Biomarker Of Clinical Severity Research Articles

Nitrous oxide abuse direct measurement for diagnosis and follow-up: update on kinetics and impact on metabolic pathways.

Recreational use of nitrous oxide (N2O) has become a major health issue worldwide, with a high number of clinical events, especially in neurology and cardiology. It is essential to be able to detect and monitor N2O abuse to provide effective care and follow-up to these patients. Current recommendations for detecting N2O in cases of recreational misuse and consumption markers are lacking. We aimed to update current knowledge through a review of the literature on N2O measurement and kinetics. We reviewed the outcomes of experiments, whether in preclinical models (in vitro or in vivo), or in humans, with the aim to identify biomarkers of intoxication as well as biomarkers of clinical severity, for laboratory use. Because N2O is eliminated 5 min after inhalation, measuring it in exhaled air is of no value. Many studies have found that urine and blood matrices concentrations are connected to ambient concentrations, but there is no similar data for direct exposure. There have been no studies on N2O measurement in direct consumers. Currently, patients actively abusing N2O are monitored using effect biomarkers (biomarkers related to the effects of N2O on metabolism), such as vitamin B12, homocysteine and methylmalonic acid.

Contribution of S100A4-expressing fibroblasts to anti-SSA/Ro-associated atrioventricular nodal calcification and soluble S100A4 as a biomarker of clinical severity.

Fibrosis and dystrophic calcification disrupting conduction tissue architecture are histopathological lesions characterizing cardiac manifestations of neonatal lupus (cardiac-NL) associated with maternal anti-SSA/Ro antibodies. Increased appreciation of heterogeneity in fibroblasts encourages re-examination of existing models with the consideration of multiple fibroblast subtypes (and their unique functional differences) in mind. This study addressed fibroblast heterogeneity by examining expression of α-Smooth Muscle Actin (myofibroblasts) and of S100 Calcium-Binding Protein A4 (S100A4). Using a previously established model of rheumatic scarring/fibrosis in vitro, supported by the evaluation of cord blood from cardiac-NL neonates and their healthy (anti-SSA/Ro-exposed) counterparts, and autopsy tissue from fetuses dying with cardiac-NL, the current study was initiated to more clearly define and distinguish the S100A4-positive fibroblast in the fetal cardiac environment. S100A4 immunostaining was observed in 4 cardiac-NL hearts with positional identity in the conduction system at regions of dystrophic calcification but not fibrotic zones, the latter containing only myofibroblasts. In vitro, fibroblasts cultured with supernatants of macrophages transfected with hY3 (noncoding ssRNA) differentiated into myofibroblasts or S100A4+ fibroblasts. Myofibroblasts expressed collagen while S100A4+ fibroblasts expressed pro-angiogenic cytokines and proteases that degrade collagen. Cord blood levels of S100A4 in anti-SSA/Ro-exposed neonates tracked disease severity and, in discordant twins, distinguished affected from unaffected. These findings position the S100A4+ fibroblast alongside the canonical myofibroblast in the pathogenesis of cardiac-NL. Neonatal S100A4 levels support a novel biomarker of poor prognosis.

Serum sulfonylurea receptor-1 as a biomarker of clinical severity and prognosis in patients with traumatic brain injury

BackgroundSulfonylurea receptor-1 (Sur1) plays an important role in acute brain injury. We determine whether serum Sur1 concentrations are associated with traumatic severity and clinical outcome after traumatic brain injury (TBI). MethodsSerum Sur1 concentrations were measured in 100 healthy controls and 138 patients with moderate to severe TBI. Glasgow coma scale (GCS) and Rotterdam computed tomography (CT) classification were recorded to assess traumatic severity. Glasgow outcome scale (GOS) score of 1–3 at posttraumatic 3 months was defined as an unfavorable outcome. ResultsSerum Sur1 concentrations were markedly higher in patients than in controls. Serum Sur1 concentrations of patients were highly correlated with GCS score, Rotterdam CT classification and GOS score. Patients with unfavorable outcome displayed markedly higher serum Sur1 concentrations than those presenting with favorable outcome. Under receiver operating characteristic curve, serum Sur1 concentrations significantly distinguished patients at risk of unfavorable outcome. Serum Sur1 emerged as an independent predictor for unfavorable outcome. ConclusionsRising serum Sur1 concentrations are highly correlated with traumatic severity and are independently associated with poor prognosis after TBI, indicating that serum Sur1 may have the potential to be a useful prognostic biomarker of TBI.

Immunohistochemical expression of HIF-1α, IDH1 and TP53: Prognostic profile of Moroccan patients with diffuse glioma

Diffuse gliomas are growing brain tumors that occur in adult life. This study was designed to determine whether the immunohistochemical analysis of IDH1, HIF-1alpha, or TP53 can provide useful biomarkers of clinical severity and progression of diffuse gliomas. Also, it is hypothesized that the expression of IDH1 mutant induces HIF-1alpha. Immunohistochemical staining for HIF-1alpha, IDH1, and TP 53 was performed in biopsy or resection (sub-total or gross-total) tissue from diffuse gliomas in a clinical series of 32 patients. Associations of the HIF-1alpha, IDH1, and TP53 with clinical characteristics were evaluated and the co-expression of two biomarkers (HIF-1alpha and IDH1) was tested. Our data revealed that each biomarker is expressed in a subset of gliomas (IDH1 was positive in 56% cases, HIF-1alpha was positive in 50% cases and TP53 was positive in 44% cases). While no associations were found between clinical characteristics and the expression of HIF-1alpha, and TP53, IDH1 expression was associated with less severe clinical presentation (Karnofsky Performance Status) and disease progression and was more often expressed in females than males. In addition, there was no clear association between IDH1 and HIF-1alpha expression (21.9% of patients co-expressed IDH1 and HIF-1alpha). The current series provides clinical and immunohistochemical findings that can be useful for the clinical management of patients with diffused gliomas.

Low serum calcium: a new, important indicator of COVID-19patients from mild/moderatetosevere/critical.

Background: Coronavirus disease 2019 (COVID-19) virus is still spreading, finding out the initial hits of viral infection is important to minimize the mild/moderate population, prevent disease aggravation and organs dysfunction.Objective: We investigated COVID-19 patients with different serum calcium levels.Design: We checked the serum calcium level of the patients based on days after symptom onset as well as the severity of COVID-19. We also checked multiorgan injuries and immune cytokines level in their blood.Results: Both mild/moderate and severe critical cases we observed showed low calcium level in the early stage of viral infection, while the severe/critical cases showed significant lower calcium level than mild/moderate cases in the early stage. We also found that low calcium level related to severe/critical multiorgan injuries especially in the mild/moderate population. Proinflammatory cytokine IL-6 also correlated to calcium change in both mild/moderate and severe/critical cases.Conclusions: Our finding indicates that calcium balance is a primal hit of COVID-19 and a biomarker of clinical severity at the beginning of symptom onset. Calcium is closely associated with virus-associated multiple organ injuries and the increase in inflammatory cytokines. Our results provide a new, important indicator of COVID-19 patients from mild/moderate to severe/critical: serum calcium.

Machine learning integration of scleroderma histology and gene expression identifies fibroblast polarisation as a hallmark of clinical severity and improvement

ObjectiveWe sought to determine histologic and gene expression features of clinical improvement in early diffuse cutaneous systemic sclerosis (dcSSc; scleroderma).MethodsFifty-eight forearm biopsies were evaluated from 26 individuals with dcSSc in...

Cortisol profiles and clinical severity in MECP2 duplication syndrome

BackgroundMECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder primarily affecting males which is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Core clinical features of MDS include choreiform movements, progressive spasticity, recurrent respiratory infections, developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism. Prior studies suggest that HPA axis activity may be altered in MDS and measures of HPA axis activity may offer insight into disease severity.MethodsTo ascertain whether cortisol profiles are a potential biomarker of clinical severity, diurnal profiles of cortisol and the cortisol awakening response were examined from saliva samples in 31 participants with MDS (ages 2–24 years), and 27 of these samples were usable. Documentation of a positive diagnostic test for MECP2 duplication was required for entry into the study. Samples were collected on each of two consecutive weekdays at four time points during the day: immediately after waking, 30 min after waking, between 3 and 4 PM, and in the evening before bedtime. Correlations with duplication size, clinical severity, sleep problems, and behavior were also examined.ResultsResults revealed that a majority of participants with MDS exhibit a declining cortisol awakening response (n = 17). A declining CAR was significantly associated with increased clinical severity scores (r = − .508; p = .03), larger duplication size, waking later, and an increased number of hospitalizations for infections.ConclusionsFuture mechanistic studies will have to determine whether the declining CAR in MDS is attributable to problems with “flip-flop switching” of regional brain activation (involving the suprachiasmatic nucleus and the hippocampus, and the HPA axis) that is responsible for the switch from reduced to increased adrenal sensitivity. Taken together, results suggest the possibility that cortisol profiles could potentially be a biomarker of clinical severity and utilized for the purposes of patient stratification for future clinical trials in MDS.

Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019.

The aim of this study was to investigate the correlations between serum calcium and clinical outcomes in patients with coronavirus disease 2019 (COVID-19). In this retrospective study, serum calcium levels, hormone levels and clinical laboratory parameters on admission were recorded. The clinical outcome variables were also recorded. From February 10 to February 28, 2020, 241 patients were enrolled. Of these patients, 180 (74.7%) had hypocalcemia on admission. The median serum calcium levels were 2.12 (IQR, 2.04-2.20) mmol/L, median parathyroid hormone (PTH) levels were 55.27 (IQR, 42.73-73.15) pg/mL, and median 25-hydroxy-vitamin D (VD) levels were 10.20 (IQR, 8.20-12.65) ng/mL. The serum calcium levels were significantly positively correlated with VD levels (P =0.004) but negatively correlated with PTH levels (P =0.048). Patients with lower serum calcium levels (especially ≤2.0 mmol/L) had worse clinical parameters, higher incidences of organ injury and septic shock, and higher 28-day mortality. The areas under the receiver operating characteristic curves of multiple organ dysfunction syndrome, septic shock, and 28-day mortality were 0.923 (P <0.001), 0.905 (P =0.001), and 0.929 (P <0.001), respectively. In conclusion, serum calcium was associated with the clinical severity and prognosis of patients with COVID-19. Hypocalcemia may be associated with imbalanced VD and PTH levels.

X-Chromosome Inactivation Is a Biomarker of Clinical Severity in Female Carriers of RPGR-Associated X-Linked Retinitis Pigmentosa

X-linked retinitis pigmentosa can manifest in female carriers with widely variable severity, whereas others remain unaffected. The contribution of X-chromosome inactivation (XCI) to phenotypic variation has been postulated but not demonstrated. Furthermore, the impact of genotype and genetic modifiers has been demonstrated in affected males but has not been well established in female carriers. The purpose of this study was to describe the scope of clinical phenotype in female carriers with mutations in RPGR and quantify the contribution of genotype, genetic modifiers, and XCI to phenotypic severity. Cohort study. Seventy-seven female carriers with RPGR mutations from 41 pedigrees. Coding single nucleotide polymorphisms were sequenced in candidate genetic modifier genes encoding known RPGR-interacting proteins. X-chromosome inactivation ratios were determined in genomic DNA isolated from blood (n= 42) and saliva (n= 20) using methylation status of X-linked polymorphic repeats. These genetic data were compared with disease severity based on quantitative clinical parameters. Visual acuity, Humphrey visual field (HVF) results, full-field electroretinography results, and dark adaptation. Most individuals at all ages were mildly affected or unaffected, whereas those who progressed to moderate or severe vision loss were older than 30 years. RPGR genotype was not associated with clinical severity. The D1264N variant in RPGRIP1L was associated with more severe disease. Skewed XCI toward inactivation of the normal RPGR allele was associated with more severe disease. The XCI ratio in both blood and saliva was a predictor of visual function as measured by HVF diameter, rod amplitude, flicker amplitude, and flicker implicit time. For carriers with extreme XCI skewing of 80:20 or more, 57% were affected severely compared with 8% for those with XCI of less than 80:20 (P= 0.002). Female carriers with mutations in RPGR demonstrate widely variable clinical severity. X-chromosome inactivation ratios correlate with clinical severity and may serve as a predictor of clinically significant disease. Because RPGR gene therapy trials are underway, a future imperative exists to determine which carriers require intervention and when to intervene. X-chromosome inactivation analysis may be useful for identifying candidates for early intervention.

The Oxygenscan Provides Clinically Relevant Biomarkers for Treatment Efficacy That Are Associated with Frequency of Vaso-Occlusive Crisis in Sickle Cell Disease

The Oxygenscan Provides Clinically Relevant Biomarkers for Treatment Efficacy That Are Associated with Frequency of Vaso-Occlusive Crisis in Sickle Cell Disease

Pyruvate Kinase (PK) Protein and Enzyme Levels in the Diagnosis and Clinical Phenotype of PK Deficiency

Background: Pyruvate Kinase (PK) deficiency is caused by mutations in the PKLR gene leading to chronic hereditary non-spherocytic hemolytic anemia. Diagnostic evaluation can be challenging with falsely normal PK enzyme activity levels in chronically transfused patients, in those with profound reticulocytosis, or in patients with mutations with unusual biochemical properties. Genetic testing can also be complex, as up to 20% of affected patients have new PKLR variants and up to 10% of patients have variants not routinely detected through exon sequencing. The phenotypic spectrum is broad, and biomarkers of clinical severity would be helpful for both prognosis and monitoring. Aims: To describe the correlation of PK enzyme activity, red cell PK (PK-R) protein level, and red cell metabolites [adenosine triphosphate (ATP), 2,3-diphosphoglycerate (2,3-DPG)] with clinical phenotype. To estimate the sensitivity of PK enzyme activity to diagnose PK deficiency in a cohort of patients with genetically confirmed PK deficiency. Methods: Blood samples were collected from a subset of 41 patients enrolled in the PK Deficiency Natural History Study, all with two confirmed PKLR mutations and no red cell transfusions for ≥3 months prior to the blood sample. PK and hexokinase (HK) enzyme activity testing were performed using standard biochemical assays (Beutler 1985) at the Stanford Red Blood Cell Special Studies Laboratory (normal ranges: PK activity: 3.2-6.5 EU/gm Hb, HK activity: 0.14-0.37 EU/gm Hb). Baseline PK-R protein was quantitated by antibody-based capture and detection using a Meso Scale assay and the signal normalized to a control sample without PK deficiency. ATP and 2,3-DPG concentrations (μg/ml) in blood were analyzed using qualified tandem mass spectrometry methods and then normalized for individual hemoglobin (Hb) values (ATP and 2,3-DPG concentrations were converted to g/dL and divided by Hb (g/dL)). Spearman correlation coefficients were calculated to estimate the correlation between continuous variables, and Wilcoxon rank-sum testing was used to assess the association of continuous and binary variables. Results: The median age was 25.3 years (range 1.4-60.4) and 80% of patients were splenectomized (Table). The mean PK enzyme activity level was 1.1 EU/gm Hb with 90% (37/41) of patients with low PK activity. Normal PK activity was observed in 4 patients, 3 of whom had high HK activity and a low PK/HK ratio (normal mean PK/HK ratio 15.6, range: 8.7-22.5), with a sensitivity of 98% (40/41) when both PK activity and PK/HK ratio were used together. There were no correlations between PK enzyme activity and clinical severity indicators, including transfusion status (p=0.3), splenectomy status (p=0.4), or post-splenectomy Hb (r=0.109). Normalized ATP levels were significantly correlated with normalized 2,3-DPG levels (r=0.93) and higher in ever transfused (median=0.0022, range=0.0011-0.0029) compared with never transfused patients (median=0.0012 , range=0.0008-0.0020), (p=0.004). PK-R protein level was inversely correlated with the total number of transfusions prior to enrollment (r= -0.53) and was higher in never transfused (median=40.1%, range=9.8-73.9%) compared with ever transfused patients (median=7.7%, range=0.4%-15.1%), (p=0.0014). Conclusions: In this cohort with a molecularly confirmed diagnosis, PK deficiency was detected by enzyme testing with 98% sensitivity by utilizing both the PK activity and the PK/HK ratio. Although these assays cannot distinguish between heterozygotes and affected patients, the combination of PK activity and the PK/HK ratio is useful as a screening test to determine which patients require genetic testing. There was no correlation between PK enzyme activity and clinical phenotype. PK-R protein and ATP levels were inversely correlated with clinical severity and may be a helpful marker of disease phenotype. Disclosures Al-Samkari: Agios: Consultancy, Research Funding; Moderna: Consultancy; Dova: Consultancy, Research Funding. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Thompson:bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Kwiatkowski:Celgene: Consultancy; Terumo: Research Funding; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy. Kung:Agios Pharmaceuticals, Inc: Employment, Other: Stakeholder. Kosinski:Agios Pharmaceuticals, Inc: Employment, Other: Stakeholder. London:United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace:Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The Oxygenscan: A Rapid and Reproducible Test to Determine Patient-Specific, Clinically Relevant Biomarkers of Disease Severity in Sickle Cell Anemia

Background: In sickle cell anemia (SCA), hemoglobin S (HbS) polymerizes upon deoxygenation, resulting in sickling of red blood cells (RBCs). These deoxygenated RBCs have strongly reduced deformability, which contributes to the etiology of vaso-occlusive crises and chronic hemolytic anemia. There are no widely available clinical laboratory tests to directly monitor effects of disease modifying therapies (i.e. hydroxyurea) on RBC deformability. RBC deformability can be measured using a Laser Optical Rotational Red Cell Analyzer (Lorrca) ektacytometer (RR Mechatronics, the Netherlands), which measures RBC deformability over a range of osmolalities. Recently, a new module was added which consists of a method to measure RBC deformability, expressed as Elongation Index (EI), during controlled deoxygenation. This test, termed oxygenscan, has 3 key read out parameters: 1) EImax, which represents RBC deformability at normoxia; 2) EImin represents deformability upon deoxygenation; and 3) the point of sickling (PoS), the point at which a >5% decrease in EI is observed during deoxygenation, reflecting the patient-specific pO2 at which sickling begins (Figure 1). In this study, we correlated laboratory parameters associated with SCA disease severity with oxygenscan parameters to establish the clinical utility of this test.Methods: The discovery cohort consisted of 15 SCA patients (median age 22.0 years, 33.3% on hydroxyurea (HU)) enrolled at University Medical Center Utrecht (UMCU). The validation cohort consisted of 21 patients with SCA (median age 12.5 years, 76.2% on HU) from Texas Children's Hematology Center (TCHC). Oxygenscans were carried out in duplicates at both sites. Percentage dense RBC (%DRBC) were measured using an ADVIA hematology analyzer (Siemens) at TCHC only. In this study, we used Pearson's correlation to test for linear correlations between oxygenscan parameters EImax, EImin and PoS and clinically relevant laboratory parameters: total hemoglobin (Hb), absolute reticulocyte count (ARC), %HbS and %HbF, and %DRBC.Results: In both cohorts PoS significantly positively correlated with ARC (Figure 2A-B). In the UMCU cohort, total Hb levels also significantly positively correlated with EImax (Figure 2C), which was validated in the TCHC cohort (Figure 2D). HbF positively correlated with the EImin in both cohorts (Figure 2E-F). EImin also significantly negatively correlated with HbS (r=-0.828 p=<0.001 in the UMCU cohort, r=-0.936, p=<0.001 in the TCHC cohort data not shown). EImax showed a strong negative correlation with the %DRBC (Figure 2G) in the TCHC cohort. Individual test results were highly reproducible at both sites, with a median coefficient of variability of all tested parameters below 3%.Conclusion: The oxygenscan is a semi-automated, inexpensive, highly reproducible, and rapid test to fully characterize patient-specific RBC deformability under a range of oxygen concentrations. Key oxygenscan measurements- PoS, EImin, and EImax- correlated with known measures of SCA disease severity, namely ARC, HbF, HbS, total Hb and %DRBC. Patients with higher reticulocyte counts showed a clinically unfavorable increase of oxygen concentration at which RBCs start to sickle (termed PoS), than patients with lower ARC. Patients with higher HbF had more deformable RBCs even at the lowest oxygen concentrations, or EImin, while patients with higher HbS had lower EImin (low values indicate poor deformability under deoxygenated conditions). Patients with high %DRBC had lower EImax, indicating poor RBC deformability at normoxic conditions. Conversely, patients with high total Hb had high EImax.The very strong correlations of key oxygenscan measurements with different measures of SCA disease severity suggest that these parameters could be exploited as useful biomarkers of clinical severity and in the follow-up and treatment of SCA patients and warrant further investigation. [Display omitted] DisclosuresRab:RR Mechatronics: Research Funding. Bos:RR Mechatronics: Research Funding. Cnossen:Roche: Research Funding; CSL Behring: Research Funding; Novartis: Research Funding; Novo Nordisk: Research Funding; Bayer: Research Funding; Shire: Research Funding; Pfizer: Research Funding. Schutgens:Bayer: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; Uniqure BV: Research Funding; Novo Nordisk: Research Funding; Baxalta/Shire: Research Funding. van Wijk:Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; RR Mechatronics: Research Funding. van Beers:RR Mechatronics: Research Funding; Bayer: Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Increased plasma levels of thrombopoietin in patients with severe acute pancreatitis

The aim of this study was to evaluate the accuracy of thrombopoietin (TPO) plasma levels as a biomarker of clinical severity in patients with acute pancreatitis (AP). TPO is a humoral growth factor that stimulates megakaryocyte proliferation and differentiation [1]. Furthermore, it favors platelet aggregation and polymorphonuclear leukocyte activation [2]. Elevated plasmatic concentrations of TPO have been shown in patients with critical diseases, including ACS, burn injury and sepsis [2]. In particular, clinical severity is the major determinant of elevated TPO levels in patients with sepsis [3]. AP is a relatively common disease whose diagnosis and treatment are often difficult, especially in the clinical setting of the emergency department (ED). About 20% of patients with AP develop a severe form of the disease. In order to early identify those patients affected by severe AP, several biomarkers have been studied. No data regarding TPO plasma levels in patients with AP are currently available.

Brainstem metabolites in multiple system atrophy of cerebellar type: 3.0‐T magnetic resonance spectroscopy study

The aim of this study was to find biomarkers of disease severity in multiple system atrophy of cerebellar type by imaging disease specific regions using proton magnetic resonance spectroscopy on a 3.0 T system. We performed proton magnetic resonance spectroscopy separately in the pons and medulla on 12 multiple system atrophy of cerebellar type patients and 12 age and gender matched control subjects. The metabolite concentrations were estimated from single-voxel proton magnetic resonance spectra measured by point resolved spectroscopy, which were then correlated with clinical severity using Part I, II, and IV of the unified multiple system atrophy rating scale. Proton magnetic resonance spectroscopy showed that myo-inositol concentrations in both the pons and medulla were significantly higher in multiple system atrophy of cerebellar type patients compared to those of the control subjects (P < 0.05). By contrast, total N-acetylaspartate (the sum of N-acetylaspartate and N-acetylaspartylglutamate) and total choline compounds concentrations in both the pons and medulla were significantly lower in multiple system atrophy of cerebellar type patients compared to control subjects (P < 0.05). Creatine concentration in the pons was significantly higher in multiple system atrophy of cerebellar type patients compared to the control subjects (P < 0.05). Furthermore, a significant correlation was found between the myo-inositol/creatine ratio in the pons and clinical severity, defined by the sum score of unified multiple system atrophy rating scale (I+II+IV) (r = 0.76, P < 0.01). Proton magnetic resonance spectroscopy, in conjunction with a 3.0 T system, can be feasible to detect part of pathological changes in the brainstem, such as gliosis and neuronal cell loss, and the metabolites can be used as biomarkers of clinical severity in multiple system atrophy of cerebellar type patients.