-
1.
Feasibility and Biological Activity of a Ketogenic/Intermittent-Fasting Diet in Patients With Glioma.
Schreck, KC, Hsu, FC, Berrington, A, Henry-Barron, B, Vizthum, D, Blair, L, Kossoff, EH, Easter, L, Whitlow, CT, Barker, PB, et al
Neurology. 2021;(9):e953-e963
-
-
Free full text
-
Abstract
OBJECTIVE To examine the feasibility, safety, systemic biological activity, and cerebral activity of a ketogenic dietary intervention in patients with glioma. METHODS Twenty-five patients with biopsy-confirmed World Health Organization grade 2 to 4 astrocytoma with stable disease after adjuvant chemotherapy were enrolled in an 8-week Glioma Atkins-Based Diet (GLAD). GLAD consisted of 2 fasting days (calories <20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates ≤20 g/d) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, insulin-like growth factor-1, and magnetic resonance spectroscopy at baseline and week 8. RESULTS Twenty-one patients (84%) completed the study. Eighty percent of patients reached ≥40 mg/dL urine acetoacetate during the study. Forty-eight percent of patients were adherent by food record. The diet was well tolerated, with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity, including hemoglobin A1c, insulin, and fat body mass, decreased significantly, while lean body mass increased. Magnetic resonance spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate [bHB] and acetone) in both lesional and contralateral brain compared to baseline. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB R s = 0.52, p = 0.05). Subgroup analysis of isocitrate dehydrogenase-mutant glioma showed no differences in cerebral metabolites after controlling for ketonuria. CONCLUSION The GLAD dietary intervention, while demanding, produced meaningful ketonuria and significant systemic and cerebral metabolic changes in participants. Ketonuria in participants correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records. TRIAL REGISTRATION INFORMATION ClinicalTrials.gov Identifier: NCT02286167.
-
2.
Deep-learning-based synthesis of post-contrast T1-weighted MRI for tumour response assessment in neuro-oncology: a multicentre, retrospective cohort study.
Jayachandran Preetha, C, Meredig, H, Brugnara, G, Mahmutoglu, MA, Foltyn, M, Isensee, F, Kessler, T, Pflüger, I, Schell, M, Neuberger, U, et al
The Lancet. Digital health. 2021;(12):e784-e794
Abstract
BACKGROUND Gadolinium-based contrast agents (GBCAs) are widely used to enhance tissue contrast during MRI scans and play a crucial role in the management of patients with cancer. However, studies have shown gadolinium deposition in the brain after repeated GBCA administration with yet unknown clinical significance. We aimed to assess the feasibility and diagnostic value of synthetic post-contrast T1-weighted MRI generated from pre-contrast MRI sequences through deep convolutional neural networks (dCNN) for tumour response assessment in neuro-oncology. METHODS In this multicentre, retrospective cohort study, we used MRI examinations to train and validate a dCNN for synthesising post-contrast T1-weighted sequences from pre-contrast T1-weighted, T2-weighted, and fluid-attenuated inversion recovery sequences. We used MRI scans with availability of these sequences from 775 patients with glioblastoma treated at Heidelberg University Hospital, Heidelberg, Germany (775 MRI examinations); 260 patients who participated in the phase 2 CORE trial (1083 MRI examinations, 59 institutions); and 505 patients who participated in the phase 3 CENTRIC trial (3147 MRI examinations, 149 institutions). Separate training runs to rank the importance of individual sequences and (for a subset) diffusion-weighted imaging were conducted. Independent testing was performed on MRI data from the phase 2 and phase 3 EORTC-26101 trial (521 patients, 1924 MRI examinations, 32 institutions). The similarity between synthetic and true contrast enhancement on post-contrast T1-weighted MRI was quantified using the structural similarity index measure (SSIM). Automated tumour segmentation and volumetric tumour response assessment based on synthetic versus true post-contrast T1-weighted sequences was performed in the EORTC-26101 trial and agreement was assessed with Kaplan-Meier plots. FINDINGS The median SSIM score for predicting contrast enhancement on synthetic post-contrast T1-weighted sequences in the EORTC-26101 test set was 0·818 (95% CI 0·817-0·820). Segmentation of the contrast-enhancing tumour from synthetic post-contrast T1-weighted sequences yielded a median tumour volume of 6·31 cm3 (5·60 to 7·14), thereby underestimating the true tumour volume by a median of -0·48 cm3 (-0·37 to -0·76) with the concordance correlation coefficient suggesting a strong linear association between tumour volumes derived from synthetic versus true post-contrast T1-weighted sequences (0·782, 0·751-0·807, p<0·0001). Volumetric tumour response assessment in the EORTC-26101 trial showed a median time to progression of 4·2 months (95% CI 4·1-5·2) with synthetic post-contrast T1-weighted and 4·3 months (4·1-5·5) with true post-contrast T1-weighted sequences (p=0·33). The strength of the association between the time to progression as a surrogate endpoint for predicting the patients' overall survival in the EORTC-26101 cohort was similar when derived from synthetic post-contrast T1-weighted sequences (hazard ratio of 1·749, 95% CI 1·282-2·387, p=0·0004) and model C-index (0·667, 0·622-0·708) versus true post-contrast T1-weighted MRI (1·799, 95% CI 1·314-2·464, p=0·0003) and model C-index (0·673, 95% CI 0·626-0·711). INTERPRETATION Generating synthetic post-contrast T1-weighted MRI from pre-contrast MRI using dCNN is feasible and quantification of the contrast-enhancing tumour burden from synthetic post-contrast T1-weighted MRI allows assessment of the patient's response to treatment with no significant difference by comparison with true post-contrast T1-weighted sequences with administration of GBCAs. This finding could guide the application of dCNN in radiology to potentially reduce the necessity of GBCA administration. FUNDING Deutsche Forschungsgemeinschaft.
-
3.
Cerebral phosphoester signals measured by 31P magnetic resonance spectroscopy at 3 and 7 Tesla.
Li, S, van der Veen, JW, An, L, Stolinski, J, Johnson, C, Ferraris-Araneta, M, Victorino, M, Tomar, JS, Shen, J
PloS one. 2021;(3):e0248632
Abstract
Abnormal cell membrane metabolism is associated with many neuropsychiatric disorders. Free phosphomonoesters and phosphodiesters, which can be detected by in vivo 31P magnetic resonance spectroscopy (MRS), are important cell membrane building blocks. However, the quantification of phosphoesters has been highly controversial even in healthy individuals due to overlapping signals from macromolecule membrane phospholipids (MP). In this study, high signal-to-noise ratio (SNR) cerebral 31P MRS spectra were acquired from healthy volunteers at both 3 and 7 Tesla. Our results indicated that, with minimal spectral interference from MP, the [phosphocreatine (PCr)]/[phosphocholine (PC) + glycerophosphocholine (GPC)] ratio measured at 7 Tesla agreed with its value expected from biochemical constraints. In contrast, the 3 Tesla [PCr]/[PC+GPC] ratio obtained using standard spectral fitting procedures was markedly smaller than the 7 Tesla ratio and than the expected value. The analysis suggests that the commonly used spectral model for MP may fail to capture its complex spectral features at 3 Tesla, and that additional prior knowledge is necessary to reliably quantify the phosphoester signals at low magnetic field strengths when spectral overlapping is significant.
-
4.
Benfotiamine and Cognitive Decline in Alzheimer's Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial.
Gibson, GE, Luchsinger, JA, Cirio, R, Chen, H, Franchino-Elder, J, Hirsch, JA, Bettendorff, L, Chen, Z, Flowers, SA, Gerber, LM, et al
Journal of Alzheimer's disease : JAD. 2020;(3):989-1010
-
-
Free full text
-
Abstract
BACKGROUND In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer's disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation. OBJECTIVE To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine. METHODS A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome. RESULTS Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOEɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOEɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002). CONCLUSION Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.
-
5.
Cerebral Ketones Detected by 3T MR Spectroscopy in Patients with High-Grade Glioma on an Atkins-Based Diet.
Berrington, A, Schreck, KC, Barron, BJ, Blair, L, Lin, DDM, Hartman, AL, Kossoff, E, Easter, L, Whitlow, CT, Jung, Y, et al
AJNR. American journal of neuroradiology. 2019;(11):1908-1915
Abstract
BACKGROUND AND PURPOSE Ketogenic diets are being explored as a possible treatment for several neurological diseases, but the physiologic impact on the brain is unknown. The objective of this study was to evaluate the feasibility of 3T MR spectroscopy to monitor brain ketone levels in patients with high-grade gliomas who were on a ketogenic diet (a modified Atkins diet) for 8 weeks. MATERIALS AND METHODS Paired pre- and post-ketogenic diet MR spectroscopy data from both the lesion and contralateral hemisphere were analyzed using LCModel software in 10 patients. RESULTS At baseline, the ketone bodies acetone and β-hydroxybutyrate were nearly undetectable, but by week 8, they increased in the lesion for both acetone (0.06 ± 0.03 ≥ 0.27 ± 0.06 IU, P = .005) and β-hydroxybutyrate (0.07 ± 0.07 ≥ 0.79 ± 0.32 IU, P = .046). In the contralateral brain, acetone was also significantly increased (0.041 ± 0.01 ≥ 0.16 ± 0.04 IU, P = .004), but not β-hydroxybutyrate. Acetone was detected in 9/10 patients at week 8, and β-hydroxybutyrate, in 5/10. Acetone concentrations in the contralateral brain correlated strongly with higher urine ketones (r = 0.87, P = .001) and lower fasting glucose (r = -0.67, P = .03). Acetoacetate was largely undetectable. Small-but-statistically significant decreases in NAA were also observed in the contralateral hemisphere at 8 weeks. CONCLUSIONS This study suggests that 3T MR spectroscopy is feasible for detecting small cerebral metabolic changes associated with a ketogenic diet, provided that appropriate methodology is used.
-
6.
Effect of High-Intensity Exercise on Multiple Sclerosis Function and Phosphorous Magnetic Resonance Spectroscopy Outcomes.
Orban, A, Garg, B, Sammi, MK, Bourdette, DN, Rooney, WD, Kuehl, K, Spain, RI
Medicine and science in sports and exercise. 2019;(7):1380-1386
-
-
Free full text
-
Abstract
PURPOSE We determined if a high-intensity aerobic exercise program would be safe, improve expected fitness and clinical outcomes, and alter exploratory phosphorous magnetic resonance spectroscopy (P MRS) outcomes in persons with multiple sclerosis (PwMS). METHODS This open-label prospective pilot study compared two cohorts of ambulatory PwMS matched for age, sex and V˙O2max. Cohorts underwent 8 wk of high-intensity aerobic exercise (MS-Ex, n = 10) or guided stretching (MS-Ctr, n = 7). Aerobic exercise consisted of four 30-min sessions per week while maintaining ≥70% maximal HR. Changes in cardiorespiratory fitness, clinical outcomes, and P MRS of tibialis anterior (TA) muscle and brain were compared. Cross-sectional P MRS comparisons were made between all MS participants and a separate matched healthy control population. RESULTS The MS-Ex cohort achieved target increases in V˙O2max (mean, +12.7%; P = <0.001, between-group improvement, P = 0.03). One participant was withdrawn for exercise-induced syncope. The MS-Ex cohort had within-group improvements in fat mass (-5.8%; P = 0.04), lean muscle mass (+2.6%; P = 0.02), Symbol Digit Modalities Test (+15.1%; P = 0.04), and cognitive subscore of the Modified Fatigue Impact Scale (-26%; P = 0.03), whereas only the physical subscore of the Modified Fatigue Impact Scale improved in MS-Ctr (-16.1%; P = 0.007). P MRS revealed significant within-group increases in MS-Ex participants in TA rate constant of phosphocreatine (PCr) recovery (+31.5%; P = 0.03) and adenosine triphosphate/PCr (+3.2%; P = 0.01), and near significant between-group increases in TA PCr recovery rate constant (P = 0.05) but no significant changes in brain P MRS after exercise. Cross-sectional differences existed between MS and healthy control brain PCr/inorganic phosphate (4.61 ± 0.44, 3.93 ± 0.19; P = 0.0019). CONCLUSIONS High-intensity aerobic exercise in PwMS improved expected cardiorespiratory and clinical outcomes but provoked one serious adverse event. The P MRS may serve to explore underlying mechanisms by which aerobic exercise exerts cerebral benefits.
-
7.
Differential Effects of BMI on Brain Response to Odor in Olfactory, Reward and Memory Regions: Evidence from fMRI.
Jacobson, A, Green, E, Haase, L, Szajer, J, Murphy, C
Nutrients. 2019;(4)
Abstract
:Obesity has reached epidemic proportions, motivating research into the underlying mechanisms. Olfaction is a powerful mediator of food consumption, and obesity has been associated with altered olfactory sensitivity. The current study used an event-related functional magnetic resonance imaging (fMRI) to examine the central processing of odor in humans to gain insight into the effect of the body mass index (BMI) on the neural processes involved in rating the pleasantness of a food odor during a hunger state and in a satiety state. We hypothesized that, during the hedonic evaluation of food odor, BMI would be associated with differences in brain activation within olfactory and higher order processing areas important for perception, reward, and memory. We report novel findings of a dissociation between the relationship between BMI and activation in reward areas and in olfactory and odor memory areas, i.e., activation in reward areas decreased as BMI increased, whereas activation in primary olfactory and memory regions increased as BMI increased. A greater BMI is associated with decreased activation in the reward and frontal regions, supporting a blunted reward response in obesity. These findings have important potential implications for decision making, response inhibition, and reward-based behaviors that may play key roles as causal and maintenance factors in obesity. In contrast, a greater BMI is associated with an increased activation in the primary olfactory and memory areas, which was observed during a hunger state. These results raise the speculative hypothesis that high BMI may be associated with hyperactivation in the olfactory and memory areas, and that over time, the resulting excitotoxic effects may contribute to neurodegenerative changes in these areas.
-
8.
Imprinting methylation in SNRPN and MEST1 in adult blood predicts cognitive ability.
Lorgen-Ritchie, M, Murray, AD, Ferguson-Smith, AC, Richards, M, Horgan, GW, Phillips, LH, Hoad, G, Gall, I, Harrison, K, McNeill, G, et al
PloS one. 2019;(2):e0211799
Abstract
Genomic imprinting is important for normal brain development and aberrant imprinting has been associated with impaired cognition. We studied the imprinting status in selected imprints (H19, IGF2, SNRPN, PEG3, MEST1, NESPAS, KvDMR, IG-DMR and ZAC1) by pyrosequencing in blood samples from longitudinal cohorts born in 1936 (n = 485) and 1921 (n = 223), and anterior hippocampus, posterior hippocampus, periventricular white matter, and thalamus from brains donated to the Aberdeen Brain Bank (n = 4). MEST1 imprint methylation was related to childhood cognitive ability score (-0.416 95% CI -0.792,-0.041; p = 0.030), with the strongest effect evident in males (-0.929 95% CI -1.531,-0.326; p = 0.003). SNRPN imprint methylation was also related to childhood cognitive ability (+0.335 95%CI 0.008,0.663; p = 0.045). A significant association was also observed for SNRPN methylation and adult crystallised cognitive ability (+0.262 95%CI 0.007,0.517; p = 0.044). Further testing of significant findings in a second cohort from the same region, but born in 1921, resulted in similar effect sizes and greater significance when the cohorts were combined (MEST1; -0.371 95% CI -0.677,-0.065; p = 0.017; SNRPN; +0.361 95% CI 0.079,0.643; p = 0.012). For SNRPN and MEST1 and four other imprints the methylation levels in blood and in the five brain regions were similar. Methylation of the paternally expressed, maternally methylated genes SNRPN and MEST1 in adult blood was associated with cognitive ability in childhood. This is consistent with the known importance of the SNRPN containing 15q11-q13 and the MEST1 containing 7q31-34 regions in cognitive function. These findings, and their sex specific nature in MEST1, point to new mechanisms through which complex phenotypes such as cognitive ability may be inherited. These mechanisms are potentially relevant to both the heritable and non-heritable components of cognitive ability. The process of epigenetic imprinting-within SNRPN and MEST1 in particular-and the factors that influence it, are worthy of further study in relation to the determinants of cognitive ability.
-
9.
Structural and functional brain changes in perimenopausal women who are susceptible to migraine: a study protocol of multi-modal MRI trial.
Hu, B, Wang, X, He, JB, Dai, YJ, Zhang, J, Yu, Y, Sun, Q, Lin-FengYan, , Hu, YC, Nan, HY, et al
BMC medical imaging. 2018;(1):26
Abstract
BACKGROUND As a common clinical symptom that often bothers midlife females, migraine is closely associated with perimenopause. Previous studies suggest that one of the most prominent triggers is the sudden decline of estrogen during perimenopausal period. Hormone replacement therapy (HRT) is widely used to prevent this suffering in perimenopausal women, but effective diagnostic system is lacked for quantifying the severity of the diseaase. To avoid the abuse and overuse of HRT, we propose to conduct a diagnostic trial using multimodal MRI techniques to quantify the severity of these perimenopausal migraineurs who are susceptible to the decline of estrogen. METHODS Perimenopausal women suffering from migraine will be recruited from the pain clinic of our hospital. Perimenopausal women not suffering from any kind of headache will be recruited from the local community. Clinical assessment and multi-modal MR imaging examination will be conducted. A follow up will be conducted once half year within 3 years. Pain behavior, neuropsychology scores, fMRI analysis combined with suitable statistical software will be used to reveal the potential association between these above traits and the susceptibility of migraine. DISCUSSION Multi-modal imaging features of both healthy controls and perimenopausal women who are susceptible to estrogen decline will be acquired. Imaging features will include volumetric characteristics, white matter integrity, functional characteristics, topological properties, and perfusion properties. Clinical information, such as basic information, blood estrogen level, information of migraine, and a bunch of neurological scale will also be used for statistic assessment. This clinical trial would help to build an effective screen system for quantifying the severity of illness of those susceptible women during the perimenopausal period. TRIAL REGISTRATION This study has already been registered at Clinical Trials. gov (ID: NCT02820974 ). Registration date: September 28th, 2014.
-
10.
Neuropsychological and Neurophysiological Indicators of General and Food-Specific Impulsivity in Children with Overweight and Obesity: A Pilot Study.
Schmidt, R, Sebert, C, Kösling, C, Grunwald, M, Hilbert, A, Hübner, C, Schäfer, L
Nutrients. 2018;(12)
Abstract
Impulsivity, particularly towards food, is a potential risk factor for increased energy intake and the development and maintenance of obesity in children. However, neuropsychological and neurophysiological indicators of general and food-specific impulsivity and their association with children's weight status are poorly understood. This pilot study examined electroencephalography (EEG) frequency band profiles during eyes-closed and eyes-open resting state in n = 12 children with overweight or obesity versus n = 22 normal-weight controls and their link to child- and parent-reported and experimentally assessed impulsivity of children (e.g., risk-taking behavior, approach-avoidance behavior towards food). The main results indicated that children with overweight/obesity versus normal weight showed significantly increased delta and decreased alpha band activity during eyes-closed resting state. Across the total sample, EEG slow-wave band activity was particularly linked to self- and parent-reported impulsivity and greater risk-taking behavior, but not to approach behavior towards food, after controlling for children's age and weight status. The identification of specific EEG patterns in children with excess weight may provide a new basis for developing neurophysiological diagnostic and treatment approaches for childhood obesity. Future studies with larger samples and longitudinal designs are needed to replicate the present findings and test their stability over time.