A comparison of biofluid cytokine markers across platform technologies: Correspondence or divergence?

BACKGROUND: Quantification of biofluid cytokines is a rapidly growing area of translational research. However, comparability across the expanding number of available assay platforms for detection of the same proteins remains to be determined. We aimed to directly compare a panel of commonly measured cytokines in plasma of typically aging adults across two high sensitivity quantification platforms, Meso Scale Discovery high performance electrochemiluminiscence (HPE) and single-molecule immunosorbent assays (Simoa) by Quanterix. METHODS: 57 community-dwelling older adults completed a blood draw, neuropsychological assessment, and brain MRI as part of a healthy brain aging study. Plasma samples from the same draw dates were analyzed for IL-10, IP-10, IL-6, TNFα, and IL-1ß on HPE and Simoa, separately. Reliable detectability (coefficient of variance (CV) < 20% and outliers 3 interquartiles above the median removed), intra-assay precision, absolute concentrations, reproducibility across platforms, and concurrent associations with external variables of interest (e.g., demographics, peripheral markers of vascular health, and brain health) were examined. RESULTS: The proportion of cytokines reliably measured on HPE (87.7-93.0%) and Simoa (75.4-93.0%) did not differ (ps > 0.32), with the exception of IL-1ß which was only reliably measured using Simoa (68.4%). On average, CVs were acceptable at <8% across both platforms. Absolute measured concentrations were higher using Simoa for IL-10, IL-6, and TNFα (ps < 0.05). HPE and Simoa shared only small-to-moderate proportions of variance with one another on the same cytokine proteins (range: r = 0.26 for IL-10 to r = 0.64 for IL-6), though platform agreement did not dependent on cytokine concentrations. Cytokine ratios within each platform demonstrated similar relative patterns of up- and down-regulation across HPE and Simoa, though still significantly differed (ps < 0.001). Supporting concurrent validity, all 95% confidence intervals of the correlations between cytokines and external variables overlapped between the two platforms. Moreover, most associations were in expected directions and consistently so across platforms (e.g., IL-6 and TNFα), though with several notable exceptions for IP-10 and IL-10. CONCLUSIONS: HPE and Simoa showed comparable detectability and intra-assay precision measuring a panel of commonly examined cytokine proteins, with the exception of IL-1ß which was not reliably detected on HPE. However, Simoa demonstrated overall higher concentrations and the two platforms did not show agreement when directly compared against one another. Relative cytokine ratios and associations demonstrated similar patterns across platforms. Absolute cytokine concentrations may not be directly comparable across platforms, may be analyte dependent, and interpretation may be best limited to discussion of relative associations.

Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0 ± 5.2 years compared with 41.1 ± 7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.

More than memory impairment in voltage-gated potassium channel complex encephalopathy.

BACKGROUND AND PURPOSE: Autoimmune encephalopathies (AEs) are a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly endorsed, few reports of AEs inclusively assess all cognitive domains in detail. Our aim was to perform an unbiased cognitive evaluation of AE patients with voltage-gated potassium channel complex antibodies (VGKCC -Abs) in order to delineate cognitive strengths and weaknesses. METHODS: Serial VGKCC -Ab AE subjects (n = 12) were assessed with a comprehensive evaluation of memory, executive functions, visuospatial skills and language. Clinical magnetic resonance imaging (MRI) (n = 10/12) was evaluated. Five subjects had serial cognitive testing available, permitting descriptive analysis of change. RESULTS: Subjects demonstrated mild to moderate impairment in memory (mean Z = -1.9) and executive functions (mean Z = -1.5), with variable impairments in language and sparing of visuospatial skills. MRI findings showed T2 hyperintensities in medial temporal lobe (10/10) and basal ganglia (2/10). Serial cognitive examination revealed heterogeneity in cognitive function; whereas most patients improved in one or more domains, residual impairments were observed in some patients. CONCLUSIONS: This study augments previous neuropsychological analyses in VGKCC -Ab AE by identifying not only memory and executive function deficits but also language impairments, with preservation of visuospatial functioning. The study further highlights the importance of domain-specific testing to parse out the complex cognitive phenotypes of VGKCC -Ab AE.

Longitudinal inflammation, cognitive decline, and Alzheimer's disease: a mini-review.

The role of inflammation in cognitive decline has generated considerable interest, although few longitudinal evaluations have been conducted. A review of the literature yields mixed findings but suggests that inflammatory dysregulation is evident and may be related to clinical outcomes. The directionality, magnitude, and progression of these associations remain unclear. Future studies employing multiple time points of inflammatory data along with Alzheimer's disease (AD) biomarkers are critical for explication of longitudinal inflammation in cognitive decline.