+), respectively. We classified individuals into these groups: A−/T−/N−, A+/T−/N−, A+/T+ or N+, or A−/T+ or N+. Using linear and mixed linear regression, we compared levels of CSF sTREM2, YKL-40, clusterin, fractalkine, MCP-1, IL-6, IL-1, IL-18, and IFN-γ both cross-sectionally and longitudinally between groups. A post hoc analysis was also performed to assess biomarker differences between cognitively healthy and impaired individuals in the A+/T+ or N+ group.ResultsCross-sectionally, CSF sTREM2, YKL-40, clusterin and fractalkine were higher only in groups with tau pathology, independent of amyloidosis (p < 0.001, A+/T+ or N+ and A−/T+ or N+, compared to A−/T−/N−). No significant group differences were observed for the cytokines CSF MCP-1, IL-6, IL-10, IL18 or IFN-γ. Longitudinally, CSF YKL-40, fractalkine and IFN-γ were all significantly lower in stable A+/T−/N− cases (all p < 0.05). CSF sTREM2, YKL-40, clusterin, fractalkine (p < 0.001) and MCP-1 (p < 0.05) were all higher in T or N+, with or without amyloidosis at baseline, but remained stable over time. High CSF sTREM2 was associated with preserved cognitive function within the A+/T+ or N+ group, relative to the cognitively impaired with the same A/T/N biomarker profile (p < 0.01).ConclusionsImmune hypoactivation and reduced neuron–microglia communication are observed in isolated amyloidosis while activation and increased fractalkine accompanies tau pathology in predementia AD. Glial hypo- and hyperactivation through the predementia AD continuum suggests altered glial interaction with Ab and tau pathology, and may necessitate differential treatments, depending on the stage and patient-specific activation patterns.

Peripheral Blood and Cerebrospinal Fluid Levels of YKL-40 in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

The pathogenesis associated with Alzheimer's disease (AD) is particularly complicated, and early diagnosis and course monitoring of the disease are not ideal based on the available core biomarkers. As a biomarker closely related to neuroinflammation, YKL-40 provides a potential scalable approach in AD, but its association remains controversial and inconclusive with AD. We conducted this study to assess the utility of YKL-40 levels in peripheral blood and cerebrospinal fluid (CSF) of AD patients and healthy controls (HCs) by meta-analysis. We systematically searched and screened relevant trials for comparing YKL-40 levels between AD patients and HCs in PubMed, Embase, Cochrane, and Web of Science, with a search deadline of 14 March 2023 for each database. A total of 17 eligible and relevant studies involving 1811 subjects, including 949 AD patients and 862 HCs, were included. The results showed that YKL-40 levels in the peripheral blood of AD patients and HCs did not possess significant differences. Subgroup analysis showed YKL-40 significantly differed in plasma (SMD = 0.527, 95%CI: [0.302, 0.752]; p = 0.000), but did not in serum. In the case of comparison with HCs, YKL-40 was significantly higher in CSF of AD patients (SMD = 0.893, 95%CI: [0.665, 1.121]; p = 0.000). Besides that, when we performed a combined analysis of total YKL-40 in both peripheral blood and CSF, overall YKL-40 concentrations were also significantly increased among AD patients (SMD = 0.608, 95%CI: [0.272, 0.943]; p = 0.000). YKL-40 provides support and rationale for the neuroinflammatory pathogenesis of AD. The significance of CSF levels of YKL-40 for early screening of AD is definite. Plasma levels of YKL-40 also appear to assist in discriminating AD patients from HCs, which facilitates early screening and monitoring of the natural course of AD.

Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer's disease progression.

We studied how biomarkers of reactive astrogliosis mediate the pathogenic cascade in the earliest Alzheimer's disease (AD) stages. We performed path analysis on data from 384 cognitively unimpaired individuals from the ALzheimer and FAmilies (ALFA)+ study using structural equation modeling to quantify the relationships between biomarkers of reactive astrogliosis and the AD pathological cascade. Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/40 was associated with Aβ aggregation on positron emission tomography (PET) and with CSF p-tau181 , which was in turn directly associated with CSF neurofilament light (NfL). Plasma glial fibrillary acidic protein (GFAP) mediated the relationship between CSF Aβ42/40 and Aβ-PET, and CSF YKL-40 partly explained the association between Aβ-PET, p-tau181 , and NfL. Our results suggest that reactive astrogliosis, as indicated by different fluid biomarkers, influences the pathogenic cascade during the preclinical stage of AD. While plasma GFAP mediates the early association between soluble and insoluble Aβ, CSF YKL-40 mediates the latter association between Aβ and downstream Aβ-induced tau pathology and tau-induced neuronal injury. Lower CSF Aβ42/40 was directly linked to higher plasma GFAP concentrations. Plasma GFAP partially explained the relationship between soluble Aβ and insoluble Aβ. CSF YKL-40 mediated Aβ-induced tau phosphorylation and tau-induced neuronal injury.

Serum and CSF brain damage markers NFL and GFAP correlate with tick-borne encephalitis disease severity - a multicenter study on Lithuanian and Swedish patients.

Our aim was to examine the correlation between biomarkers of neuronal and glial cell damage and severity of disease in patients with tick-borne encephalitis. One hundred and fifteen patients with tick-borne encephalitis diagnosed in Lithuania and Sweden were prospectively included, and CSF and serum samples obtained shortly after hospitalization. Using pre-defined criteria, cases were classified as mild, moderate, or severe TBE. Additionally, the presence of spinal nerve paralysis (myelitis) and/or cranial nerve affection were noted. Concentrations of brain cell biomarkers glial fibrillary acidic protein (GFAP), YKL40, S-100B, neurogranin, neurofilament light (NFL), and tau were analyzed in CSF, and in addition, NFL, GFAP and S-100B levels were measured in serum. The Jonckheere Terpstra test was used for group comparisons of continuous variables and Spearman's partial correlation test to adjust for age. CSF and serum concentrations of GFAP and NFL correlated with disease severity, independent of age, and with presence of nerve paralysis. The markers neurogranin, YKL40, tau and S-100B in CSF and S-100B in serum were detected, but their concentrations did not correlate with disease severity. Neuronal cell damage and astroglial cell activation with increased NFL and GFAP in CSF and serum were associated with a more severe disease, independent of age. Increased GFAP and NFL concentrations in CSF and NFL in serum were also indicative of spinal and/or cranial nerve damage. NFL and GFAP are promising prognostic biomarkers in TBE, and future studies should focus on determining the association between these biomarkers and long-term sequelae.

Central and Peripheral Inflammation in Mild Cognitive Impairment in the Context of Alzheimer's Disease.

Mild cognitive impairment (MCI) is characterized by an abnormal decline in mental and cognitive function compared with normal cognitive aging. It is an underlying condition of Alzheimer's disease (AD), an irreversible neurodegenerative disease. In recent years, neuroinflammation has been investigated as a new leading target that contributes to MCI progression into AD. Understanding the mechanism underlying inflammatory processes involved in the early onset of the disease could help find a safe and effective way to diagnose and treat patients. In this article, we assessed over twenty different blood and cerebrospinal fluid (CSF) inflammatory biomarker concentrations with immunoassay methods in patients with MCI (mild cognitive impairment), non-impaired control (NIC), and serum healthy control (HC). We performed group comparisons and analyzed in-group correlations between the biomarkers. We included 107 participants (mean age: 64.7 ± 7.8, women: 58.9%). CSF osteopontin and YKL-40 were significantly increased in the MCI group, whereas serum C-reactive protein and interleukin-6 were significantly higher (p < 0.001) in the NIC group compared with the MCI and HC groups. Stronger correlations between interleukin-1β and inflammasome markers were observed in the serum of the MCI group. We confirmed specific inflammatory activation in the central nervous system and interleukin-1β pathway upregulation in the serum of the MCI cohort.

Increased Cerebrospinal Fluid Levels of Soluble Triggering Receptor Expressed on Myeloid Cells 2 and Chitinase-3-Like Protein 1 in Idiopathic Normal-Pressure Hydrocephalus.

Neurodegenerative disease pathology is associated with neuroinflammation, but evidence on idiopathic normal pressure hydrocephalus (iNPH) remains limited and cerebrospinal fluid (CSF) biomarker profiles need to be elucidated. To investigate whether iNPH pathological mechanisms are associated with greater CSF markers of core Alzheimer's disease pathology (amyloid-β42 (Aβ42), phosphorylated tau (P-tau)), neurodegeneration (total tau (T-tau)), and neuroinflammation (soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40)). The study analyzed lumbar CSF samples from 63 patients with iNPH and 20 age-matched orthopedic surgery patients who had no preoperative gait or cognitive impairment (control group). Aβ42, T-tau, P-tau, sTREM2, and YKL-40 in different subgroups were investigated. CSF sTREM2 levels were significantly higher in the iNPH group than in the control group, but no significant between-group difference was noted in YKL-40. Moreover, YKL-40 levels were significantly higher in the tap test non-responders than in the tap test responders (p = 0.021). At the 1-year follow-up after shunt surgery, the CSF P-tau levels were significantly lower (p = 0.020) in those with gait improvement and the CSF sTREM2 levels were significantly lower (p = 0.041) in those with cognitive improvement. In subgroup analysis, CSF sTREM2 levels were strongly correlated with CSF YKL-40 in the iNPH group (r = 0.443, p < 0.001), especially in the tap test non-responders (r = 0.653, p = 0.002). YKL-40 and sTREM2 are disease-specific markers of neuroinflammation, showing higher CSF levels in iNPH. In addition, sTREM2 is positively associated with YKL-40, indicating that interactions of glial cells play an important role in iNPH pathogenesis.

Elevated cerebrospinal fluid YKL-40 levels in patients with anti-gamma-aminobutyric- acid-B receptor encephalitis

ObjectiveAnti-gamma-aminobutyric-acid-B receptor (GABAbR) encephalitis is a rare form of autoimmune encephalitis. Until now, there are few biomarkers that can indicate the severity and prognosis of patients with anti-GABAbR encephalitis. The objective of this study was to exam the changes of chitinase-3-like protein 1 (YKL-40) in patients with anti-GABAbR encephalitis. In addition, whether YKL-40 could indicate the disease severity was also evaluated. MethodsThe clinical features of 14 patients with anti-GABAbR encephalitis and 21 patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis were retrospectively studied. YKL-40 levels in serum and cerebral fluid (CSF) of patients were detected by enzyme-linked immunosorbent assay. The correlation of modified Rankin Scale (mRS) score of encephalitis patients and YKL40 levels were analyzed. ResultsYKL-40 levels in CSF were significantly higher in patients with anti-GABAbR encephalitis or anti-NMDAR encephalitis than those in controls. YKL-40 levels between these two encephalitis groups were not different. Moreover, YKL-40 levels in CSF from patients with anti-GABAbR encephalitis were positively correlated with the mRS score at admission and at 6-month follow-up. ConclusionYKL-40 level is elevated in CSF from patients with anti-GABAbR encephalitis at early disease stage. YKL-40 may be a potential biomarker indicating the prognosis of patients with anti-GABAbR encephalitis.

Molecules of senescent glial cells differentiate Alzheimer’s disease from ageing

BackgroundAgeing is a major risk factor for Alzheimer’s disease (AD), which is accompanied by cellular senescence and thousands of transcriptional changes in the brain.ObjectivesTo identify the biomarkers in the cerebrospinal...

Early approaches of YKL-40 as a biomarker and therapeutic target for Parkinson's disease.

Aim: To investigate whether the estimation of cerebrospinal fluid (CSF) and brain YKL-40 levels may be used as an efficient biomarker for Parkinson's disease (PD). Methods: Lipopolysaccharides (LPS) was injected into the right substantia nigra pars compacta (SNpc). Rats were divided into: control group, early LPS-induced PD group (14 days), and advanced LPS-induced PD group (28 days). YKL-40 and other related factors were detected in CSF and brain tissue. Results: Increased expression of YKL-40 was observed in brain tissue and CSF of PD-induced rats associated with triggered inflammatory cytokine release. Conclusion: The current study was limited to detecting YKL-40 and other inflammatory factors in brain and CSF. YKL-40 may be considered as an early biomarker and therapeutic target for PD.

Cerebrospinal fluid YKL‐40 level evolution is associated with autoimmune encephalitis remission

Because of its heterogeneity in clinical presentation and course, predicting autoimmune encephalitis (AIE) evolution remains challenging. Hence, our aim was to explore the correlation of several biomarkers with the clinical course of disease. Thirty-seven cases of AIE were selected retrospectively and divided into active (N= 9), improved (N= 12) and remission (N= 16) AIE according to their disease evolution. Nine proteins were tested in both serum and cerebrospinal fluid (CSF) at diagnosis (T0) and during the follow-up (T1), in particular activated MMP-9 (MMP-9A) and YKL-40 (or chitinase 3-like 1). From diagnosis to revaluation, AIE remission was associated with decreased YKL-40 and MMP-9A levels in the CSF, and with decreased NfL and NfH levels in the serum. The changes in YKL-40 concentrations in the CSF were associated with (1) still active AIE when increasing >10% (P-value=0.0093); (2) partial improvement or remission when the changes were between +9% and -20% (P-value=0.0173); and remission with a reduction > -20% (P-value=0.0072; overall difference between the three groups: P-value=0.0088). At T1, the CSF YKL-40 levels were significantly decreased between active and improved as well as improved and remission AIE groups but with no calculable threshold because of patient heterogeneity. The concentration of YKL-40, a cytokine-like proinflammatory protein produced by glial cells, is correlated in the CSF with the clinical course of AIE. Its introduction as a biomarker may assist in following disease activity and in evaluating therapeutic response.

Astrocyte biomarker signatures of amyloid-β and tau pathologies in Alzheimer’s disease

Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer’s disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-β (Aβ) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for Aβ ([18F]AZD4694) and tau ([18F]MK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated Aβ-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not Aβ-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of Aβ and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain Aβ and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression.

Galectin-3 is elevated in CSF and is associated with Aβ deposits and tau aggregates in brain tissue in Alzheimer’s disease

Galectin-3 (Gal-3) is a beta-galactosidase binding protein involved in microglial activation in the central nervous system (CNS). We previously demonstrated the crucial deleterious role of Gal-3 in microglial activation in Alzheimer’s disease (AD). Under AD conditions, Gal-3 is primarily expressed by microglial cells clustered around Aβ plaques in both human and mouse brain, and knocking out Gal-3 reduces AD pathology in AD-model mice. To further unravel the importance of Gal-3-associated inflammation in AD, we aimed to investigate the Gal-3 inflammatory response in the AD continuum. First, we measured Gal-3 levels in neocortical and hippocampal tissue from early-onset AD patients, including genetic and sporadic cases. We found that Gal-3 levels were significantly higher in both cortex and hippocampus in AD subjects. Immunohistochemistry revealed that Gal-3+ microglial cells were associated with amyloid plaques of a larger size and more irregular shape and with neurons containing tau-inclusions. We then analyzed the levels of Gal-3 in cerebrospinal fluid (CSF) from AD patients (n = 119) compared to control individuals (n = 36). CSF Gal-3 levels were elevated in AD patients compared to controls and more strongly correlated with tau (p-Tau181 and t-tau) and synaptic markers (GAP-43 and neurogranin) than with amyloid-β. Lastly, principal component analysis (PCA) of AD biomarkers revealed that CSF Gal-3 clustered and associated with other CSF neuroinflammatory markers, including sTREM-2, GFAP, and YKL-40. This neuroinflammatory component was more highly expressed in the CSF from amyloid-β positive (A+), CSF p-Tau181 positive (T+), and biomarker neurodegeneration positive/negative (N+/−) (A + T + N+/−) groups compared to the A + T−N− group. Overall, Gal-3 stands out as a key pathological biomarker of AD pathology that is measurable in CSF and, therefore, a potential target for disease-modifying therapies involving the neuroinflammatory response.

119 NeuroToolkit CSF biomarkers track the progression of Alzheimer’s disease at very early stages

IntroductionNeuroToolkit is a set of cerebrospinal fluid (CSF) biomarkers developed to identify Alzheimer’s disease co-pathologies, identify and characterize disease progression and treatment response. We assess the association between NeuroToolkit biomarkers and cerebral amyloid deposition in the ALFA+ cohort [1].Methods326 cognitively unimpaired individuals from the ALFA+ cohort [1] underwent a lumbar puncture and amyloid [18F]flutemetamol PET imaging. Biomarkers in NeuroToolkit (Figure 1) were determined using prototype Roche Elecsys® assays. CSF pTau levels were measured using the Elecsys® CSF assay. We cal- culated cross-correlation values between NeuroToolkit biomarkers and Centiloids. Voxel-wise associations between NeuroToolkit biomarkers and [18F]flutemetamol images were sought, accounting for the effect of various demographics. Additional analyses were performed after correcting also for the Aα42/40 ratio or Centiloid values.ResultsFigure 1. Shows associations between NeuroToolkit biomarkers and Centiloids. NeuroToolkit bio- markers were significantly associated with cerebral amyloid deposition measured by [18F]flutemetamol PET (Figure 2). Correcting for global amyloid deposition, higher levels CSF YKL-40, an astroglial activity marker, were associated to increased cerebral amyloid deposition in the inferior and lateral temporal lobe, in parietal and orbitofrontal areas, and the caudate heads (Figure 3).ConclusionsResults of NeuroToolkit biomarkers support early involvement of the astroglial response to cerebral amyloid deposition.DisclosureThis study was conducted through a collaboration with Roche Diagnostics International. These data will be presented at Advances in Alzheimer’s and Parkinson’s Therapies. Ref: Molinuevo. TRCI 2 (2016) 82–92gwendlyn.kollmorgen@roche.com

Assessment of the YKL-40 concentration in patients with tick-borne encephalitis

Tick-borne encephalitis (TBE) is a viral infection of the central nervous system (CNS) caused by tick-borne encephalitis virus (TBEV). It might take several clinical courses such as: meningitis, meningoencephalitis or meningoencephalomyelitis. The aim this study was to compare the YKL-40 concentration in cerebrospinal fluid (CSF) of patients with different clinical presentations of TBE and patients with excluded meningitis (control group). The concentration of YKL-40 in CSF was determined using Fujirebio tests (Ghent, Belgium) in 32 patients with TBE: Group I—patients with meningoencephalitis (n = 16); Group II—patients with meningitis (n = 16). The control group (CG) consisted of 17 patients in whom any inflammatory process in central nervous system was excluded. The concentration of YKL-40 was significantly higher in encephalitis group than in the CG after 7 days from the last dose of treatment. The concentration in patients with neuroinflammation had a significantly different concentration of YKL-40 compared to patients from the neuroinflammation control group. The ROC curve analysis indicates that CSF YKL-40 concentration at cut-off 783.87 differentiated TBE patients from CG with 100% specificity and 70% sensitivity and CSF YKL-40 concentration at cut-off 980.11 differentiated meningitis from meningoencephalitis with 87.5% specificity and 62.5% sensitivity. YKL-40 takes part in TBE pathogenesis, its concentration is the highest at the early stage of CNS involvement and decreases in the convalescent period. As YKL-40 was significantly higher in the meningitis than in the meningoencephalitis group, it might be used as biomarker in differentiation of these clinical forms of TBE.

Alzheimer’s disease genetic risk variants show brain cell type‐specific associations with protein levels in cerebrospinal fluid

Neuronal dysfunction is central to the clinical manifestation of Alzheimer's disease (AD). However, genome-wide studies also suggest important roles for non-neuronal brain cell-types such as microglia and astrocytes. Our objective was to study whether brain cell type-specific polygenic risk scores (PGRS) for AD, including single nucleotide polymorphisms (SNPs) of genes expressed in one brain cell type, showed relationships with levels of cerebrospinal fluid (CSF) AD markers in individuals across the clinical spectrum of AD. We selected 1,535 subjects (552 controls/709 mild cognitive impairment/274 AD-dementia, age 71±8 years, 48%female) from the ADNI (N=617) and EMIF-AD MBD (N=918) study, who had genetic data available. We labelled AD risk genes as specific for neurons, astrocytes, microglia, oligodendrocytes or endothelial cells when more than 50% of the gene expression was produced by one cell type (otherwise as 'non-specific') according to the BRAIN RNASeq database (Zhang et al., 2014). We calculated cell type-specific-PGRS with cell type-corresponding SNPs (P<5e-8 ) using weights from De Rojas et al., (2020) AD case-control summary statistics. Associations between cell type-specific-PGRS and CSF biomarkers (amyloid-beta, total tau (t-tau), phosphorylated tau (p-tau), neurofilament light, neurogranin and YKL-40) were examined using linear regressions, adjusted for population structure, study, age and sex. Of 40 AD risk genes, 26 had detectable RNA levels in at least one brain cell type. Of these, sixteen were cell type-specific: 11 were microglia-specific, 4 astrocyte-specific (including APOE) and 1 neuron-specific (Figure 1). Astrocyte-PGRS (P=1.4e-6 , Pwithout_APOE =.1) and microglia-PGRS (P=6.3e-3 ) were increased in AD-type dementia compared to controls, whereas other PGRS were not (Figure 2). Astrocyte-PGRS (including APOE) were most strongly associated with CSF amyloid-beta (P=1.4e-31 ), t-tau (P=6.3e-10 ), p-tau (P=4.9e-9 ), and neurogranin (P=0.01). Astrocyte-specific (excluding APOE) and microglia-specific PGRS-AD also associated with CSF amyloid-beta (P<0.05), and with p-tau at trend-level (Figure 2). Apart from the tentative association between neuron-PGRS and CSF YKL-40, no other associations were observed. Findings indicate that AD risk variants have cell type-specific associations with amyloid and tau pathology, which seems mostly expressed by astrocytes (also without APOE) and microglia, suggesting that these cell types play a role in amyloid pathogenesis.