Interactions of synaptic and inflammatory biomarkers in Alzheimer’s Disease

BackgroundLoss of synaptic functionality has been recently identified as an early-stage indicator of neurological diseases. Consequently, monitoring changes in synaptic protein levels may be relevant for observing disease evolution or treatment responses in patients. Here, we have studied the relationship between fluid biomarkers of neurodegeneration and synaptic dysfunction in patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD), and subjective cognitive decline (SCD).MethodsThe exploratory cohort consisted of cerebrospinal fluid (CSF) samples (n = 60) from patients diagnosed with AD (n = 20), FTD (n = 20), and SCD (n = 20) from the Amsterdam Dementia Cohort. We developed two novel immunoassays for the synaptic proteins synaptosomal-associated protein-25 (SNAP25) and vesicle-associated membrane protein-2 (VAMP2). We measured the levels of these biomarkers in CSF, in addition to neuronal pentraxin-2 (NPTX2), glutamate ionotropic receptor-4 (GluR4), and neurogranin (Ng) for this cohort. All in-house immunoassays were validated and analytically qualified prior to clinical application. CSF neurogranin (Ng) was measured using a commercially available ELISA.ResultsThis pilot study indicated that SNAP25, VAMP2, and Ng may not be specific biomarkers for AD as their levels were significantly elevated in patients with both AD and FTD compared to SCD. Moreover, the strength of the correlations between synaptic proteins was lower in the AD and FTD clinical groups compared to SCD. SNAP25, VAMP2, and Ng correlated strongly with each other as well as with total Tau (Tau) and phosphorylated Tau (PTau) in all three clinical groups. However, this correlation was weakened or absent with NPTX2 and GluR4. None of the synaptic proteins correlated to neurofilament light (NfL) in any clinical group.ConclusionThe correlation of the synaptic biomarkers with CSF Tau and PTau but the lack thereof with NfL implies that distinct pathological pathways may be involved in synaptic versus axonal degeneration. Our results reflect the diversity of synaptic pathology in neurodegenerative dementias.

BackgroundPeople with multiple sclerosis (PwMS) experience various degrees of cognitive impairment (CI). Synaptic dysfunction may contribute to CI in PwMS but cerebrospinal fluid (CSF) synaptic biomarkers are unexplored in MS.ObjectiveTo assess the role of CSF synaptosomal-associated protein 25 (SNAP-25), β-synuclein, neurogranin and neurofilament light chain protein (NfL) in patients with early relapsing MS with and without CI.MethodsWe measured CSF SNAP-25, β-synuclein, and neurogranin in 48 untreated PwMS and 50 controls with other neurological diseases (ONDs) and tested their associations with neuropsychological and MRI data.ResultsCSF synaptic protein levels did not discriminate between MS subjects and patients with ONDs, with only SNAP-25 values being slightly increased in MS (p = 0.009). CSF synaptic markers were positively correlated with each other and with CSF NfL. Moreover, lower biomarker levels were found to be correlated with longer disease duration and lower brain volumes (especially of the thalamus). Moreover, we found significantly lower CSF SNAP-25 (p = 0.025), β-synuclein (p = 0.044), and neurogranin (p = 0.007) levels in PwMS with vs. without domain-specific cognitive impairment.ConclusionLower CSF synaptic biomarker levels were found in PwMS with longer disease duration and lower brain volumes and may identify PwMS at risk of CI.

The interaction between natural killer group 2 members D and their ligands (NKG2D-NKG2DLs) may play a role in the immunopathology of multiple sclerosis (MS). Owing to their measurable presence in biofluids, soluble NKG2DLs may serve as potential biomarkers for disease activity. NKG2DL family proteins have been previously investigated in the central nervous system (CNS) or biofluids of MS patients but have typically been analyzed individually rather than collectively. To our knowledge, this was the first study to comprehensively evaluate soluble forms of MHC class I chain-related proteins A and B (MICA and MICB), UL16 binding protein 4 (ULBP4), and neurofilament light chains (NFLs) in the serum and cerebrospinal fluid (CSF) of relapsing-remitting MS patients, patients with multifocal demyelinating CNS damage (Pre-MS observation group), and a control group. Results revealed comparable levels of NKG2DLs in the serum and CSF between the groups. This suggested that they may not be suitable as diagnostic and predictive markers in MS. However, the analysis confirmed the established significance of NFL, demonstrating its elevated levels in CSF and serum from MS patients compared with other groups, along with a notable correlation between NFL levels in serum and CSF.

ObjectiveTo investigate whether cerebrospinal fluid (CSF) neurogranin concentrations are altered in sporadic Creutzfeldt-Jakob disease (CJD), comparatively with Alzheimer’s disease (AD), and associated with neuronal degeneration in brain tissue.MethodsCSF neurogranin, total...

BackgroundWhile neurogranin has no value as plasma biomarker for Alzheimer’s disease, it may be a potential blood biomarker for traumatic brain injury. This evokes the question whether there are changes in neurogranin levels in blood in other conditions of brain injury, such as acute ischemic stroke (AIS).MethodsWe therefore explored neurogranin in paired cerebrospinal fluid (CSF)/plasma samples of AIS patients (n = 50) from a well-described prospective study. In parallel, we investigated another neuronal protein, i.e. tau, which has already been suggested as potential AIS biomarker in CSF and blood. ELISA as well as Single Molecule Array (Simoa) technology were used for the biochemical analyses. Statistical analyses included Shapiro-Wilk testing, Mann-Whitney analyses and Pearson’s correlation analysis.ResultsIn contrast to tau, of which high levels in both CSF and plasma were related to stroke characteristics like severity and long-term outcome, plasma neurogranin levels were only correlated with infarct volume. Likewise, CSF neurogranin levels were significantly higher in patients with an infarct volume > 5 mL than in patients with smaller infarct volumes. Finally, neurogranin and tau were significantly correlated in CSF, whereas a weaker relationship was observed in plasma.ConclusionsThese findings indicate that although plasma and CSF neurogranin may reflect the volume of acute cerebral ischemia, this synaptic protein is less likely to be a potential AIS biomarker. Levels of tau correlated with severity and outcome of stroke in both plasma and CSF, in the present study as well as previous reports, confirming the potential of tau as an AIS biomarker.

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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.

Cerebrospinal fluid (CSF) and brain tissue sodium levels increase during migraine. However, little is known regarding the underlying mechanisms of sodium homeostasis disturbance in the brain during the onset and propagation of migraine. Exploring the cause of sodium dysregulation in the brain is important, since correction of the altered sodium homeostasis could potentially treat migraine. Under the hypothesis that disturbances in sodium transport mechanisms at the blood-CSF barrier (BCSFB) and/or the blood-brain barrier (BBB) are the underlying cause of the elevated CSF and brain tissue sodium levels during migraines, we developed a mechanistic, differential equation model of a rat's brain to compare the significance of the BCSFB and the BBB in controlling CSF and brain tissue sodium levels. The model includes the ventricular system, subarachnoid space, brain tissue and blood. Sodium transport from blood to CSF across the BCSFB, and from blood to brain tissue across the BBB were modeled by influx permeability coefficients PBCSFB and PBBB, respectively, while sodium movement from CSF into blood across the BCSFB, and from brain tissue to blood across the BBB were modeled by efflux permeability coefficients and , respectively. We then performed a global sensitivity analysis to investigate the sensitivity of the ventricular CSF, subarachnoid CSF and brain tissue sodium concentrations to pathophysiological variations in PBCSFB, PBBB, and . Our results show that the ventricular CSF sodium concentration is highly influenced by perturbations of PBCSFB, and to a much lesser extent by perturbations of . Brain tissue and subarachnoid CSF sodium concentrations are more sensitive to pathophysiological variations of PBBB and than variations of PBCSFB and within 30 min of the onset of the perturbations. However, PBCSFB is the most sensitive model parameter, followed by PBBB and , in controlling brain tissue and subarachnoid CSF sodium levels within 3 h of the perturbation onset.

To study the influence of the vasopressin level on osmotic pressure and sodium concentration in plasma and cerebrospinal fluid (CSF), plasma and CSF were sampled simultaneously in 27 patients with central nervous system lesions. A significant elevation of arginine vasopressin (AVP) levels in plasma and CSF and a significant increase in the osmotic pressure gradients of plasma and CSF were observed in hyponatremic patients. The significant increases in the osmotic pressure gradients may be attributable to hemodilution and CSF concentration resulting from the elevated AVP level, because the sodium concentration gradients of plasma and CSF did not significantly increase. The elevated AVP levels in plasma and CSF and the increased osmotic pressure gradients of plasma and CSF normalized in parallel with improvement of consciousness. These findings suggest that the increased osmotic pressure gradients of plasma and CSF, derived from increased AVP secretion into blood and CSF, exacerbates brain edema induced by the primary lesion and may contribute to the clinical deterioration of some patients with intracranial lesions.

Failures in Alzheimer's disease (AD) drug trials highlight the need to further explore disease mechanisms and alterations of biomarkers during the development of AD. Using cross‐sectional data from 377 participants in the BioFINDER study, we examined seven cerebrospinal fluid (CSF) and six plasma biomarkers in relation to β‐amyloid (Aβ) PET uptake to understand their evolution during AD. In CSF, Aβ42 changed first, closely followed by Aβ42/Aβ40, phosphorylated‐tau (P‐tau), and total‐tau (T‐tau). CSF neurogranin, YKL‐40, and neurofilament light increased after the point of Aβ PET positivity. The findings were replicated using Aβ42, Aβ40, P‐tau, and T‐tau assays from five different manufacturers. Changes were seen approximately simultaneously for CSF and plasma biomarkers. Overall, plasma biomarkers had smaller dynamic ranges, except for CSF and plasma P‐tau which were similar. In conclusion, using state‐of‐the‐art biomarkers, we identified the first changes in Aβ, closely followed by soluble tau. Only after Aβ PET became abnormal, biomarkers of neuroinflammation, synaptic dysfunction, and neurodegeneration were altered. These findings lend in vivo support of the amyloid cascade hypotheses in humans.

BackgroundAlzheimer's dementia (AD) is a neurodegenerative condition characterized by progressive cognitive decline. Synaptopathy—defined as loss and dysfunction of existing synapses—is a hallmark pathological feature of AD and can directly contribute to underlying cognitive deficits. In this study, we meta‐analyzed several cerebrospinal fluid (CSF) and blood exosomal biomarkers associated with synaptopathy in AD and healthy controls (HCs).MethodOriginal peer‐reviewed articles that reported synaptic biomarker concentrations in CSF or blood exosomes were reviewed. Specifically, synaptosome associated protein‐25 (SNAP‐25), growth associated protein‐43 (GAP‐43), neuronal pentraxin receptor (NPTXR), neuronal pentraxin‐1 (NPTX‐1), neuronal pentraxin‐2 (NPTX‐2), complexin‐2, syntaxin‐1B, syntaxin‐7, and vesicle‐associated membrane protein‐2 (VAMP‐2) in AD and HCs were included for meta‐analysis. A random‐effects model was used to determine standardized mean differences (SMDs) and 95% confidence intervals (CIs). Heterogeneity was quantified using I2.ResultThe meta‐analysis included 43 study cohorts. In CSF, concentrations of SNAP‐25 (NAD/NHC = 394/539, SMD [95% CI] = 1.08 [0.73, 1.42], p < 0.001; I2 = 81.43%), GAP‐43 (NAD/NHC = 851/557, SMD [95% C] = 1.02 [0.69, 1.34], p < 0.001; I2 = 83.97%), and VAMP‐2 (NAD/NHC = 398/490, SMD [95% CI] = 0.32 [0.05, 0.60], p = 0.02; I2 = 64.91%) were elevated, and NPTXR (NAD/NHC = 575/470, SMD [95% CI] = ‐0.68 [‐0.96, ‐0.40], p < 0.001; I2 = 75.59%), NPTX‐1 (NAD/NHC = 344/333, SMD [95% CI] = ‐0.48 [‐0.64, ‐0.31], p < 0.001; I2 = 9.05%), and NPTX‐2 (NAD/NHC = 462/496, SMD [95% CI] = ‐0.78 [‐1.02, ‐0.54], p < 0.001; I2 = 66.43%) were decreased in AD compared to HCs. In blood exosomes, SNAP‐25 (NAD/NHC = 161/159, SMD [95% CI] = ‐1.05 [‐1.28, ‐0.82], p < 0.001; I2 = 0%) and GAP‐43 (NAD/NHC = 110/110, SMD [95% CI] = ‐1.66 [‐2.43, ‐0.88], p < 0.001; I2 = 77%) concentrations were decreased in AD.ConclusionThis study found that several synaptic biomarkers were significantly altered in AD in CSF and blood exosomes. There was significant heterogeneity for most comparisons (with the exception of CSF NPTX‐1 and blood exosome SNAP‐25) that remains to be explored. Nonetheless, further review of the identified biomarkers may provide fundamental insight into AD pathophysiology and disease trajectory.

BackgroundLack of early molecular biomarkers in sporadic behavioral variants of frontotemporal dementia (bvFTD) and its clinical overlap with primary psychiatric disorders (PPD) hampers its diagnostic distinction. Synaptic dysfunction is an early feature in bvFTD and identification of specific biomarkers might improve its diagnostic accuracy. Our goal was to understand the differential diagnostic potential of cerebrospinal fluid (CSF) synaptic biomarkers in bvFTD versus PPD and their specificity towards bvFTD compared with Alzheimer’s disease (AD) and controls. Additionally, we explored the association of CSF synaptic biomarkers with social cognition, cognitive performance, and disease severity in these clinical groups.MethodsParticipants with probable bvFTD (n = 57), PPD (n = 71), AD (n = 60), and cognitively normal controls (n = 39) with available CSF, cognitive tests, and disease severity as frontotemporal lobar degeneration-modified clinical dementia rating scale (FTLD-CDR) were included. In a subset of bvFTD and PPD cases, Ekman 60 faces test scores for social cognition were available. CSF synaptosomal-associated protein 25 (SNAP25), neurogranin (Ng), neuronal pentraxin 2 (NPTX2), and glutamate receptor 4 (GluR4) were measured, along with neurofilament light (NfL), and compared between groups using analysis of covariance (ANCOVA) and logistic regression. Diagnostic accuracy was assessed using ROC analyses, and biomarker panels were selected using Wald’s backward selection. Correlations with cognitive measures were performed using Pearson’s partial correlation analysis.ResultsNPTX2 concentrations were lower in the bvFTD group compared with PPD (p < 0.001) and controls (p = 0.003) but not compared with AD. Concentrations of SNAP25 (p < 0.001) and Ng (p < 0.001) were elevated in patients with AD versus those with bvFTD and controls. The modeled panel for differential diagnosis of bvFTD versus PPD consisted of NfL and NPTX2 (AUC = 0.96, CI: 0.93–0.99, p < 0.001). In bvFTD versus AD, the modeled panel consisted of NfL, SNAP25, Ng, and GluR4 (AUC = 0.86, CI: 0.79–0.92, p < 0.001). In bvFTD, lower NPTX2 (Pearson’s r = 0.29, p = 0.036) and GluR4 (Pearson’s r = 0.34, p = 0.014) concentrations were weakly associated with worse performance of total cognitive score. Lower GluR4 concentrations were also associated with worse MMSE scores (Pearson’s r = 0.41, p = 0.002) as well as with worse executive functioning (Pearson’s r = 0.36, p = 0.011) in bvFTD. There were no associations between synaptic markers and social cognition or disease severity in bvFTD.ConclusionOur findings of involvement of NTPX2 in bvFTD but not PPD contribute towards better understanding of bvFTD disease pathology.

In order to study the effect of bromocriptine on prolactinoma, the gel filtration chromatographic behavior of prolactin was measured in both serum and cerebrospinal fluid (CSF) of six cases of prolactinoma which showed high concentration of prolactin after surgery and administration of bromocriptine. Prolactin levels of paired blood and CSF samples were measured by using a doubleantibody radioimmunoassay. Molecular weights of prolactin were estimated using an Ultrogel AcA 44® column with standard molecular markers. Although the postoperative prolactin level in serum decreased from 1, 657 ng/ml to 468 ng/ml on the average, the prolactin level in CSF showed an increase from 761 ng/ml to 1, 503 ng/ml on average. Long term administration of bromocriptine contributed to normalizing the prolactin level in serum. However, the level in the CSF could not be settled in the normal range. Gel filtration of serum and CSF gave three types of prolactin with different molecular weights: “little” “big” and “big-big”. In postoperative serum samples, the proportions of the three components were 71±4%, 19±2%, and 10±4%, respectively. In postoperative CSF samples, the proportions were 96±2%, 2 ±1%, and 2±1%, respectively. “Little” prolactin was much less in proportion after administration of bromocriptine. These results indicate that prolactin molecules in the tumor parenchyma leaks into the CSF, and that there would be different mechanisms of bromocriptine in reducing prolactin level in both serum and CSF among individual cases. Large molecular prolactin may arise as a derivative or aggregates of standard prolactin.

The effect of the administration of cortisol on the levels of cortisol and electrolytes in blood and cerebrospinal fluid in man

BackgroundLecanemab is a humanized immunoglobulin G1 monoclonal antibody targeting neurotoxic Aβ protofibrils and Aβ plaques, which reduces markers of amyloid and significantly slows clinical decline on multiple cognition and function measures. Cerebrospinal fluid (CSF) microtubule‐binding region (MTBR) of tau containing the residue 243 (MTBR‐tau243) is an emerging tau pathology biomarker that tracks with tangle formation in Alzheimer’s disease (AD) [Horie et al. Nat Med. 2023;29:1954‐1963]. In order to evaluate effects of lecanemab on MTBR‐tau243, CSF was analyzed in a subset of early AD participants from the phase 3 (Clarity AD) trial.MethodCSF from n = 167 early AD participants from Clarity AD was analyzed using an IP‐MS based method [Horie et al. Nat Med. 2023;29:1954‐1963.]. Pearson correlation analysis was performed to assess relationships between CSF MTBR‐tau243, AD fluid biomarkers, amyloid PET and tau PET SUVR in multiple regions of interest. Mixed model for repeated measures was used to analyze change from baseline and assess treatment effect over 18 months.ResultBaseline correlation analysis show that CSF MTBR‐tau243 has the highest correlation with Tau PET SUVR across regions of interest (ROI) (Braak 1‐6, whole cortical grey (WCG) vs. all other fluid biomarkers assessed (CSF markers: ptau181, total tau, neurogranin, NfL, Aβ40 and Aβ42; plasma markers: pTau217, pTau181, Aβ42/40, NfL and GFAP). CSF MTBR‐tau243 has a higher correlation with Tau PET SUVR (r = 0.74, WCGROI) vs. amyloid PET Centiloids (r = 0.39, WCG ROI). Levels of CSF MTBR‐tau243 increased over time in early AD (placebo). Treatment with lecanemab slowed the rate of increase of MTBR‐tau243 vs. placebo, with a greater separation from placebo observed at 18 month (77 weeks) vs. 12 months (53 weeks). While the results have limitations due to sample size and do not reach statistical significance, at 18 months lecanemab slowed the rate of increase in CSF MTBR‐tau243 by 44% vs. placebo.ConclusionThese results support that CSF MTBR‐tau243 is a specific biomarker of tau tangle pathology and are consistent with the effects of lecanemab on Tau PET, which similarly showed a slowing of tau accumulation vs. placebo. These results demonstrate that lecanemab‐associated amyloid removal slows the formation of tau pathology in the brain.