Frederic Brosseron

Body Fluid Cytokine Levels in Mild Cognitive Impairment and Alzheimer’s Disease: a Comparative Overview

This article gives a comprehensive overview of cytokine and other inflammation associated protein levels in plasma, serum and cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). We reviewed 118 research articles published between 1989 and 2013 to compare the reported levels of 66 cytokines and other proteins related to regulation and signaling in inflammation in the blood or CSF obtained from MCI and AD patients. Several cytokines are evidently regulated in (neuro-) inflammatory processes associated with neurodegenerative disorders. Others do not display changes in the blood or CSF during disease progression. However, many reports on cytokine levels in MCI or AD are controversial or inconclusive, particularly those which provide data on frequently investigated cytokines like tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6). The levels of several cytokines are possible indicators of neuroinflammation in AD. Some of them might increase steadily during disease progression or temporarily at the time of MCI to AD conversion. Furthermore, elevated body fluid cytokine levels may correlate with an increased risk of conversion from MCI to AD. Yet, research results are conflicting. To overcome interindividual variances and to obtain a more definite description of cytokine regulation and function in neurodegeneration, a high degree of methodical standardization and patients collective characterization, together with longitudinal sampling over years is essential.

sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early‐stage Alzheimer's disease and associate with neuronal injury markers

TREM2 is an innate immune receptor expressed on the surface of microglia. Loss‐of‐function mutations of TREM2 are associated with increased risk of Alzheimers disease (AD). TREM2 is a type‐1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross‐sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non‐AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho‐tau181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration.

The central biobank and virtual biobank of BiOMarKaPD: a resource for studies on neurodegenerative diseases

Biobanks are important resources for biomarker discovery and assay development. Biomarkers for Alzheimer’s and Parkinson’s disease (BIOMARKAPD) is a European multicenter study, funded by the EU Joint Programme-Neurodegenerative Disease Research, which aims to improve the clinical use of body fluid markers for the diagnosis and prognosis of Alzheimer’s disease (AD) and Parkinson’s disease (PD). The objective was to standardize the assessment of existing assays and to validate novel fluid biomarkers for AD and PD. To support the validation of novel biomarkers and assays, a central and a virtual biobank for body fluids and associated data from subjects with neurodegenerative diseases have been established. In the central biobank, cerebrospinal fluid (CSF) and blood samples were collected according to the BIOMARKAPD standardized pre-analytical procedures and stored at Integrated BioBank of Luxembourg. The virtual biobank provides an overview of available CSF, plasma, serum, and DNA samples at each site. Currently, at the central biobank of BIOMARKAPD samples are available from over 400 subjects with normal cognition, mild cognitive impairment (MCI), AD, frontotemporal dementia (FTD), vascular dementia, multiple system atrophy, progressive supranuclear palsy, PD, PD with dementia, and dementia with Lewy bodies. The virtual biobank contains information on over 8,600 subjects with varying diagnoses from 21 local biobanks. A website has been launched to enable sample requests from the central biobank and virtual biobank.

Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics

BACKGROUND Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples. OBJECTIVE To prepare and test alternative matrices for QC samples that could facilitate intra- and inter-laboratory QC of the NDD biomarkers. METHODS Three matrices were validated in this study: (A) human pooled CSF, (B) Aβ peptides spiked into human prediluted plasma, and (C) Aβ peptides spiked into solution of bovine serum albumin in phosphate-buffered saline. All matrices were tested also after supplementation with an antibacterial agent (sodium azide). We analyzed short- and long-term stability of the biomarkers with ELISA and chemiluminescence (Fujirebio Europe, MSD, IBL International), and performed an inter-laboratory variability study. RESULTS NDD biomarkers turned out to be stable in almost all samples stored at the tested conditions for up to 14 days as well as in samples stored deep-frozen (at - 80°C) for up to one year. Sodium azide did not influence biomarker stability. Inter-center variability of the samples sent at room temperature (pooled CSF, freeze-dried CSF, and four artificial matrices) was comparable to the results obtained on deep-frozen samples in other large-scale projects. CONCLUSION Our results suggest that it is possible to replace self-made, CSF-based QC samples with large-scale volumes of QC materials prepared with artificial peptides and matrices. This would greatly facilitate intra- and inter-laboratory QC schedules for NDD measurements.

Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer’s disease

The neural basis of reserve capacity in Alzheimer’s disease is yet to be fully determined. Franzmeier et al. show that greater left frontal hub connectivity within the fronto-parietal control network is associated with greater resilience of cognitive performance during the early stages of autosomal dominant and sporadic Alzheimer’s disease.

Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer’s disease

BackgroundNeuroinflammation has gained increasing attention as a potential contributing factor in Alzheimer’s disease (AD) pathology. A clinical cerebrospinal fluid biomarker capable of monitoring this process during the course of the disease has yet to emerge, chiefly owing to contradictory research findings. In this study, we sought to clarify the utility of inflammatory biomarkers in diagnostic procedures of AD in three steps: (1) to screen for proteins that are robustly detectable in cerebrospinal fluid; (2) based on this analysis, to explore any associations between the analytically robust markers and salient pathological features of AD; and (3) to determine the discriminative power of these markers in the clinical diagnosis of AD.MethodsFrom a total of 46 proteins, 15 that were robustly detectable in cerebrospinal fluid were identified. A subsequent analysis of these markers in a cohort of 399 patients (nondemented subjects, patients with mild cognitive impairment [MCI], and patients with AD, supplemented by smaller cohorts of other diseases) was conducted. Fluid biomarker data were related to AD pathology and neuropsychological markers and adjusted for confounders such as age, sex, apolipoprotein E genotype, and biobank storage time.ResultsCerebrospinal fluid levels of C-reactive protein and soluble TREM2 differed between nondemented subjects, patients with MCI, or patients with AD and were associated with amyloid and tau pathology. Several markers were associated with tau pathology only or with other neurodegenerative diseases. Correlations between neuropsychological performance and inflammatory markers were weak, but they were most prominent in AD and for the most challenging cognitive tests. All investigated covariates had significant influence, with varying effects across the markers. Still, none of the markers achieved discriminative power of more than 70% to distinguish between patient groups defined by clinical or neuropathological categories.ConclusionsBasic analytical considerations proved indispensable for this type of study because only one-third of the tested markers were robustly detectable in cerebrospinal fluid. Detectable inflammatory protein markers were associated in multiple ways with AD pathology. Yet, even significantly associated markers were not powerful enough in terms of effect strength, sensitivity, and specificity, and hence they were not suited for direct use in clinical diagnostic practice. Targets other than those most commonly considered in this field of research might provide results with better clinical applicability.

Tau plasma levels in subjective cognitive decline: Results from the DELCODE study

Previous studies have demonstrated increased tau plasma levels in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) due to AD. Much less is known whether increased tau plasma levels can already be detected in the pre-MCI stage of subjective cognitive decline (SCD). In the present study we measured tau plasma levels in 111 SCD patients and 134 age- and gender-matched cognitively healthy controls participating in the DZNE (German Center for Neurodegenerative Diseases) longitudinal study on cognition and dementia (DELCODE). Tau plasma levels were measured using ultra-sensitive, single-molecule array (Simoa) technology. We found no significant different tau plasma levels in SCD (3.4 pg/ml) compared with healthy controls (3.6 pg/ml) after controlling for age, gender, and education (p = 0.137). In addition, tau plasma levels did not correlate with Aβ42 (r = 0.073; p = 0.634), tau (r = −0.179; p = 0.240), and p-tau181 (r = −0.208; p = 0.171) cerebrospinal fluid (CSF) levels in a subgroup of 45 SCD patients with available CSF. In conclusion, plasma tau is not increased in SCD patients. In addition, the lack of correlation between tau in plasma and CSF in the examined cohort suggests that tau levels are affected by different factors in both biofluids.

TAU PLASMA LEVELS IN SUBJECTIVE COGNITIVE DECLINE: RESULTS FROM THE DELCODE STUDY

Background: Alcadeina (Alca) is a member of alcadein family composed of Alca, Alcb and Alcg, which is largely expressed in brain neuron and prone to form a tripartite complex with APP mediated by cytoplasmic neural-specific adaptor protein X11like (X11L). p3-Alca is generated from Alca by cleavage of aand g-secretases, and secreted into cerebrospinal fluid (CSF) and then into blood as does Ab from APP. The p3-Alca35 exists in CSF as a major species, as like as Ab40, while p3-Alca38 is minor as like as Ab42. p3-Alca is non-aggregatable so easily detected in CSF and plasma by sELISA (Hata 2009). To establish an effective AD diagnosis, we verified p3-Alca38/35, a ratio of p3-Alca38 to p3-Alca35. Methods: Previously, we showed the plasma level of p3-Alca35 using sELISAwith p3-Alca35 specific antibody (Omori 2014). To measure p3-Alca38/35 level, we tried to prepare new antibody raised to p3-Alca38 with higher affinity. Using cell surface display method, p3-Alca38 chimeric protein was expressed on cell surface and the cells were immunized. Several clones generating antibody specifically react to p3Alca38 were isolated, and we developed new sELISA system to quantify p3-Alca38 with higher sensitivity. Results:We first characterized the new sELISA systems to quantify p3-Alca38. With a combination of sELISA to quantify p3-Alca35, both p3-Alca35 and p3-Alca38 in body fluid were quantified. The levels p3Alca38/35 ratio in MCI and AD subjects showed a tendency increasing along with cognitive impairment degree compared to non-demented controls. The p3-Alca38/35 ratio significantly increased along with the increase of Ab42/40 ratio in vitro, while in vivo, the significant increase of p3-Alca38/35 correlated with the significant decrease of Ab42/40. Conclusions:Our study suggested that p3-Alca38/35 can be an effective biomarker of AD not only in CSF but also in plasma, which indicates a qualitative change of g-secretase activity. Further studies with samples from various cohorts (for example, with chronologically chasing and taking samples) will be performed to confirm the efficiency of p3-Alca38/35 as a biomarker to find prodromal and/or early stage MCI/AD subjects who shows an altered/attenuated g-secretase activity.

MULTICENTER RESTING STATE FUNCTIONAL CONNECTIVITY IN PRODROMAL AND DEMENTIA STAGES OF ALZHEIMER’S DISEASE: RESULTS FROM THE DZNE DELCODE STUDY

tients (n1⁄430; age 7466.8; disease duration 4.061.8; MMSE 20.064.3), and NL (n1⁄420; age 67.265.7). Expression values for PDRP and PDCP were significantly elevated in PD, PDD and DLB patients compared to normal controls (Figures 1&2). PDD and DLB patients exhibited increased PDCP and ADRP expression at a similar level compared to non-demented PD patients (one-way ANOVA; PDCP: p<0.0001; ADRP p<0.0001) (Figures 2&3). Conclusions: PD, PDD and DLB patients showed elevated expression of all studied patterns compared to normal controls. PDD and DLB patients showed similar expression levels of PDCP and ADRP, which was significantly higher compared to PD, pointing to enhanced cognitive decline and more cortical involvement. Thus, PDD and DLB seem to share common underlying metabolic abnormalities indicating a shared pathobiological mechanism.

NEUROPSYCHIATRIC SYMPTOMS IN AT-RISK GROUPS FOR AD DEMENTIA AND THEIR RELATION TO AD BIOMARKERS: DATA FROM THE DELCODE STUDY

executive functioning and cognitive flexibility depended on ESR1 Pvu II polymorphism. Processing speed was better in women being TT homozygotes than in women with TC and CC genotypes. Executive functioning and cognitive flexibility were lower in women with TT genotype than in those with TC and CC genotypes. Memory, verbal memory, visual memory and processing speed depended on ESR1 XbaI. AA and AG genotypes was linked to better function in those domains than GG homozygotes. NCI and six cognitive functions differed between genotypes of PvuII and XbaI combined. Presence of CC PvuII and GG XbaI was linked to the lowest cognitive performance Carriers of TCAA, or CC -AG – demonstrated the highest, while TT AA, or TC -AG – with moderate levels of cognitive function. Conclusions: ESR1 (PvuII and XbaI) polymorphisms influences cognitive performance in postmenopausal women NCI, memory, verbal memory, processing speed, psychomotor speed as well as reaction time were noticed to be decreased in postmenopausal women, who simultaneously carried the CC PvuII and GG XbaI genotypes.