Creatine Peak Research Articles

Raman Spectroscopic Analysis of Urinary Creatine and Phosphate in Athletes: Pre- and Post-Training Assessment.

The aim of this study was to detect biochemical components in the urine of bodybuilders who ingested creatine pretraining compared to individuals who did not ingest creatine after physical exercise using Raman spectroscopy. Twenty volunteers practicing bodybuilding were selected to collect pre- and post-training urine samples, where 10 volunteers ingested creatine 30 min before pretraining urine collection (creatine group), and 10 did not (control group). The samples were subjected to Raman spectroscopy, and the spectra of both creatine and control groups and the difference (post-pre) for both groups were analyzed. Principal component analysis (PCA) technique was applied to the samples. The results showed peaks of creatine and phosphate in urine after training (creatine post-training group), suggesting that part of the creatine was absorbed and metabolized, and part was excreted. Raman spectroscopy could be applied to detect biocompounds in urine, such as unmetabolized creatine and phosphate.

Cerebellar Structural and N-Acetylaspartate, Choline, and Creatine Metabolic Profiles in Parkinson's Disease and Essential Tremor.

The role of the cerebellum in Parkinson's disease (PD), particularly in tremor-dominant subtypes, is increasingly recognized. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) provide anatomical and metabolic insights, suggesting compensatory hyperactivity or degenerative changes in the cerebellum in PD. Volumetric analysis of cerebellar structures in MRI images, combined with metabolic profiles from MRS, offers possibilities for differentiating PD from essential tremor (ET). The cerebellum may be a potential therapeutic target due to its role in neurocircuitry of PD and ET. Brain structural data were obtained using MRI, and cerebellar metabolic profiles, focusing on the quantification of N-acetylaspartate (NAA), choline, and creatine peaks were obtained using MRS. This study enrolled patients with ET and PD, both with and without tremor, as well as disease controls with cerebellar atrophy (including spinocerebellar ataxia and multiple system atrophy). Volumetric analysis of cerebellar structures was performed. Differences in MRI and MRS parameters were analyzed using one-way analysis of covariance with a significance threshold of p < 0.05. From November 2018 to March 2023, 111 patients were enrolled, including 29 ET, 29 cerebellar atrophy, 12 PD without tremor, and 41 PD with tremor. No significant differences in cerebellar volume and N-acetylaspartate/creatine and choline/creatine ratios were found between ET and PD with tremor. This preliminary retrospective study suggests similarities in cerebellar structures and metabolic profiles between ET and PD, highlighting the need for advanced imaging techniques to better differentiate between these conditions. Future research should integrate clinical data, such as tremor severity and cognitive assessments, to explore the relationships with cerebellar MRI parameters.

Glioblastoma: Overview and Magnetic Resonance Spectroscopy Analysis for Treatment.

Glioblastoma multiforme (GBM) is a very aggressive and fast-growing cancer of the brain that has a low life expectancy. Many new cases are diagnosed every year witheach having a very poor prognosis. It is therefore of utmost concern to develop cures for such a devastating condition. Magnetic resonance spectroscopy details certain peaks that are of interest. In particular, later-stage astrocytomas exhibit prominent choline and creatine peaks. The creatine peak is known to enhance glioblastoma survival.

Spectrophotometric and chromatographic analysis of creatine:creatinine crystals in urine

Creatinine is the end product of the catabolism of creatine and creatine phosphate. Creatine phosphate serves as a reservoir of high-energy phosphate, especially in skeletal and cardiac muscle. Besides typical known changes in serum and urinary creatinine concentrations, rare cases associated with changes in serum and urinary creatine levels have been described in the literature in humans. These cases are mostly linked to an excessive intake of creatine ethyl ester or creatine monohydrate, often resulting in increased urine creatinine concentrations. In addition, it is known that at such elevated creatinine concentrations, creatinine crystallisation may occur in the urine. Analysis of crystals and urinary concrements, often of heterogenous chemical composition, may provide diagnostic and therapeutic hints to the benefit of the patient. The aim of the present work was to analyze urine crystals of unclear composition with microscopic and spectroscopic techniques.On routine microscopic analysis of urine, a preliminary suspicion of uric acid or creatinine crystals was expressed. The crystals were of a cuboid shape and showed polarization effects in microscopy. The dried urine sample was whitish-orange in colour, odourless and dissolved well in water. Protein concentration in dry weight (DW) urine was about 0.3 mg/mg. The measured zinc content in the studied sample was approximately 660 µg/g DW sample and copper content was approximately 64 µg/g DW sample. A lead signal of around 10 µg/g DW sample was also observed. UV–Vis analysis showed a maximum creatine peak around 220 nm, compatible with the spectrum of creatinine with a maximum peak of 230 nm. Using HPLC technique, an extreme high ratio of creatine to creatinine of about 38 was measured, which led to the conclusion of the occurrence of rare creatine crystals in urine.

Assessment of Cerebral Hypoxemia and Its Impact on Cognitive and Psychological Functions in Patients With Obstructive Sleep Apnea Syndrome

Background and Objective The precise pathophysiology of cognitive impedance and mental illness in obstructive sleep apnea (OSA) patients remains elusive. Therefore, there is a need for studies on novel diagnoses and therapeutic strategies for cognitive impairment in OSA patients. This work aimed to evaluate cerebral hypoxemia, its consequences on brain metabolism, and local and systemic inflammation, and their subsequent impact on cognitive and psychological functioning.Methods This cross-sectional case-control study was conducted on 30 eligible OSA patients and 20 age/sex-matched healthy controls. All the participants underwent one-night polysomnography, and cognitive evaluation was done using the Mini-Mental State Examination, Montreal Cognitive Assessment, Brief Kingston Standardized Cognitive Assessment, D2 Test of Consideration (to evaluate attention problems), and Wisconsin card sorting test. The psychiatric assessment included the Arabic form of the Hamilton Depression Rating Scale and Beck Depression Inventory-II. A radiology assessment was done using proton magnetic resonance spectroscopy. Neurophysiological assessment was done using the potential cortical (N20) latency and amplitude of somatosensory evoked potential. Laboratory examinations included serum levels of NF-κB, HMGB1, and HIF-1α.Results Polysomnography demonstrated noteworthy increase in the apnea-hypopnea index, respiratory disturbance index, arousal index, snoring index, and wake after sleep onset. It also showed diminished sleep efficiency, total sleep time, and SaO2 nadir in the OSA group. Neuropsychological scales demonstrated poor performance in global cognitive tests, particular cognitive domains impedance, and depression in the OSA group, with noteworthy differences within the group. Magnetic resonance spectroscopy highlighted that OSA patients had a noteworthy bilateral decrement in N-acetylaspartate (NAA) peak, creatine peak, and NAA/choline proportion and an increment in choline peak, lipid peak, lactate peak, choline/creatine proportion, and NAA/creatine proportion in the frontal white matter, hippocampus, and parieto-occipital cortex. Moreover. OSA patients had either missing or decreased amplitude and delayed latency of N20. There was a noteworthy rise of serum inflammatory marker NF-κB, HMGB1, and oxidative stress marker HIF-1α in OSA patients.Conclusions Chronic intermittent hypoxia with resulting amplified inflammatory and oxidative stress in OSA patients may affect brain metabolism; consequently, leading to cognitive and psychological dysfunctions.

Magnetic Resonance Spectroscopy metabolites as biomarkers of Alzheimer’s Disease

AbstractBackgroundMagnetic resonance spectroscopy (MRS) is a non‐invasive method of evaluating metabolite levels in the cerebral cortex. Measurable metabolites can provide markers of neuronal damage, glial activation and, neurotransmission, pathological features of Alzheimer’s disease. Here we sought to establish the effectiveness of several metabolites as biomarkers for Alzheimer’s disease.Method198 participants with a single‐voxel 1H MRS scan were enrolled (n = 170 participants living with Alzheimer’s disease, n = 28 healthy controls). All participants underwent 3‐tesla magnetic resonance imaging and cognitive assessment with the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS‐cog). An experienced radiographer placed an 8cm3 voxel within the posterior cingulate cortex for single‐voxel 1H MRS acquisition. Scans were then processed to evaluate levels of N‐acetylaspartate, myo‐inositol, choline, and glutamate. Creatine peak was additionally evaluated as a reference. N‐acetylaspartate/creatine, myo‐inositol /creatine, choline/creatine ratios and glutamate were compared between Alzheimer’s participants and controls to calculate the effect size. Correlations were then performed between metabolite ratios and ADAS‐cog scores.ResultN‐acetylaspartate/creatine effectively distinguished between Alzheimer’s patients and healthy controls (Cohens D = 0.83) with a lowered ratio in Alzheimer’s participants. Elevated glutamate signal and myo‐inositol/creatine ratios were also displayed in Alzheimer’s patients (Cohens D = 0.62 and 0.69, respectively). Choline/creatine ratio displayed no significant difference between groups (Cohens D = 0.26). Lower N‐acetylaspartate /creatine and glutamate correlated with higher ADAS‐cog scores (r = ‐0.29, p &lt; 0.001, CIs: ‐0.42 to ‐0.14 and r = ‐0.30, p &lt; 0.001, CIs: ‐0.44 to ‐0.16, respectively). Myo‐inositol and choline failed to correlate with cognitive impairment.ConclusionN‐acetylaspartate, a signature of neuronal damage, is an effective biomarker of Alzheimer’s disease and associated cognitive decline. Enhanced glial activity, measured with myo‐inositol, was shown in Alzheimer’s disease, suggesting that glial‐reactivity markers deserve consideration in the diagnosis of Alzheimer’s disease. Glutamate demonstrated the strongest association with cognitive impairment, despite showing a smaller effect size than N‐acetylaspartate and myo‐inositol in distinguishing between Alzheimer’s patients and controls. Together we establish MRS is a useful, non‐invasive biomarker of several pathological processes involved in the development of Alzheimer’s. Evaluation of N‐acetylaspartate, glutamate, and myo‐inositol may aid in the diagnosis of neurodegenerative disease, detecting markers undetectable by conventional MRI methodology.

Abstract 121: Misdiagnosis in a case of pediatric stroke

Introduction Pediatric patients presenting with atypical stroke symptoms pose a diagnostic challenge, which often causes delays in management. Around a quarter of pediatric stroke patients will present with new onset seizures. We report this case to emphasize the importance of early consideration of ischemia as a differential diagnosis. We also want to emphasize the collaborative approach between pediatric and adult neurologists in challenging cases. Methods Case report Results A 15‐year‐old male presented to an outside hospital for new onset seizure. The patient later mentioned that he had difficulty writing the morning of the seizure. Initial blood work, CBC, CMP, urine analysis and toxicology were unremarkable. A second seizure occurred while in the ED. CT head revealed a questionable area of decreased attenuation in the left frontal lobe, felt to be artifact. Patient was transferred to our hospital for higher level of care. MRI of the brain showed gyriform signal abnormality within the left frontal lobe with restricted diffusion, no abnormal enhancement. Serum MOG, NMDA, LGI1, NMO antibodies were sent. LP was done and there was no evidence of infection. MRI of the C, T and L spine were unremarkable. CTA/CTV of the head was done and there was no evidence of vessel abnormalities or sinus thrombosis. Patient was started on high dose steroids for possible autoimmune etiology on hospital day 2. On Hospital Day 3, the case was re‐evaluated, and the possibility of infarction was proposed. The case was discussed with an adult vascular neurology attending physician, thus further imaging was obtained. CT Perfusion of Brain revealed a subacute left frontal infarct and possible dural AVF. A diagnostic cerebral angiography revealed enhanced capillary blush consistent with shunt in region of left peri‐Sylvian infarct. There was no evidence of other vascular malformations. A hypercoagulable panel was unremarkable. The patient was discharged on Hospital Day 6 on Vimpat and aspirin with outpatient follow‐up. Echo revealed a PFO on Valsalva maneuver. MRI spectroscopy revealed depressed creatine peak, low NAA and a high choline peak in the left frontal opercular T2 hyperintensity ‐ findings consistent with an evolving infarct with increased choline due to gliosis. He is planned for PFO closure and has not had further recurrent seizures. Conclusion According to Hollist et al., pediatric stroke incidence is 2.5‐13 per 100,000 children per year [1]. There are thousands of stroke misdiagnoses every year [2]. Stroke misdiagnosis is more likely in younger patients [2, 3]. 60% of pediatric stroke patients will end up with disability and half will have a decreased quality of life [4]. Misdiagnosis also results in misutilization of health care resources. Similar to our case, a collaborative approach between adult stroke neurologists and pediatric neurologists, where pediatric stroke neurologists are not available, helps avoid stroke misdiagnosis. As a result, this helps better patient outcomes and avoids preventable morbidity and mortality.

Diagnosis and Treatment of X-Linked Creatine Transporter Deficiency: Case Report and Literature Review.

(1) Background: X-linked creatine transporter deficiency (CTD) (OMIM 300036) is a rare group of inherited metabolic disorders characterized by global developmental delay/intellectual disability (GDD/ID), seizures, autistic behavior, and movement disorders. Pathogenic variants in the SLC6A8 gene, located at Xq28, are causative of the disease, leading to impaired creatine transport into the brain. Supplementation with creatine and its precursors, glycine and arginine, has been attempted, yet the treatment efficacy remains controversial. (2) Methods: Here we report a de novo SLC6A8 variant in a boy aged 3 years 9 months presenting with GDD, autistic behavior, and epilepsy. Elevated urinary creatine/creatinine ratio and diminished creatine peak on brain MR spectroscopy suggested the diagnosis of CTD. Genetic sequencing revealed a de novo hemizygous frameshift variant (NM_005629: c.1136_1137del, p. Glu379ValfsTer85). Creatine supplementation therapy was initiated after definitive diagnosis. Electroencephalography and MR spectroscopy were monitored during follow-up in concurrence with neuropsychological evaluations. The clinical phenotype and treatment response of CTD were summarized by systematic view of the literature. (3) Results: In silico analysis showed this variant to be deleterious, probably interfering with substrate binding and conformational changes during creatine transport. Creatine supplementation therapy led to seizure cessation and modest cognitive improvement after half-year's treatment. (4) Conclusions: This case highlights the importance of MR spectroscopy and metabolic screening in males with GDD/ID, allowing for early diagnosis and therapeutic intervention. Mechanistic understanding and case-per-se analysis are required to enable precision treatment for the patients.

Peripheral inflammation is associated with alterations in brain biochemistry and mood: evidence from in vivo proton magnetic resonance spectroscopy study

Abstract Tumor necrosis factor (TNF)-α is a protein implicated in the prognosis of psoriatic arthritis (PsA), an autoimmune disease associated with episodes of clinical depression (CD). CD has been linked to abnormalities in the forebrain and subcortical structures, which can be probed noninvasively using proton magnetic resonance spectroscopy (1H-MRS). Thus, this 1H-MRS study assessed biochemical differences between healthy subjects and PsA patients in the frontal and bilateral hippocampal brain regions. Biochemical and mood responses in the anterior cingulate cortex and bilateral hippocampi following the administration of anti-TNF-α medication to the PsA patients were also assessed. Fifteen volunteers in each of the PsA and control groups participated in the study. Patients underwent MRS examination before and after 6–8 weeks of anti-TNF-α medication. Mood was assessed at baseline and after medication using the Beck’s Depression Inventory (BDI). Psychiatric symptoms were ruled out in all volunteers using the 12-item General Health Questionnaire. MRS studies were conducted using the PRESS sequence at 3 T. Spectral and statistical analyses were conducted using the LC Model and Minitab software, respectively. Metabolite levels were expressed as ratios, relative to the creatine peak. The PsA patients showed higher left hippocampal baseline Choline/Creatine ratio than controls (p = 0.014). After medication, decrease in frontal brain Choline/Creatine ratio was associated with decrease in BDI scores (r = 0.628; p = 0.025), while frontal brain NAA/Creatine ratio was significantly lower in the PsA patients compared to the controls (p = 0.023). No other significant differences were found in all comparisons, including metabolite ratios between the left and right hippocampi. The results of this study provide some evidence for biochemical alterations in the mood regulating segments of the brain, which has consequences for mood states of the affected patients.

Guanidinoacetate Methyltransferase Deficiency, a Treatable Neurodevelopmental Disorder

AbstractGuanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive inborn error of creatine synthesis that results in intellectual disability, epilepsy, expressive language delay, and dystonia. We report data from two siblings with an uncommon GAMT deficiency phenotype and their clinical, biochemical, imaging, and treatment findings. The older sibling had intellectual disability, epilepsy, and generalized dystonia. The younger sibling had intellectual disability and generalized dystonia. After treatment with creatine, verbal fluency improved, as well as dystonia and aggression. This study confirms that in patients with unexplained intellectual disability, epilepsy, and/or movement disorders, GAMT deficiency should be considered. GAMT-associated cerebral creatine deficiency syndrome is a potentially treatable condition and can be identified by elevated levels of guanidinoacetate in plasma or urine or by a significantly decreased creatine peak on magnetic resonance spectroscopy.

MR-spectroscopy in metachromatic leukodystrophy: A model free approach and clinical correlation

Background and purposeMetachromatic leukodystrophy (MLD) is a lysosomal enzyme deficiency disorder leading to demyelination and subsequently to a progressive decline in cognitive and motor function. It affects mainly white matter where changes during the course of the disease can be visualized on T2-weighted MRI as hyperintense areas. Associated changes in brain metabolism can be quantified by MR spectroscopy (MRS) and may give complementary information as biomarkers for disease characterisation and progression. Our study aimed to further investigate the correlation of MRS with clinical parameters for motor and cognitive function by using a model free MRS analysis approach that would be precise and straightforward to implement. Materials and methods53 MRS datasets derived from 29 patients (10 late-infantile, 19 juvenile) and 12 controls were acquired using a semi-LASER CSI sequence covering a slice through the centrum semiovale above the corpus callosum. We defined four regions of interest in the white matter (frontal white matter [FWM] and the cortico-spinal tract [CST] area, each left and right) and one in cortical grey matter. Spectra were analysed using a model and fitting free approach by calculating the definite integral of 10 intervals which were distributed along the whole spectrum. These 10 intervals were orientated towards the main peaks of the metabolites N-acetylaspartate (NAA), creatine, myo-inositol, choline, glutamine/glutamate and aspartate to approximately attribute changes in the intervals to corresponding metabolites. Their ratios to the main creatine peak integral were correlated with clinical parameters assessing motor and cognitive abilities. Furthermore, in a post-hoc analysis, NAA levels of a subset of 21 MR datasets were correlated to NAA levels in urine measured by 1H (proton) nuclear magnetic resonance (NMR) spectroscopy.The applied interval integration method was validated in the control cohort against the standard approach, using spectral profile templates of known metabolites (LCModel). Both methods showed good agreement, with coefficients of variance being slightly lower for our approach compared to the related LCModel results. Moreover, the new approach was able to extract information out of the frequency range around the main peaks of aspartate and glutamine where LCModel showed only few usable values for the respective metabolites. ResultsMLD spectra clearly differed from controls. The most pronounced differences were found in white matter (much less in grey matter), with larger values corresponding to main peaks of myo-inositol, choline and aspartate, and smaller values associated with NAA and glutamine. Late-infantile patients had more severe changes compared to later-onset patients, especially in intervals corresponding to NAA, aspartate, myo-inositol, choline and glutamine.There was a high correlation of several intervals in the corticospinal tract region with motor function (with the most relevant interval corresponding to NAA peak with a correlation coefficient of −0.75; p < 0.001), while cognitive function, by means of IQ, was found to be most correlating in frontal white matter corresponding to the NAA peak (r = 0.84, p < 0.001).The post-hoc analysis showed that the main NAA peak interval correlated negatively with the NAA in urine (r = −0.584, p < 0.001). ConclusionThe applied model and fitting free interval integration approach to analyse MRS data of a semi-LASER sequence at 3T suits well to detect and quantify pathological changes in MLD patients through the different courses of the disease and correlates well with clinical symptoms while showing smaller dimensions of variation compared to the more sophisticated single metabolite analysis using LCModel. NAA seems the most clinically meaningful biomarker to use in this context. Its correlation with urine measurements further underlines its potential as a clinically and biologically useful parameter of disease progression in MLD.

Acute Left Circumflex Coronary Artery Occlusion - Diagnostic Problems of Initial Electrocardiographic Changes.

Background: Acute coronary syndrome (ACS) with occlusion of the left circumflex coronary artery (LCX) poses diagnostic problems that may lead to a delay in reperfusion.Methods and Results: From a group of 1,269 consecutive patients with ACS, 138 patients with ACS due to LCX occlusion were analyzed for clinical, electrocardiographic, and angiographic presentations, as well as door-to-balloon (DTB) time. Electrocardiographic changes were classified into 4 patterns: ST-segment elevation in inferior/lateral leads (ST-E); ST-segment depression in V1–V4 (ST-D); no significant ST changes (No-ST); and others. The No-ST group was associated with a longer DTB time (P<0.0001) compared with the ST-E and ST-D groups. Compared with the No-ST and ST-E groups, the ST-D group presented with a more advanced Killip class (P=0.003), greater peak creatine phosphokinase (P=0.007) and peak creatine kinase-MB (P=0.006), more frequent proximal LCX occlusion (P=0.007), and worse 1-year outcomes (P=0.0034).Conclusions: One-third of ACS patients with LCX occlusion showed no ST-segment changes, resulting in significantly longer DTB time. Improving diagnostic accuracy is challenging but critical to avoid delayed reperfusion in these patients without electrocardiographic changes.

Elevation of brain gamma‐aminobutyric acid levels is associated with vigabatrin‐associated brain abnormalities on magnetic resonance imaging

ObjectiveVigabatrin (VGB) is an effective antiseizure medication for West syndrome. It works by irreversibly inhibiting gamma-aminobutyric acid (GABA) transaminase and increasing central GABA levels. Vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM) are an adverse effect of VGB that has only been reported in children, but the pathophysiology of this effect is unknown. In this study, we evaluated the relationship of VGB and brain GABA levels as well as the association between VABAM and GABA. MethodsFor the 15 consecutive pediatric patients treated with VGB, free GABA, glutamine, and glutamate in cerebrospinal fluid (CSF) and plasma, GABA to creatine and phosphocreatine (Cr) peak ratio (GABA/Cr), glutamine (Gln)/Cr, and glutamate (Glu)/Cr as quantified by proton MR spectroscopy (1H-MRS) were retrospectively examined. GABA/Cr was compared with in-house normal pediatric controls. Differences in the levels of each metabolite in VABAM and non-VABAM cases were also examined. ResultsThirteen of the included subjects underwent magnetic resonance imaging (MRI) and 1H-MRS, and two of them presented VABAM; both cases were very-low-birth-weight preterm infants with post-hemorrhagic hydrocephalus. CSF levels of free GABA were significantly higher in VABAM (5.26 ± 1.95 μmol/L) than in non-VABAM (0.59 ± 0.63 μmol/L) cases (P = 0.03). The GABA/Cr was significantly higher in patients with VGB (0.34 ± 0.16) than in pediatric controls (0.20 ± 0.05) (P = 0.02). The GABA/Cr tended to be higher in VABAM (0.48 ± 0.10) than in non-VABAM cases (0.31 ± 0.15) (P = 0.31). SignificanceElevated brain GABA levels were observed in VABAM patients, suggesting its involvement in the pathogenesis of this condition. In particular, a marked increase in CSF-free GABA was characteristic. Although the elevation of the GABA/Cr is mild, it may be useful for early identification of patients with risk of VABAM.

Cerebral creatine deficiency disorders – A clinical, genetic and follow up study from India

IntroductionCerebral creatine deficiency syndromes (CCDS) are a group of potentially treatable neurometabolic disorders. The clinical, genetic profile and follow up outcome of Indian CCDS patients is presented. Materials and methodsThis was a retrospective cohort of CCDS patients seen over six-years. Diagnosis was based either on low creatine peak on proton magnetic resonance spectroscopy (MRS) and/or genetic evaluation. ResultsThirteen patients were eligible [8 creatine transporter deficiency (CTD), 4 guanidinoacetate methyltransferase (GAMT) deficiency and 1 could not be classified]. The mean (±SD) age at diagnosis was 7.2(±5.0) years.Clinical manifestations included intellectual disability (ID) with significant expressive speech delay in all. Most had significant behavior issues (8/13) and/or autism (8/13). All had history of convulsive seizures (11/13 had epilepsy; 2 patients only had febrile seizures) and 2/13 had movement disorder. Constipation was the commonest non-neurological manifestation (5/13 patients).Cranial MRI was normal in all CTD patients but showed globus pallidus hyperintensity in all four with GAMT deficiency. MRS performed in 11/13 patients, revealed abnormally low creatine peak. A causative genetic variant (novel mutation in nine) was identified in 12 patients.Three GAMT deficiency and one CTD patient reported neurodevelopmental improvement and good seizure control after creatine supplementation. ConclusionIntellectual disability, disproportionate speech delay, autism, and epilepsy, were common in our CCDS patients. A normal structural neuroimaging with easily controlled febrile and/or afebrile seizures differentiated CTD from GAMT deficiency patients who had abnormal neuroimaging and often difficult to control epilepsy and movement disorder.

The role of magnetic resonance spectroscopy in differentiation of neoplastic from non-neoplastic pediatric intracerebral brain lesions

Background Pediatric brain tumors are considered a significant health problem and present several imaging challenges. The role of imaging is no longer limited to merely providing anatomical details. In this research, we explained the role of magnetic resonance spectroscopy (MRS) in the differentiation of neoplastic from non-neoplastic intracerebral brain lesions in pediatric patients. The aim was to assess the role of MRS in pediatric brain tumors by discrimination between tumors and tumor-like lesions, differentiation between primary and secondary neoplasms, differentiation between high-grade and low-grade tumors, and determination of tumor extension. Patients and methods A total of 30 pediatric patients with cerebral lesions were examined by MRS. Choline (Cho), creatine (cr), N-acetylaspartate (NAA), and lipid-lactate peaks were evaluated. Of the 30 patients, 26 underwent stereotactic biopsy. Histopathological results were compared with the MRS results. Results Diagnostic accuracy of spectroscopic data for prediction of neoplastic lesions in the current study was assessed. Regarding Cho/NAA, a cutoff point greater than 2 had 88% sensitivity and 75% specificity for prediction of neoplastic lesions, with areas under the curve (AUC) of 0.91 (P = 0.01). Regarding Cho/Cr, a cutoff point greater than 1.86 had 85% sensitivity and 75% specificity for prediction of neoplastic lesions, with AUC of 0.85 (P = 0.02). Regarding Cho/NAA+Cr, a cutoff point greater than 0.8 had 88% sensitivity and 100% specificity for prediction of neoplastic lesions, with AUC of 0.91 (P = 0.009). Conclusion MRS can potentially overcome the limitations of sampling errors with histopathologic grading of the tumor for determining the most optimal therapy regimen and regularity and aggressiveness of postoperative follow-up and treatment.

NIMG-12. 18F-FLUORETHYLTYROSINE POSITRON EMISSION TOMOGRAPHY VERSUS MAGNETIC RESONANCE SPECTROSCOPY IN PREOPERATIVE DETECTION OF NEWLY DIAGNOSED GLIOMAS BY USING MACHINE LEARNING

Abstract BACKGROUND Advanced imaging techniques entered the field of neurooncology. In this analysis we compare the diagnostic potential of 18F-fluorethyltyrosine (FET) positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) in their potential to preoperatively predict certain glioma subtypes. AIMS Goal of this analysis ist the evaluation of FET PET and MRS regarding the preoperative prediction of glioma subtypes. METHODS We analyzed 33 patients with histopathologically confirmed newly diagnosed glioma. The patients received FET PET and MRS during one single preoperative diagnostic session. According to the molecular portfolio patients were subdivided in IDH wildtype glioblastoma patients (GBM), IDH wildtype WHO grade II/III glioma patients (Astro_IDHwt), IDH mutant WHO grade II/III glioma patients without 1p/19q codeletion (Astro_IDHmut) and with 1p/19q codeletion (ODG). Mean and maximum tumor-to-brain ratio (TBRmean and TBRmax), N-acetylaspartate, choline and creatine peaks were correlated with postoperative tumor diagnosis. To gain generalizable implications we subdivided the study cohort into a development and validation subcohort. A support vector machine model was fitted to the development subcohort and evaluated on the validation subcohort. Receiver operating characteristic curve served to assess model performance. RESULTS GBM patients had highest TBRmax and TBRmean values (mean: 3.5 and 3.8) and the ODG patients showed the second highest TBRmax and TBRmean values (mean: 2.6 and 3). The distribution of MRS markers exhibited to clear trend. The performance of glioma subtyping was comparatively low for the TBR values (AUC: 0.68) and even lower for the MRS markers (AUC: 0.60). These results are in line with preliminary investigations performed by our institute for the comparison of 11C-methionine PET with MRS in preoperative glioma subtyping. CONCLUSIONS FET PET and MRS bear limited potential in glioma subgrouping. However, FET PET appears to be slightly superior. Investigation in a larger cohort is required to draw definite conclusions.

Diabetes and pre-infarct angina. Time to rethink comorbidities in the reperfusion-injury phenomenon?

Abstract Background Pre-infarct angina (PIA) has been shown to reduce reperfusion injury and infarct size in patients with ST-elevation myocardial infarction (STEMI) and currently represents the most efficient form of myocardial conditioning yet discovered. The role of diabetes on ischemic preconditioning remains controversial – while some pre-clinical studies suggest that diabetes blunts ischemic conditioning, clinical studies are lacking. Methods We retrospectively evaluated consecutive patients with STEMI admitted in our hospital from January 2008 to August 2018 who underwent primary angioplasty (PCI). PIA was defined as chest, arm or jaw pain during the preceding 48h before STEMI diagnosis. Peak creatine kinase and peak Troponin T levels were used as a surrogate of infarct size. Ischemic time (IT) was defined as the time between the onset of symptoms to the restoration of flow after either guidewire passage, thrombus aspiration or first balloon inflation. Results Of the 1143 included patients, 74% (n=845) were male and mean age was 62.6±13.1 years. A quarter of STEMI-patients had diabetes (25%, n=285). Almost a third of the patients (32%, n=359) had a history of angina in the preceding 48h before STEMI (PIA). The proportion of PIA was similar between diabetic and non-diabetic patients. In patients with diabetes, PIA was associated with lower creatine kinase (CK) (1144 [500–2212] vs 1715 [908–3309] U/L, p=0.0029) and Troponin T (TnT 3.30 [1.90–6.58] vs 4.88 [2.50–9.58] ng/mL, p=0.0022) despite similar IT as compared to those without PIA (328 [200–554] vs. 258 [180–530] minutes, p=0.1365). In non-diabetic patients, PIA was not significantly associated with infarct size (TnT 3.74 [2.23–7.11] vs 4.56 [2.44–7.77] ng/mL, p=0.1945; CK 1549 [910 - 2909] vs 1793 [996 - 3078] U/L, p=0.0653) even after adjustment for the increased ischemic time (240 [150–550] vs. 210 [140–405] minutes, p=0.0128) (β=−0.12, p=0.085 for CK and β=−0.11, p=0.183 for TnT). A significant interaction was observed between the existence of PIA and diabetes on peak TnT (p=0.026 for interaction) and CK (p=0.047 for interaction), which was independent of the culprit vessel and IT. During a median follow-up period of 18.0 [12.1–25.5] months, 268 (24.0%) MACE events have occurred (165 deaths, 27 strokes, 46 myocardial infarctions and 26 target vessel revascularization). PIA was associated with a significant reduction in the incidence of MACE (HR 0.66 (95% CI: 0.48–0.89)) driven by a reduction on mortality (HR 0.44 (95% CI: 0.28–0.70)). Diabetes was associated with an increased incidence of MACE (HR 1.42 (95% CI: 1.07–1.89)). No interaction was found between diabetes and PIA on their effect on MACCE events. Conclusion PIA is a strong predictor of favourable outcomes in the setting of STEMI. The effect of PIA on myocardial protection in patients with STEMI undergoing primary PCI seems to be modulated by the presence of diabetes. Distribution of Peak CK and Peak TnT Funding Acknowledgement Type of funding source: None

MITOCHONDRIAL DISEASES & METABOLIC MYOPATHIES: P.321 Mitochondrial myopathy in X-linked creatine transporter deficiency due to a novel mutation of SLC6A8 gene

Creatine (Cr) is essential in energy metabolism since it allows the ADP-ATP conversion. Creatine transporter (CRTR) gene SLC6A8 is required for brain and muscle creatine uptake from the blood. Mutations in SLC6A8 are responsible for X-linked CRTR deficiency (CRTR-D) leading to mental retardation, global development delay, seizures and behavioral disorders. Excepted motor milestone delay, muscle involvement has been only exceptionally reported in CRTR-D. We aim to report a novel SLC6A8 mutation in a family with a particular clinical picture including a muscle mitochondrial phenotype. A 44-year-old man developed early infantile hypotonia and mental retardation and delayed motor milestones. At the time of assessment, he harbored a profound intellectual disability associated with mutism, facial dysmorphia, epilepsy, generalized muscle weakness and diarrhea. His eldest brother had severe intellectual disability, epilepsy, ptosis, muscle weakness and died at the age of 35 years. The proband's work-up results were: normal CK level, a major increase of urinary creatine/creatinine ratio: 2.5 (N≤0.37), a decreased creatine peak on brain magnetic resonance imaging spectroscopy and mitochondrial myopathic changes on muscle biopsy. A severe decrease of Cr uptake was measured on cultured fibroblasts: 0.3/8.6 nmol/mg-protein (N>18.8/31.9) with [Cr] of 25/500 µM. Clinical exome (4427 genes) allowed the identification of the novel missense mutation c.827T>C (p.Leu276Pro) on the SLC6A8 gene. It was inherited from his asymptomatic mother, absent in an asymptomatic brother and in the control database gnomAD (gnomad.broadinstitute.org). Moreover, it was predicted pathogenic from 4 prediction tools (SIFT, PolyPhen2, Mutation Taster, Mutation Assessor). In conclusion, reporting a novel pathogenic missense mutation in SLC6A8 gene associated with an unexpected mitochondrial myopathy taking part of the clinical picture, we expand the genetic and phenotypic spectrum of CRTR-D.

Magnetic Resonance Spectroscopy for Prediction of Grades of Diffusely Infiltrating Intracranial Astrocytomas.

Abstarct Objective Gliomas, the most frequent primary brain tumors, have various grades, among which grade II, III, and IV are diffusely infiltrating astrocytomas. As therapeutic approaches and outcome differ considerably, depending on the grade of these tumors, prediction is important regarding outcome. Magnetic resonance spectroscopy (MRS) can be of help in understanding of the biochemical changes of pathological state to study, monitor, predict grading and outcome of gliomas. Materials and Methods All the 30 patients in the study with intracranial diffusely infiltrating astrocytoma had MRS study using 1.5 Tesla MR scanner. The study population was divided into three groups on the basis of the grades of the tumor according to histopathology. Mean height of choline (Ch), N-acetyl aspartate (NAA), creatine (Cr) peak, and choline/creatine (Ch/Cr) ratio was documented. Mean value of each variable among three grades was analyzed and compared with analysis of variance (ANOVA) test (F-test). Results There was positive relationship regarding Ch/Cr ratio among astrocytomas grade II to IV and the result was significant ( p = 0.047). A positive relationship of Ch peak was also observed for grade II to IV astrocytoma, though the result was not significant ( p = 0.578). The result was nonsignificant for NAA ( p = 0.696) and Cr ( p = 0.740) peak also. Conclusion We recommend Ch/Cr ratio to be considered as a dependable MRS data to comment on low- or high-grade astrocytomas. MRS can be done as a routine investigation in the developing countries for astrocytomas where other facilities are less accessible for reliable prediction and counseling.

Circulating miR-1 as a potential predictor of left ventricular remodeling following acute ST-segment myocardial infarction using cardiac magnetic resonance.

The identification of patients with a high likelihood of left ventricular (LV) remodeling with a high-risk prognosis has critical implications for risk stratification after acute ST-segment elevation myocardial infarction (STEMI). This study aimed to evaluate the relationship between circulating miR-1 and 6-month post-infarct LV remodeling based on cardiac magnetic resonance (CMR) imaging. A total of 80 patients with a first STEMI treated with primary percutaneous coronary intervention (PCI) who underwent CMR imaging 1 week and 6 months after STEMI were evaluated. The percentage changes of LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), LV end-systolic volume index (LVESV) at 1 week and 6 months after PCI (%ΔLVEF, %ΔLVEDV and %ΔLVESV) were calculated. miR-1 was measured using polymerase chain reaction (PCR)-based technologies in plasma samples that were collected at admission. The study group was divided into two groups based on a 10% cutoff value for the percentage of change in the LV end-diastolic volume (%ΔLVEDV): remodeling at high risk of major adverse cardiac events (MACEs) (%ΔLVEDV ≥10%, termed the LV remodeling group) and remodeling at lower risk of MACEs (%ΔLVEDV <10%, termed the non-LV remodeling group). The associations of miR-1 expression with the %ΔLVEDV, percentage change in the LV end-systolic volume (%ΔLVESV), and percentage change in the LV ejection fraction at follow-up were estimated. Twenty-two patients (27.5%) showed adverse LV remodeling, and 58 patients (72.5%) did not show adverse LV remodeling at the 6-month follow-up of CMR. The mean LVEF, LVEDV index, and LVESV index values at 1 week were 50.6%±8.2%, 74.6±12.8 mL/m2, and 37.2±10.2 mL/m2, respectively. Mean LVEF at follow-up (53.5%±10.6%) was increased compared with baseline (P<0.001). There were significant decreases in LVEDV index and LVESV index values at follow-up (72.0±14.9 mL/m2 and 33.7±11.0 mL/m2, respectively; P=0.009 and P<0.001, respectively). The expression of miR-1 at admission was positively correlated with the %ΔLVEDV (r=0.611, P<0.001) and %ΔLVESV (r=0.268, P=0.016). Receiver operating characteristic (ROC) analysis showed that miR-1 expression predicted LV remodeling with an area under the curve (AUC) value of 0.68 (95% CI: 0.56-0.78). Compared with the clinical factors of peak creatine kinase-myocardial band (CK-MB) and peak troponin T level, peak logNT-proBNP showed the highest predictive power, with an AUC value of 0.75 (95% CI: 0.64-0.84). A model including the clinical, CMR, and miR-1 factors showed greater predictive power (P=0.034) than a model including only clinical and CMR factors, with AUCs of 0.89 (95% CI: 0.80-0.95) and 0.81 (95% CI: 0.71-0.89), respectively. Circulating miR-1 at admission is an independent predictor of LV remodeling 6 months after STEMI. miR-1 showed incremental value in predicting LV remodeling compared with the clinical and CMR measurements.