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Since the NAD+-dependent histone deacetylases sirtuin-1 (SIRT1) and sirtuin-2 (SIRT2) are critically involved in epigenetics, endocrinology and immunology and affect the longevity in model organisms, we investigated their expression in brains of 3-month-old and 14–15 months old rat model of depression Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats. In view of the dysregulated NPY system in depression, we also studied NPY in young and old FSL to explore the temporal trajectory of depressive-like–ageing interaction. Sirt1, Sirt2 and Npy mRNA were determined using qRT-PCR in prefrontal cortex (PFC) from young and old FSL and FRL, and in hippocampi from young FSL and FRL. PFC: Sirt1 expression was decreased in FSL (p = 0.001). An interaction between age and genotype was found (p = 0.032); young FSL had lower Sirt1 with respect to both age (p = 0.026) and genotype (p = 0.001). Sirt2 was lower in FSL (p = 0.003). Npy mRNA was downregulated in FSL (p = 0.001) but did not differ between the young and old rat groups. Hippocampus: Sirt1 was reduced in young FSL compared to young FRL (p = 0.005). There was no difference in Sirt2 between FSL and FRL. Npy levels were decreased in hippocampus of young FSL compared to young FRL (p = 0.003). Effects of ageing could not be investigated due to loss of samples. To conclude, i this is the first demonstration that SIRT1 and SIRT2 are changed in brain of FSL, a rat model of depression; ii the changes are age-dependent; iii sirtuins are potential targets for treatment of age-related neurodegenerative diseases.

Peripheral immune activation can influence neurodevelopment and is increased in autism, but is less explored in attention deficit hyperactivity disorder (ADHD). Patients with ADHD often display comorbid autism traits and gastrointestinal (GI) symptoms. Plasma protein levels of two acute phase reactants, C-reactive protein (CRP) and serum amyloid A (SAA), and two endothelial adhesion molecules, soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1), which share important roles in inflammation, were analyzed in 154 patients with ADHD and 61 healthy controls. Their associations with ADHD diagnosis, severity, medication and comorbid autistic symptoms, emotion dysregulation and GI symptoms were explored. The ADHD patients had increased levels of sICAM-1 and sVCAM-1 compared to healthy controls (p = 8.6e–05, p = 6.9e–07, respectively). In children with ADHD, the sICAM-1 and sVCAM-1 levels were higher among those with ADHD medication than among children (p = 0.0037, p = 0.0053, respectively) and adults (p = 3.5e–09, p = 1.9e–09, respectively) without ADHD medication. Among the adult ADHD patients, higher sICAM-1 levels were associated with increased comorbid autistic symptoms in the domains attention to detail and imagination (p = 0.0081, p = 0.00028, respectively), and higher CRP levels were associated with more GI symptoms (p = 0.014). sICAM-1 and sVCAM-1 levels were highly correlated with each other, and so were CRP and SAA levels. To conclude, vascular inflammatory activity may be overrepresented in ADHD, with elevated sICAM-1 and sVCAM-1 levels and this may in children be a consequence of current ADHD medication, and in adults relate to increased comorbid autistic symptoms. Replication is warranted.

Short-chain fatty acids (SCFAs), produced during bacterial fermentation, have been shown to be mediators in the microbiota-gut-brain axis. This axis has been proposed to influence psychiatric symptoms seen in attention deficit hyperactivity disorder (ADHD). However, there is no report of plasma SCFA concentrations in ADHD. The aim of this study was to explore the plasma concentrations of SCFAs in children and adults with ADHD and the possible factors that could influence those levels. We collected data on age group, sex, serum vitamin D levels, delivery mode, body mass index, diet, medication and blood samples from 233 ADHD patients and 36 family-related healthy controls. The concentrations of SCFAs and the intermediary metabolite succinic acid, were measured using liquid chromatography-mass spectrometry. Adults with ADHD had lower plasma concentrations of formic, acetic, propionic and succinic acid than their healthy family members. When adjusting for SCFA-influential factors among those with ADHD, children had lower concentrations of formic, propionic and isovaleric acid than adults, and those who had more antibiotic medications during the last 2 years had lower concentrations of formic, propionic and succinic acid. When adjusting for antibiotic medication, we found that among children, those currently on stimulant medication had lower acetic and propionic acid levels, and adults with ADHD had lower formic and propionic acid concentrations than adult healthy family members. In all, our findings show lower-than-normal plasma concentrations of SCFAs in ADHD explained in-part by antibiotic medication, age and stimulant medication. Whether or not this is of clinical significance is yet to be explored.

Some prebiotics and probiotics have been proposed to improve psychiatric symptoms in children with autism. However, few studies were placebo-controlled, and there is no study on persons with an attention deficit hyperactivity disorder (ADHD) diagnosis. Our aim was to study effects of Synbiotic 2000 on psychiatric symptoms and functioning in children and adults with ADHD without an autism diagnosis. Children and adults (n = 182) with an ADHD diagnosis completed the nine weeks randomized double-blind parallel placebo-controlled trial examining effects of Synbiotic 2000 on the primary endpoints ADHD symptoms, autism symptoms and daily functioning, and the secondary endpoint emotion regulation, measured using the questionnaires SNAP-IV, ASRS, WFIRS, SCQ, AQ and DERS-16. Levels at baseline of plasma C-reactive protein and soluble vascular cell adhesion molecule-1 (sVCAM-1), central to leukocyte-endothelial cell adhesion facilitating inflammatory responses in tissues, were measured using Meso Scale Discovery. Synbiotic 2000 and placebo improved ADHD symptoms equally well, and neither active treatment nor placebo had any statistically significant effect on functioning or sub-diagnostic autism symptoms. However, Synbiotic 2000, specifically, reduced sub-diagnostic autism symptoms in the domain restricted, repetitive and stereotyped behaviors in children, and improved emotion regulation in the domain of goal-directed behavior in adults. In children with elevated sVCAM-1 levels at baseline as well as in children without ADHD medication, Synbiotic 2000 reduced both the total score of autism symptoms, and the restricted, repetitive and stereotyped behaviors. In adults with elevated sVCAM-1 at baseline, Synbiotic 2000 significantly improved emotion regulation, both the total score and four of the five subdomains. To conclude, while no definite Synbiotic 2000-specific effect was detected, the analysis of those with elevated plasma sVCAM-1 levels proposed a reduction of autism symptoms in children and an improvement of emotion regulation in adults with ADHD. Trial registration number: ISRCTN57795429.