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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.
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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.
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Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia.
Lieve, KVV, Verhagen, JMA, Wei, J, Bos, JM, van der Werf, C, Rosés I Noguer, F, Mancini, GMS, Guo, W, Wang, R, van den Heuvel, F, et al
Heart rhythm. 2019;(2):220-228
Abstract
BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. OBJECTIVE The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. METHODS We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. RESULTS Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy. CONCLUSION Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.
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CT-based attenuation correction and resolution compensation for I-123 IMP brain SPECT normal database: a multicenter phantom study.
Inui, Y, Ichihara, T, Uno, M, Ishiguro, M, Ito, K, Kato, K, Sakuma, H, Okazawa, H, Toyama, H
Annals of nuclear medicine. 2018;(5):311-318
Abstract
OBJECTIVE Statistical image analysis of brain SPECT images has improved diagnostic accuracy for brain disorders. However, the results of statistical analysis vary depending on the institution even when they use a common normal database (NDB), due to different intrinsic spatial resolutions or correction methods. The present study aimed to evaluate the correction of spatial resolution differences between equipment and examine the differences in skull bone attenuation to construct a common NDB for use in multicenter settings. METHODS The proposed acquisition and processing protocols were those routinely used at each participating center with additional triple energy window (TEW) scatter correction (SC) and computed tomography (CT) based attenuation correction (CTAC). A multicenter phantom study was conducted on six imaging systems in five centers, with either single photon emission computed tomography (SPECT) or SPECT/CT, and two brain phantoms. The gray/white matter I-123 activity ratio in the brain phantoms was 4, and they were enclosed in either an artificial adult male skull, 1300 Hounsfield units (HU), a female skull, 850 HU, or an acrylic cover. The cut-off frequency of the Butterworth filters was adjusted so that the spatial resolution was unified to a 17.9 mm full width at half maximum (FWHM), that of the lowest resolution system. The gray-to-white matter count ratios were measured from SPECT images and compared with the actual activity ratio. In addition, mean, standard deviation and coefficient of variation images were calculated after normalization and anatomical standardization to evaluate the variability of the NDB. RESULTS The gray-to-white matter count ratio error without SC and attenuation correction (AC) was significantly larger for higher bone densities (p < 0.05). The count ratio error with TEW and CTAC was approximately 5% regardless of bone density. After adjustment of the spatial resolution in the SPECT images, the variability of the NDB decreased and was comparable to that of the NDB without correction. CONCLUSION The proposed protocol showed potential for constructing an appropriate common NDB from SPECT images with SC, AC and spatial resolution compensation.
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Diagnostic impact of [18F]flutemetamol PET in early-onset dementia.
Zwan, MD, Bouwman, FH, Konijnenberg, E, van der Flier, WM, Lammertsma, AA, Verhey, FR, Aalten, P, van Berckel, BN, Scheltens, P
Alzheimer's research & therapy. 2017;(1):2
Abstract
BACKGROUND Early-onset dementia patients often present with atypical clinical symptoms, hampering an accurate clinical diagnosis. The purpose of the present study was to assess the diagnostic impact of the amyloid-positron emission tomography (PET) imaging agent [18F]flutemetamol in early-onset dementia patients, in terms of change in (confidence in) diagnosis and patient management plan. METHODS This prospective bi-center study included 211 patients suspected of early-onset dementia who visited a tertiary memory clinic. Patients were eligible with Mini Mental State Examination ≥ 18 and age at diagnosis ≤ 70 years and in whom the diagnostic confidence was <90% after routine diagnostic work-up. All patients underwent [18F]flutemetamol PET, which was interpreted as amyloid-negative or amyloid-positive based on visual rating. Before and after disclosing the PET results, we assessed the diagnostic confidence (using a visual analog scale of 0-100%) and clinical diagnosis. The impact of [18F]flutemetamol PET on the patient management plan was also evaluated. RESULTS [18F]flutemetamol PET scans were positive in 133 out of 211 (63%) patients, of whom 110 out of 144 (76%) patients had a pre-PET Alzheimer's disease (AD) diagnosis and 23 out of 67 (34%) patients had a non-AD diagnosis. After disclosure of PET results, 41/211 (19%) diagnoses changed. Overall, diagnostic confidence increased from 69 ± 12% to 88 ± 15% after disclosing PET results (P < 0.001; in 87% of patients). In 79 (37%) patients, PET results led to a change in patient management and predominantly the initiation of AD medication when PET showed evidence for amyloid pathology. CONCLUSIONS [18F]flutemetamol PET changed clinical diagnosis, increased overall diagnostic confidence, and altered the patient management plan. Our results suggest that amyloid PET may have added value over the standardized diagnostic work-up in early-onset dementia patients with uncertain clinical diagnosis. This study provides evidence for the recommendations put forward in the appropriate use criteria for amyloid PET in clinical practice. TRIAL REGISTRATION Nederlands Trial Register NTR3743 . Registered 7 December 2012.
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Longer-Term Investigation of the Value of 18F-FDG-PET and Magnetic Resonance Imaging for Predicting the Conversion of Mild Cognitive Impairment to Alzheimer's Disease: A Multicenter Study.
Inui, Y, Ito, K, Kato, T, ,
Journal of Alzheimer's disease : JAD. 2017;(3):877-887
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Abstract
BACKGROUND The value of fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) and magnetic resonance imaging (MRI) for predicting conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD) in longer-term is unclear. OBJECTIVE To evaluate longer-term prediction of MCI to AD conversion using 18F-FDG-PET and MRI in a multicenter study. METHODS One-hundred and fourteen patients with MCI were followed for 5 years. They underwent clinical and neuropsychological examinations, 18F-FDG-PET, and MRI at baseline. PET images were visually classified into predefined dementia patterns. PET scores were calculated as a semi quantitative index. For structural MRI, z-scores in medial temporal area were calculated by automated volume-based morphometry (VBM). RESULTS Overall, 72% patients with amnestic MCI progressed to AD during the 5-year follow-up. The diagnostic accuracy of PET scores over 5 years was 60% with 53% sensitivity and 84% specificity. Visual interpretation of PET images predicted conversion to AD with an overall 82% diagnostic accuracy, 94% sensitivity, and 53% specificity. The accuracy of VBM analysis presented little fluctuation through 5 years and it was highest (73%) at the 5-year follow-up, with 79% sensitivity and 63% specificity. The best performance (87.9% diagnostic accuracy, 89.8% sensitivity, and 82.4% specificity) was with a combination identified using multivariate logistic regression analysis that included PET visual interpretation, educational level, and neuropsychological tests as predictors. CONCLUSION 18F-FDG-PET visual assessment showed high performance for predicting conversion to AD from MCI, particularly in combination with neuropsychological tests. PET scores showed high diagnostic specificity. Structural MRI focused on the medial temporal area showed stable predictive value throughout the 5-year course.
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CSF biomarkers of monocyte activation and chemotaxis correlate with magnetic resonance spectroscopy metabolites during chronic HIV disease.
Anderson, AM, Fennema-Notestine, C, Umlauf, A, Taylor, MJ, Clifford, DB, Marra, CM, Collier, AC, Gelman, BB, McArthur, JC, McCutchan, JA, et al
Journal of neurovirology. 2015;(5):559-67
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Abstract
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART), supporting the need to better understand HIV neuropathogenesis. Magnetic resonance spectroscopy (MRS) of the brain has demonstrated abnormalities in HIV-infected individuals despite cART. We examined the associations between MRS metabolites and selected cerebrospinal fluid (CSF) biomarkers reflecting monocyte/macrophage activation and chemotaxis. A multicenter cross-sectional study involving five sites in the USA was conducted. The following CSF biomarkers were measured: soluble CD14 (sCD14), monocyte chemotactic protein-1 (MCP-1), interferon inducible protein 10 (IP-10), and stromal cell-derived growth factor 1 alpha (SDF-1α). The following MRS metabolites were measured from basal ganglia (BG), frontal white matter (FWM), and frontal gray matter (FGM): N-acetylaspartate (NAA), myo-inositol (MI), choline (Cho), and creatine (Cr). CSF biomarkers were compared to absolute MRS metabolites as well as metabolite/Cr ratios using linear regression. Eighty-three HIV-infected individuals were included, 78 % on cART and 37 % with HAND. The most robust positive correlations were between MCP-1 and Cho in BG (R (2) 0.179, p < 0.001) as well as MCP-1 and MI in FWM (R (2) 0.137, p = 0.002). Higher Cr levels in FWM were associated with MCP-1 (R (2) 0. 075, p = 0.01) and IP-10 (R (2) 0.106, p = 0.003). Comparing biomarkers to MRS metabolite/Cr ratios impacted some relationships, e.g., higher sCD14 levels were associated with lower Cho/Cr ratios in FGM (R (2) 0.224, p < 0.001), although higher MCP-1 levels remained associated with Cho/Cr in BG. These findings provide evidence that monocyte activation and chemotaxis continue to contribute to HIV-associated brain abnormalities in cART-treated individuals.
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Predictors for cortical gray matter volume in stroke patients with confluent white matter changes.
Xiong, Y, Wong, A, Wong, K, Chu, WC, Hu, X, Chen, X, Wong, KS, Wong, ST, Liu, X, Mok, V
Journal of the neurological sciences. 2014;(1-2):169-73
Abstract
BACKGROUND AND PURPOSE Our previous study found that cortical gray matter (cGM) volume predicted vascular cognitive impairment independent of age-related white matter changes (WMC). We aimed to investigate predictors for cGM volume in ischemic stroke patients with confluent WMC. METHODS One-hundred post-stroke patients with confluent WMC were recruited into the study. All volumetric measures were standardized by intracranial volume as volume ratio. Univariate analyses and multivariate linear regression models were used to test relationship of cGM volume with basic demography, vascular risk factors, APOE status, WMC volume (periventricular and deep WMC), infarct measures (volume, number and location) and microbleed (number, presence and location). RESULTS After controlling for significant variables in the univariate analyses, multivariate linear regression models found that old age (β=-0.288, p=0.001), low triglyceride (β=0.194, p=0.027), periventricular WMC (PVWMC) (β=-0.392, p<0.001) and presence of thalamic microbleed (β=-0.197, p=0.041) were independently predictive of less cGM volume ratio. CONCLUSIONS Age, PVWMC and left thalamic microbleed predict less cGM volume.
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The effect of souvenaid on functional brain network organisation in patients with mild Alzheimer's disease: a randomised controlled study.
de Waal, H, Stam, CJ, Lansbergen, MM, Wieggers, RL, Kamphuis, PJ, Scheltens, P, Maestú, F, van Straaten, EC
PloS one. 2014;(1):e86558
Abstract
BACKGROUND Synaptic loss is a major hallmark of Alzheimer's disease (AD). Disturbed organisation of large-scale functional brain networks in AD might reflect synaptic loss and disrupted neuronal communication. The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to enhance synapse formation and function and has been shown to improve memory performance in patients with mild AD in two randomised controlled trials. OBJECTIVE To explore the effect of Souvenaid compared to control product on brain activity-based networks, as a derivative of underlying synaptic function, in patients with mild AD. DESIGN A 24-week randomised, controlled, double-blind, parallel-group, multi-country study. PARTICIPANTS 179 drug-naïve mild AD patients who participated in the Souvenir II study. INTERVENTION Patients were randomised 1∶1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. OUTCOME In a secondary analysis of the Souvenir II study, electroencephalography (EEG) brain networks were constructed and graph theory was used to quantify complex brain structure. Local brain network connectivity (normalised clustering coefficient gamma) and global network integration (normalised characteristic path length lambda) were compared between study groups, and related to memory performance. RESULTS THE NETWORK MEASURES IN THE BETA BAND WERE SIGNIFICANTLY DIFFERENT BETWEEN GROUPS they decreased in the control group, but remained relatively unchanged in the active group. No consistent relationship was found between these network measures and memory performance. CONCLUSIONS The current results suggest that Souvenaid preserves the organisation of brain networks in patients with mild AD within 24 weeks, hypothetically counteracting the progressive network disruption over time in AD. The results strengthen the hypothesis that Souvenaid affects synaptic integrity and function. Secondly, we conclude that advanced EEG analysis, using the mathematical framework of graph theory, is useful and feasible for assessing the effects of interventions. TRIAL REGISTRATION Dutch Trial Register NTR1975.
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Occupancy of the serotonin transporter after administration of Lu AA21004 and its relation to plasma concentration in healthy subjects.
Areberg, J, Luntang-Jensen, M, Søgaard, B, Nilausen, DØ
Basic & clinical pharmacology & toxicology. 2012;(4):401-4