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Anatomical and Biological Imaging of Pediatric Brain Tumor
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Rob A. Dineen, Shivaram Avula, Andrew C. Peet, Giovanni Morana, Monika Warmuth-Metz
In addition to providing diagnostic information, MRS provides non-invasive biomarkers of prognosis which can apply across the range of tumors or be tumor-specific. The most accepted of these biomarkers is probably tumor lipids which have been validated as a marker of poor survival in a prospective study which included all tumor types.78 A retrospective analysis of other metabolites in this study indicated that scyllo-inositol was predictive of poor survival, whilst glutamine and NAA were associated with better survival. Total choline has also been proposed as a marker of poor prognosis and a study using MRS imaging found that the highest total choline levels across the tumor predicted poor survival in a cohort of non-metastatic CNS tumors.79 The fact that total choline levels were not significantly associated with survival in a single-voxel study of all tumor types78 may indicate that intratumor heterogeneity is important, with total choline identifying regions of treatment resistance. An increased pretreatment ratio of choline to NAA was found to predict shorter survival in DIPG50 and low choline-to-NAA ratio is predictive of good prognosis80 (in supratentorial astrocytoma); both of these observations support total choline as a biomarker of poor prognosis.
Postimplantation diabetic embryopathy
Published in Moshe Hod, Lois G. Jovanovic, Gian Carlo Di Renzo, Alberto de Leiva, Oded Langer, Textbook of Diabetes and Pregnancy, 2018
Ulf J. Eriksson, Parri Wentzel
High glucose concentration in vitro causes decreased levels of inositol in the embryo due to impaired uptake,141 yielding an embryonic deficiency of inositol92,100,140,158 concomitant with an increased rate of embryonic dysmorphogenesis. Supplementation of myo-inositol to high glucose–cultured embryos,97,98,139 or dietary addition to diabetic pregnant rodents,67,158–160 diminishes both the inositol deficiency and the rate of embryonic maldevelopment. Furthermore, adding the inositol uptake inhibitor scyllo-inositol to the culture medium of rodent embryos causes similar changes as excess glucose to the embryos, i.e., both inositol deficiency and embryonic maldevelopment.100,161,162 In addition, similarly to the glucose-induced damage, both inositol deficiency and embryo maldevelopment caused by scyllo-inositol can be diminished by the addition of inositol to the culture medium.100,161,162 These findings identify inositol deficiency as a likely component of diabetic teratogenesis.163
Weightlifting
Published in Ira Glick, Danielle Kamis, Todd Stull, The ISSP Manual of Sports Psychiatry, 2018
Ian Steele, Harrison Pope, Gen Kanayama
Recent data suggests that AAS may be neurotoxic, as demonstrated in vitro in human neuronal cells exposed to supraphysiologic levels of testosterone and other AAS, as well as in animal models. One recent study in humans found impairments on tests of visuospatial memory in AAS users as compared to non-using weightlifters; in this study, the degree of visuospatial impairment was significantly correlated with total lifetime AAS exposure, raising the ominous possibility that long-term AAS use might ultimately lead to symptoms of dementia. Recent neuroimaging studies of AAS users have also found evidence of possible neurotoxicity, including cortical thinning (Bjornebekk, Walhovd, Jørstad, Due-Tønnessen, Hullstein, & Fjell, 2016) and deficits of scyllo-inositol, a neurochemical essential for counteracting beta-amyloid toxicity (Kaufman, Janes, Hudson, & Brennan, 2015).
Investigational BACE inhibitors for the treatment of Alzheimer’s disease
Published in Expert Opinion on Investigational Drugs, 2019
Bruno P. Imbimbo, Mark Watling
Detrimental effects on cognition and clinical global status have been observed not only with BACE1 inhibitors but also with other anti-Aβ drugs. An 18-month, double-blind, placebo-controlled study with the γ-secretase inhibitor semagacestat (100 and 140 mg/day) in 1,537 mild-to-moderate AD was discontinued prematurely because of deterioration in patient cognition [37]. Patients receiving the highest dose (140 mg/day) performed significantly worse than placebo-treated patients for cognition (as assessed with MMSE), functionality (as assessed with ADCS-ADL), psychiatric symptoms (as assessed with NPI) and clinical global performance (as assessed with CDR-SB). This dose of semagacestat had been shown to significantly decreased the production of CNS Aβ by 52% in a previous study [38]. Avagacestat, another γ-secretase inhibitor, worsened cognition (MMSE) compared to placebo in a 6-month study involving 209 mild-to-moderate AD patients [39]. Tarenflurbil, a γ-secretase modulator, significantly worsened CDR-SB compared to placebo in an 18-month study involving 1,684 mild AD patients [40]. CAD106, an active anti-Aβ vaccine, tended to worsen MMSE compared to placebo (p = 0.052) in a 90-week study involving 121 patients with mild AD [41]. Another Aβ antigen, AD02, worsened cognition (ADAS-Cog) and clinical global status (CDR-SB) versus control treatment in an 18-month study involving 332 patients with early AD [42]. Scyllo-inositol, an Aβ aggregation inhibitor, dose-dependently increased mortality in an 18-month study involving 353 mild-to-moderate AD patients [43].
Do BACE inhibitor failures in Alzheimer patients challenge the amyloid hypothesis of the disease?
Published in Expert Review of Neurotherapeutics, 2019
Francesco Panza, Madia Lozupone, Mark Watling, Bruno Pietro Imbimbo
Negative effects of BACE inhibitors on cognition, functionality and clinical global performance were also observed in trials of other anti-Aβ drugs. Higher mortality rate on semagacestat (a γ-secretase inhibitor) was reported in a Phase III trial involving 1,537 mild-to-moderate AD patients [15]. This trial was discontinued prematurely because of deterioration in patient cognition. At the time of trial termination, 10.2%, 23.9% and 27.3% of patients on placebo, semagacestat 100 mg and semagacestat 140 mg daily, respectively, had withdrawn from the study because of adverse events. There were six deaths on placebo (1.2%), 11 deaths on 100 mg (2.2%), and 15 deaths on 140 mg (2.8%). A previous study has shown that the doses of semagacestat used in the Phase III trial (100 and 140 mg/day) significantly decreased the production of CNS Aβ by 47% and 52%, respectively [16]. Avagacestat, a γ-secretase inhibitor, worsened cognition in both prodromal [17] and in mild-to-moderate AD patients [18]. Tarenflurbil, a γ-secretase modulator, significantly worsened CDR-SB compared to placebo in mild AD patients, although it did not affect CSF Aβ levels [19]. CAD106, an active anti-Aβ vaccine, tended to worsen MMSE compared to placebo in patients with mild AD [20]. Another Aβ antigen, AD02, worsened cognition and functionality in patients with early AD [21]. Scyllo-inositol, an Aβ aggregation inhibitor, dose-dependently increased mortality in mild-to-moderate AD patients [22].
Sialylated milk oligosaccharides alter neurotransmitters and brain metabolites in piglets: an In vivo magnetic resonance spectroscopic (MRS) study
Published in Nutritional Neuroscience, 2021
Hong Xin Wang, Yue Chen, Ziaul Haque, Michael de Veer, Gary Egan, Bing Wang
Interestingly, other important neurotransmitters and brain metabolites including mIns, TCho, TCr, SI and Glth were also significantly correlated with total white matter volume in both treatment groups compared with the control group (Figure 5C–G, P < .01). Brain white mater is mainly composed of myelinated axons. Myelination of nerve fibres significantly contributes to the postnatal CNS developmental process [33]. Neurodevelopmental markers of brain white matter volume in piglets significantly correlated with mIns, which has been proposed as a glial cell marker [34]. Choline (Cho) is an essential nutrient and the precursor molecule for the neurotransmitter acetylcholine, involved in many functions including memory and muscle control [35]. Choline is also a constituent of sphingomyelin and lecithin that are components of the myelin sheath. Creatine (Cr) facilitates the recycling of adenosine triphosphate (ATP), the energy currency of the cell, primarily in muscle and brain tissue [36,37]. Scyllo-inositol (SI) is a potential therapeutic for Alzheimer’s disease (AD) by directly interacting with the Aβ peptide to inhibit Aβ42 fibre formation and alleviate symptoms of AD in a mouse model [38,39]. Glutathione (Glth) is the archetypal antioxidant and plays a role in preventing damage to important cellular components from reactive oxygen species such as free radicals, peroxides, lipid peroxides and heavy metals [40]. We also found the absolute concentration of brain SI and Glu were significantly correlated with whole brain volume, and SI with whole brain weight in the treatment groups, either SL or SL/SLN compared to the control group respectively (Figure 5H–J, P < .01). Scyllo-inositol (SI) is the second most abundant inositol stereoisomer [41] in quantities estimated to be from 5% to 12% that of mIns [42]. Glutamate (Glu) is the most abundant excitatory neurotransmitter and is essential to brain function. Recently a study by Forde et al. [43] showed that there was a positive relationship between neurochemicals of NAA, Glu, mIns, Cho, Cr, SI and cell density within the cortex in a relatively large group of the children age range (8–12 years) [43]. Thus, the strong correlation of NNA, TNNA, mIns, TCho, TCr, SI, Glth and brain white matter volume in the treatment groups compared to the control group suggest that the presence of dietary SMOS may promote neurodevelopment potential, energy metabolism, cell protection and myelination in early postnatal life. The findings of significant positive correction between whole brain volume, brain weight and brain Glu and SI concentration in the treatment group compared to the control group also implies that SMOS supplementation might contribute to overall neurodevelopment in the developing brain. Correspondingly we found that dietary SLN and 3′SL intake were closely correlated with the levels of brain metabolites for Glu, mlns and Glx in the treatment groups only. To our knowledge, these findings have not been previously reported.