Fluid Biomarkers Of Neurodegeneration Research Articles

Fluid Biomarkers of Neurodegeneration in Mild Cognitive Impairment: A Meta‐Analysis

AbstractBackgroundMild cognitive impairment (MCI) is a well‐established prodromal stage of Alzheimer’s disease and is often accompanied by early signs of neurodegeneration (e.g., neuronal loss) that may influence subsequent prognosis. To facilitate a better characterization of the underlying neuropathology, a thorough investigation of proteins associated with neurodegenerative processes in MCI is needed. Thus, the present study systematically assessed the available literature to quantitatively evaluate cerebrospinal fluid (CSF) and peripheral blood concentrations of biomarkers related to neurodegeneration in individuals with MCI compared to healthy controls (HCs).MethodOriginal peer‐reviewed articles that assessed the following CSF and/or peripheral biomarkers: neurofilament light chain (NFL), total‐tau (T‐tau), glial fibrillary acidic protein (GFAP), heart‐type fatty acid binding protein (HFABP), neuron‐specific enolase (NSE), and S100 calcium‐binding protein B (S100B) in both MCI and HCs were included for meta‐analysis. Standardized mean differences (SMDs) and 95% confidence intervals were calculated using a random‐effects model. Heterogeneity was assessed using the I2 statistic.ResultA total of 109 study cohorts were included in the meta‐analysis. In CSF, concentrations of NFL (MCI n = 2771, HC n = 4263, SMD [95% CI] = 0.69 [0.56, 0.83], p < 0.001), GFAP (MCI n = 513, HC n = 1620, SMD [95% CI] = 0.41 [0.08, 0.74], p = 0.02), and HFABP (MCI n = 363, HC n = 245, SMD [95% CI] = 0.57 [0.23, 0.55], p < 0.001) were elevated in MCI. In peripheral blood, concentrations of NFL (MCI n = 6520, HC n = 9439, SMD [95% CI] = 0.41 [0.32, 0.49], p < 0.001), T‐tau (MCI n = 4463, HC n = 5921, SMD [95% CI] = 0.19 [0.09, 0.29], p < 0.001), and GFAP (MCI n = 1758, HC n = 3179, SMD [95% CI] = 0.39 [0.23, 0.55], p < 0.001) were increased in MCI. Significant heterogeneity was identified for all comparisons and was explored through meta regression and subgroup analysis.ConclusionThe present study identified several fluid biomarkers of neurodegeneration in MCI. Importantly, elevated biomarker levels can be detected in both CSF and less‐invasively through peripheral blood. Future studies should focus on assessing the clinical utility of monitoring these biomarkers as they may provide further insight into neuronal and astroglial pathology occurring in the early stages of cognitive decline.

Evaluation of the major pathological hallmarks in the humanized APPSAA knock‐in mouse model, in response to drug treatment

AbstractBackgroundTo improve clinical translatability of non‐clinical in‐vivo Alzheimer’s disease (AD) models, a humanized APP knock‐in mouse model (APPSAA) was recently created (Xia, D. et al., 2022). This homozygous APP knock‐in model carries a humanized Aβ1‐42 sequence and 3 disease causing mutations (Swedish, Arctic, and Austrian). These modifications lead to increased Aβ42/40 ratios in AD relevant tissues, resulting in an age‐dependent amyloid deposition in the brain. The highest plaque density is found in cortical and hippocampal regions. APPSAA mice also display clear neuroinflammation and an increase in fluid biomarkers of neurodegeneration (NF‐L and total Tau in CSF). Here we assess the value of this model as a tool for non‐clinical efficacy studies of experimental drugs with diverse mechanisms of action to facilitate the development of novel AD therapeutics.MethodAPPSAA mice and WT controls were aged and sacrificed at various time points. In addition, APPSAA mice were treated with drug or vehicle, on a daily basis for 3 months from the age of 3 months onward. The major pathological hallmarks of this model and the treatment effect will be investigated with biochemical and immunohistological assays. Monthly blood sampling will allow the follow up of pathology progression in individual mice by assessing plasma‐based biomarkers. Since APPSAA mice lack an obvious behavioral phenotype, synaptic plasticity will be investigated to serve as a functional readout.ResultThe treatment is well tolerated by the mice in study. Body weights were not altered between compound and vehicle dosing during the first 2 months of the treatment. Data on pathological outcomes and synaptic plasticity are not yet available but will be shared during the presentation.ConclusionA humanized knock‐in model for AD is hypothesized to be a broadly applicable tool to investigate disease‐modifying drugs with diverse modes of actions.

Synaptic biomarkers in the cerebrospinal fluid associate differentially with classical neuronal biomarkers in patients with Alzheimer’s disease and frontotemporal dementia

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.

Plasma Lipocalin 2 in Alzheimer\u2019s disease: potential utility in the differential diagnosis and relationship with other biomarkers

BackgroundLipocalin-2 is a glycoprotein that is involved in various physiological and pathophysiological processes. In the brain, it is expressed in response to vascular and other brain injury, as well as in Alzheimer’s disease in reactive microglia and astrocytes. Plasma Lipocalin-2 has been proposed as a biomarker for Alzheimer’s disease but available data is scarce and inconsistent. Thus, we evaluated plasma Lipocalin-2 in the context of Alzheimer’s disease, differential diagnoses, other biomarkers, and clinical data.MethodsFor this two-center case-control study, we analyzed Lipocalin-2 concentrations in plasma samples from a cohort of n = 407 individuals. The diagnostic groups comprised Alzheimer’s disease (n = 74), vascular dementia (n = 28), other important differential diagnoses (n = 221), and healthy controls (n = 84). Main results were validated in an independent cohort with patients with Alzheimer’s disease (n = 19), mild cognitive impairment (n = 27), and healthy individuals (n = 28).ResultsPlasma Lipocalin-2 was significantly lower in Alzheimer’s disease compared to healthy controls (p < 0.001) and all other groups (p < 0.01) except for mixed dementia (vascular and Alzheimer’s pathologic changes). Areas under the curve from receiver operation characteristics for the discrimination of Alzheimer’s disease and healthy controls were 0.783 (95%CI: 0.712–0.855) in the study cohort and 0.766 (95%CI: 0.627–0.905) in the validation cohort. The area under the curve for Alzheimer’s disease versus vascular dementia was 0.778 (95%CI: 0.667–0.890) in the study cohort. In Alzheimer’s disease patients, plasma Lipocalin2 did not show significant correlation with cerebrospinal fluid biomarkers of neurodegeneration and AD-related pathology (total-tau, phosphorylated tau protein, and beta-amyloid 1-42), cognitive status (Mini Mental Status Examination scores), APOE genotype, or presence of white matter hyperintensities. Interestingly, Lipocalin 2 was lower in patients with rapid disease course compared to patients with non-rapidly progressive Alzheimer’s disease (p = 0.013).ConclusionsPlasma Lipocalin-2 has potential as a diagnostic biomarker for Alzheimer’s disease and seems to be independent from currently employed biomarkers.

Distinctive effect of biological sex in AD‐related CSF and plasma biomarkers

AbstractBackgroundClinical studies indicate that Alzheimer's disease (AD) disproportionately affects women. Although previous studies reported sex differences in fluid biomarkers, there is a need for a comprehensive analysis across the disease continuum. The aim of this study was to compare AD‐related biomarkers in cerebrospinal fluid (CSF) and plasma between women and men in middle‐aged cognitively‐unimpaired individuals at risk for AD.MethodWe measured Aβ42, Aβ40, Mid (M)‐p‐tau 181, N‐terminal (N)‐p‐tau 181, N‐p‐tau 217, M‐p‐tau 231, t‐tau, NfL, neurogranin, SNAP25, GAP43, synaptotagmin1, sTREM2, YKL40, GFAp, S100B, IL6, sVCAM1, sICAM1, MCP1 and α‐synuclein in CSF; and N‐p‐tau181, NfL, GFAp, MCP1, sICAM1 and sVCAM1 in plasma. Biomarker measurements were performed using immunoassays (colorimetric, MSD, Elecsys®, Simoa and the exploratory Roche NeuroToolKit robust prototype assays) and mass spectrometry. We tested sex differences in demographic variables (using t‐test or Chi‐squared) and in cardiovascular factors (using ANCOVA adjusted for age and APOE‐ε4 status). Sex differences in biomarkers were assessed with 3 different ANCOVA models, adjusted for (i) age, (ii) age and CSF Aβ42/40 and (iii) age and cardiovascular factors that showed sexual divergence.ResultWe studied 384 participants of the ALFA+ cohort. Men had higher education, APOE‐ε4 prevalence, physical activity, diastolic blood pressure, BMI, glucose and triglycerides than women. In contrast, women had higher vitamin B12, LDL, HDL and total cholesterol as compared to men. In CSF (Table 1), men had higher NfL, GFAp, MCP1, sICAM1 and sVCAM1, while women had higher neurogranin, synaptotagmin‐1 and N‐p‐tau 217, after adjusting for age (Model I). These differences remained significant after adjusting for CSF Aβ42/40 (Model II). In plasma (Table 2), we observed an opposite pattern compared to results in CSF: women showed higher NfL, GFAp and sICAM1 after adjusting for age (Model I) and for CSF Aβ42/40 (Model II). Sex differences in CSF NfL, sICAM1, sVCAM1, and plasma sICAM1 remained significant after adjustingg for cardiovascular factors (Model III).ConclusionAD‐related fluid biomarkers of neurodegeneration and neuroinflammation/endothelial dysfunction differ between women and men, but these differences have an opposite direction for some biomarkers in CSF and plasma. These results highlight the importance of considering sex differences in AD‐related fluid biomarkers.

Association between cerebrospinal fluid biomarkers of neurodegeneration and PET measurements of synaptic density in Alzheimer’s disease

AbstractBackgroundStudies using [11C]UCB‐J–PET have shown significant reductions in synaptic glycoprotein 2A (SV2A) specific binding as a marker of synaptic density in early Alzheimer’s disease (AD). The extent of these reductions indicates widespread neocortical synaptic loss that corroborates previous postmortem studies. The relationship of PET measures of synaptic density and cerebrospinal fluid (CSF) biomarkers may provide important information related to neuronal damage and synaptic health.MethodsSV2A binding was measured with [11C]UCB‐J–PET in 21 participants with early AD (CDR=0.5‐1.0, PiB+) and 7 cognitively normal (CN) participants (CDR=0, PiB–). PET scans were performed on a HRRT from 60 or 90 min after a bolus injection of [11C]UCB‐J. Binding potential non‐displaceable (BP ND) was calculated using SRTM2 and a centrum semiovale reference and converted to a distribution volume ratio (DVR) with a cerebellum reference. CSF biomarkers of AD, as well as synaptic and neuronal health were assayed, including Aβ42, Aβ40, total tau (t‐tau), phosphorylated tau (p‐tau), neurofilament light chain (NFL), growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptosomal‐associated protein 25 (SNAP‐25), and synaptotagmin‐1 (SYT‐1).ResultsSynaptic density was significantly lower in AD participants in the hippocampus, entorhinal cortex, lateral parietal cortex, lateral temporal cortex, and lateral occipital cortex. There were significant group differences in Aβ42, Aβ42/Aβ40, t‐tau, p‐tau, GAP‐43, Ng, SNAP‐25 short, and SNAP‐25 total. In the overall sample, only Aβ42 (r=0.40, P=0.03) and Aβ42/Aβ40 (r=0.48, P=0.01) had significant correlations with synaptic density in the hippocampus. Aβ42/Aβ40 (r=0.46), t‐tau (r=‐0.38), p‐tau (r=‐0.40), NFL (r=‐0.42), GAP‐43 (r=‐0.46), and SNAP‐25 total (r=‐0.49) were significantly correlated with synaptic density in a composite of commonly affected AD regions (P&lt;0.05, Figure 1). Most CSF biomarkers were significantly correlated with synaptic density in the neocortex only (Figure 2). In addition, CSF Aβ42/Aβ40 and synaptic density were significantly correlated in regions of the medial temporal lobe (Figure 2).ConclusionThis study explores the relationship between synaptic density and CSF biomarkers of neuronal and synaptic health in AD. The spatial relationship between synaptic density reductions and CSF synaptic biomarkers may provide valuable information that will contribute to the understanding of AD and lead to novel treatments and therapeutic biomarkers.

P.2.d.022 Cerebrospinal fluid biomarkers of neurodegeneration affect cognitive functions in bipolar disorder but not healthy controls

P.2.d.022 Cerebrospinal fluid biomarkers of neurodegeneration affect cognitive functions in bipolar disorder but not healthy controls

Neurodegeneration in MS and NMO: The Eye and the Blood

Neurodegeneration in MS and NMO: The Eye and the Blood

Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases

Chronic neurological diseases (CND) like amyotrophic lateral sclerosis (ALS), dementia or multiple sclerosis (MS) share a chronic progressive course of disease that frequently leads to the common pathological pathway of neurodegeneration, including neuroaxonal damage, apoptosis and gliosis. There is an ongoing search for biomarkers that could support early diagnosis of CND and help to identify responders to interventions in therapeutic treatment trials. Cerebrospinal fluid (CSF) is a promising source of biomarkers in CND, since the CSF compartment is in close anatomical contact with the brain interstitial fluid, where biochemical changes related to CND are reflected. We review recent advances in CSF biomarkers research in CND and thereby focus on markers associated with neurodegeneration.