Temporal profiles of age-dependent changes in cytokine mRNA expression and glial cell activation after status epilepticus in postnatal rat hippocampus

<p>Abstract</p> <p>Background</p> <p>Status epilepticus (SE) is proposed to lead to an age-dependent acute activation of a repertoire of inflammatory processes, which may contribute to neuronal damage in the hippocampus. The extent and temporal profiles of activation of these processes are well known in the adult brain, but less so in the developing brain. We have now further elucidated to what extent inflammation is activated by SE by investigating the acute expression of several cytokines and subacute glial reactivity in the postnatal rat hippocampus.</p> <p>Methods</p> <p>SE was induced by an intraperitoneal (i.p.) injection of kainic acid (KA) in 9- and 21-day-old (P9 and P21) rats. The mRNA expression of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), glial-derived neurotrophic factor (GDNF), interferon gamma (IFN-γ), and transforming growth factor-beta 1 (TGF-β1) were measured from 4 h up to 3 days after KA injection with real-time quantitative PCR (qPCR). IL-1β protein expression was studied with ELISA, GFAP expression with western blotting, and microglial and astrocyte morphology with immunohistochemistry 3 days after SE.</p> <p>Results</p> <p>SE increased mRNA expression of IL-1β, TNF-α and IL-10 mRNA in hippocampus of both P9 and P21 rats, their induction being more rapid and pronounced in P21 than in P9 rats. MMP-9 expression was augmented similarly in both age groups and GDNF expression augmented only in P21 rats, whereas neither IFN-γ nor TGF-β1 expression was induced in either age group. Microglia and astrocytes exhibited activated morphology in the hippocampus of P21 rats, but not in P9 rats 3 d after SE. Microglial activation was most pronounced in the CA1 region and also detected in the basomedial amygdala.</p> <p>Conclusion</p> <p>Our results suggest that SE provokes an age-specific cytokine expression in the acute phase, and age-specific glial cell activation in the subacute phase as verified now in the postnatal rat hippocampus. In the juvenile hippocampus, transient increases in cytokine mRNA expression after SE, in contrast to prolonged glial reactivity and region-specific microglial activity after SE, suggest that the inflammatory response is changed from a fulminant and general initial phase to a more moderate and specific subacute response.</p

Multifactor effects and evidence of potential interaction between complement factor H Y402H and LOC387715 A69S in age-related macular degeneration

Peer reviewe

Physiological instability is linked to mortality in primary central nervous system lymphoma:a case–control fMRI study

Abstract Primary central nervous system lymphoma (PCNSL) is an aggressive brain disease where lymphocytes invade along perivascular spaces of arteries and veins. The invasion markedly changes (peri)vascular structures but its effect on physiological brain pulsations has not been previously studied. Using physiological magnetic resonance encephalography (MREGBOLD) scanning, this study aims to quantify the extent to which (peri)vascular PCNSL involvement alters the stability of physiological brain pulsations mediated by cerebral vasculature. Clinical implications and relevance were explored. In this study, 21 PCNSL patients (median 67y; 38% females) and 30 healthy age-matched controls (median 63y; 73% females) were scanned for MREGBOLD signal during 2018–2021. Motion effects were removed. Voxel-by-voxel Coefficient of Variation (CV) maps of MREGBOLD signal was calculated to examine the stability of physiological brain pulsations. Group-level differences in CV were examined using nonparametric covariate-adjusted tests. Subject-level CV alterations were examined against control population Z-score maps wherein clusters of increased CV values were detected. Spatial distributions of clusters and findings from routine clinical neuroimaging were compared [contrast-enhanced, diffusion-weighted, fluid-attenuated inversion recovery (FLAIR) data]. Whole-brain mean CV was linked to short-term mortality with 100% sensitivity and 100% specificity, as all deceased patients revealed higher values (n = 5, median 0.055) than surviving patients (n = 16, median 0.028) (p &lt; .0001). After adjusting for medication, head motion, and age, patients revealed higher CV values (group median 0.035) than healthy controls (group median 0.024) around arterial territories (p ≤ .001). Abnormal clusters (median 1.10 × 10₅mm₃) extended spatially beyond FLAIR lesions (median 0.62 × 10₅mm₃) with differences in volumes (p = .0055)

Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland

Abstract The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case