While not a specific disease, dementia is a term used to describe the deterioration of cognitive function beyond what would be expected because of natural biological aging ....
Thiamine (vitamin B1) is an essential nutrient that serves as a cofactor for a number of enzymes, mostly with mitochondrial localization. Some thiamine-dependent enzymes are involved in energy ...metabolism and biosynthesis of nucleic acids whereas others are part of the antioxidant machinery. The brain is highly vulnerable to thiamine deficiency due to its heavy reliance on mitochondrial ATP production. This is more evident during rapid growth (i.e., perinatal periods and children) in which thiamine deficiency is commonly associated with either malnutrition or genetic defects. Thiamine deficiency contributes to a number of conditions spanning from mild neurological and psychiatric symptoms (confusion, reduced memory, and sleep disturbances) to severe encephalopathy, ataxia, congestive heart failure, muscle atrophy, and even death. This review discusses the current knowledge on thiamine deficiency and associated morbidity of neurological and psychiatric disorders, with special emphasis on the pediatric population, as well as the putative beneficial effect of thiamine supplementation in autism spectrum disorder (ASD) and other neurological conditions.
CGG expansions between 55 and 200 in the 5′-untranslated region of the fragile-X mental retardation gene (FMR1) increase the risk of developing the late-onset debilitating neuromuscular disease ...Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). While the science behind this mutation, as a paradigm for RNA-mediated nucleotide triplet repeat expansion diseases, has progressed rapidly, no treatment has proven effective at delaying the onset or decreasing morbidity, especially at later stages of the disease. Here, we demonstrated the beneficial effect of the phytochemical sulforaphane (SFN), exerted through NRF2-dependent and independent manner, on pathways relevant to brain function, bioenergetics, unfolded protein response, proteosome, antioxidant defenses, and iron metabolism in fibroblasts from FXTAS-affected subjects at all disease stages. This study paves the way for future clinical studies with SFN in the treatment of FXTAS, substantiated by the established use of this agent in clinical trials of diseases with NRF2 dysregulation and in which age is the leading risk factor.
•Sulforaphane improved mitochondrial bioenergetics in FXTAS.•Bioenergetic improvement was observed with high CGG repeats and disease stage.•Sulforaphane promoted NRF2-dependent and -independent mechanisms of action.
A novel battery (BAFE; Valeri et al. 2015) was used in order to assess three executive function (EF) abilities (working memory, inhibition and shifting) in a sample of 27 intellectually able ...preschoolers with autism spectrum disorder (ASD) compared with 27 typically developing children matched on age and nonverbal IQ. Differences in EF skills were analyzed in participants with distinct ASD symptom severity. Children with ASD performed worse than typical controls on both set-shifting and inhibition, but not on visuo-spatial working memory. Additionally, children with more severe ASD symptoms showed a worse performance on inhibition than children with milder symptoms. These results confirm the presence of EF deficits and highlight a link between ASD symptoms and EF impairments in preschool age.
This commentary highlights the major findings and future research directions arising from the recent publication by Zuo and colleagues in Stem Cells 2017 (in press). Here, we discuss the novel ...observations that transplanted human neural stem cells can induce endogenous brain repair by specifically stimulating a host of regenerative processes in the neurogenic niche (i.e., subventricular zone SVZ) in an animal model of Parkinson's disease. That the identified therapeutic proteomes, neurotrophic factors, and anti‐inflammatory cytokines in the SVZ may facilitate brain regeneration and behavioral recovery open a new venue of research for our understanding of the pathology and treatment of Parkinson's disease. Stem Cells 2017;35:1443–1445
Polybrominated diphenyl ethers (PBDEs) represent an important group of flame retardants extensively used, tonnage of which in the environment has been steadily increasing over the past 25 years. ...PBDEs or metabolites can induce neurotoxicity and mitochondrial dysfunction (MD) through a variety of mechanisms. Recently, PBDEs with < 5 Br substitutions (i.e., 2,2',4,4'-tetrabromodiphenyl ether BDE-47 and 2,2',4,5'-tetrabromodiphenyl ether BDE-49) have gained interest because of their high bioaccumulation. In particular, congeners such as BDE-49 arise as one of the most biologically active, with concentrations typically lower than those observed for BDE-47 in biological tissues; however, its potential to cause MD at biologically relevant concentrations is unknown. To this end, the effect of BDE-49 was studied in brain mitochondria and neuronal progenitor striatal cells (NPC). BDE-49 uncoupled mitochondria at concentrations < 0.1 nM, whereas at > 1 nM, it inhibited the electron transport at Complex V (mixed type inhibition; IC(50) = 6 nM) and Complex IV (noncompetitive inhibition; IC(50) = 40 nM). These concentrations are easily achieved in plasma concentrations considering that BDE-49 (this study, 400-fold) and other PBDEs accumulate 1-3 orders of magnitude in the cells, particularly in mitochondria and microsomes. Similar effects were observed in NPC and exacerbated with PTEN (negative modulator of the PI3K/Akt pathway) deficiency, background associated with autism-like behavior, schizophrenia, and epilepsy. PBDE-mediated MD per se or enhanced by a background that confers susceptibility to this exposure may have profound implications in the energy balance of brain.
This mini-review highlights the innovative observation that transplanted human neural stem cells can bring about endogenous brain repair through the stimulation of multiple regenerative processes in ...the neurogenic area (i.e., subventricular zone SVZ) in an animal model of Parkinson's disease (PD). In addition, we convey that identifying anti-inflammatory cytokines, therapeutic proteomes, and neurotrophic factors within the SVZ may be essential to induce brain repair and behavioral recovery. This work opens up a new area of research for further understanding the pathology and treatment of PD. This paper is a review article. Referred literature in this paper has been listed in the references section. The datasets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences.
Autism spectrum disorder (ASD) is characterized by psychiatric and behavioral comorbidities. The Child Behavior Checklist (CBCL) provides valid and well-established measures of emotional, behavioral, ...and social problems in children and adolescents. The aim of the present study was to verify whether emotional, behavioral, and social problems were modulated by ASD symptom severity, cognitive development, gender, and age by analyzing the CBCL in a large group of children and adolescents with ASD. The results show that around 30% of participants with ASD exhibited internalizing problems and only 6% externalizing problems, with males exhibiting more internalizing problems than females. No correlation was found between CBCL scores and indices of ASD severity. However, higher CBCL Total Problems scores were found in older children and in children with lower cognitive abilities. The detection of behavioral and emotional problems allows children with ASD to undergo specific and individualized treatment that takes into account their psychopathological problems.
Parent-mediated intervention is widely used for pre-schoolers with autism spectrum disorder (ASD). Previous studies indicate small-to-moderate effects on social communication skills, but with a wide ...heterogeneity that requires further research. In this randomized controlled trial (RCT), cooperative parent-mediated therapy (CPMT) an individual parent coaching program for young children with ASD was administered to preschool children with ASD. All children received the same low-intensity psychosocial intervention (LPI) delivered in community settings, to evaluate the potential additional benefit of CPMT. Thirty-four participants with ASD (7 females; 27 males; aged 2, 6, 11 years) and their parents were included in the trial. The primary blinded outcome was social communication skills, assessed using the ADOS-G social communication algorithm score (ADOS-G SC). Secondary outcomes included ASD symptom severity, parent-rated language abilities and emotional/behavioral problems, and self-reported caregiver stress. Evaluations were made at baseline and post-treatment (at 6 months) by an independent multidisciplinary team. Results documented that CPMT showed an additional benefit on LPI with significant improvements of the primary blinded outcome, socio-communication skills, and of some secondary outcomes such as ASD symptom severity, emotional problems and parental stress related to parent–child dysfunctional interaction. No additional benefit was found for language abilities. Findings of our RCT show that CPMT provide an additional significant short-term treatment benefit on ASD core symptoms, when compared with active control group receiving only LPI.
A 55-200 expansion of the CGG nucleotide repeat in the 5'-UTR of the fragile X mental retardation 1 gene (
) is the hallmark of the triplet nucleotide disease known as the "premutation" as opposed to ...those with >200 repeats, known as the full mutation or fragile X syndrome. Originally, premutation carriers were thought to be free of phenotypic traits; however, some are diagnosed with emotional and neurocognitive issues and, later in life, with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Considering that mitochondrial dysfunction has been observed in fibroblasts and post-mortem brain samples from carriers of the premutation, we hypothesized that mitochondrial dysfunction-derived ROS may result in cumulative oxidative-nitrative damage. Fibroblasts from premutation carriers (
=31, all FXTAS-free except 8), compared to age- and sex-matched controls (
=25), showed increased mitochondrial ROS production, impaired Complex I activity, lower expression of MIA40 (rate-limiting step of the redox-regulated mitochondrial-disulfide-relay-system), increased mtDNA deletions, and increased biomarkers of lipid and protein oxidative-nitrative damage. Most of the outcomes were more pronounced in FXTAS-affected individuals. Significant recovery of mitochondrial mass and/or function was obtained with superoxide or hydroxyl radicals' scavengers, a glutathione peroxidase analog, or by overexpressing MIA40. The effects of ethanol (a hydroxyl radical scavenger) were deleterious, while others (by
-acetyl-cysteine, quercetin and epigallocatechin-3-gallate) were outcome- and/or carrier-specifics. The use of antioxidants in the context of precision medicine is discussed with the goal of improving mitochondrial function in carriers with the potential of decreasing the morbidity and/or delaying FXTAS onset.
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