IDH1 p.R132H ctDNA and D-2-hydroxyglutarate as CSF biomarkers in patients with IDH-mutant gliomas.

INTRODUCTION: We aimed to evaluate IDH1 p.R132H mutation and 2-hydroxyglutarate (2HG) in cerebrospinal fluid (CSF) as biomarkers for patients with IDH-mutant gliomas. METHODS: CSF was collected from patients with infiltrating glioma, and 2HG levels were measured by liquid chromatography-mass spectrometry. IDH1 p.R132H mutant allele frequency (MAF) in CSF-ctDNA was measured by digital droplet PCR (ddPCR). Tumor volume was measured from standard-of-care magnetic resonance images. RESULTS: The study included 48 patients, 6 with IDH-mutant and 42 with IDH-wildtype gliomas, and 57 samples, 9 from the patients with IDH-mutant and 48 from the patients with IDH-wildtype gliomas. ctDNA was detected in 7 of the 9 samples from patients with IDH-mutant glioma, and IDH1 p.R132H mutation was detected in 5 of the 7 samples. The MAF ranged from 0.3 to 39.95%. Total 2HG level, D-2HG level, and D/L-2HG ratio in CSF were significantly higher in patients with IDH-mutant gliomas than in patients with IDH-wildtype gliomas. D-2HG level and D/L-2HG ratio correlated with total tumor volume in patients with IDH-mutant gliomas but not in patients with IDH-wildtype gliomas. CONCLUSION: Our results suggest that detection of IDH1 p.R132H mutation by ddPCR and increased D-2HG level in CSF may help identify IDH-mutant gliomas. Our results also suggest that D-2HG level and D/L-2HG ratio correlate with tumor volume in patients with IDH-mutant gliomas. Further prospective studies with larger cohorts are needed to validate these findings.

Cerebrospinal fluid metabolomics identifies a key role of isocitrate dehydrogenase in bipolar disorder: evidence in support of mitochondrial dysfunction hypothesis.

Although evidence for mitochondrial dysfunction in the pathogenesis of bipolar disorder (BD) has been reported, the precise biological basis remains unknown, hampering the search for novel biomarkers. In this study, we performed metabolomics of cerebrospinal fluid (CSF) from male BD patients (n=54) and age-matched male healthy controls (n=40). Subsequently, post-mortem brain analyses, genetic analyses, metabolomics of CSF samples from rats treated with lithium or valproic acid were also performed. After multivariate logistic regression, isocitric acid (isocitrate) levels were significantly higher in the CSF from BD patients than healthy controls. Furthermore, gene expression of two subtypes (IDH3A and IDH3B) of isocitrate dehydrogenase (IDH) in the dorsolateral prefrontal cortex from BD patients was significantly lower than that of controls, although the expression of other genes including, aconitase (ACO1, ACO2), IDH1, IDH2 and IDH3G, were not altered. Moreover, protein expression of IDH3A in the cerebellum from BD patients was higher than that of controls. Genetic analyses showed that IDH genes (IDH1, IDH2, IDH3A, IDH3B) and ACO genes (ACO1, ACO2) were not associated with BD. Chronic (4 weeks) treatment with lithium or valproic acid in rats did not alter CSF levels of isocitrate, and mRNA levels of Idh3a, Idh3b, Aco1 and Aco2 genes in the rat brain. These findings suggest that abnormality in the metabolism of isocitrate by IDH3A in the mitochondria plays a key role in the pathogenesis of BD, supporting the mitochondrial dysfunction hypothesis of BD. Therefore, IDH3 in the citric acid cycle could potentially be a novel therapeutic target for BD.

Cerebrospinal dehydrogenases in central nervous system infections.

Cerebrospinal fluid (CSF) dehydrogenases were studied in 42 controls, 23 children with pyogenic meningitis, 22 with tuberculous meningitis and 19 with encephalitis to assess their usefulness in differentiating between the different central nervous system infections. CSF-LDH and ICD activity was increased in CNS infections (p less than 0.0001), LDH being significantly higher (p less than 0.001) in pyogenic meningitis than in tuberculous meningitis or encephalitis. However, ICD activity was significantly different in each of these conditions (p less than 0.001). The dehydrogenase activity declined with subsequent clinical improvement, in all children with meningitis. A significant direct relationship was found between the enzyme activity and CSF protein content as well as total cell count. The 95% confidence interval confirms the utility of assaying CSF dehydrogenase activity to differentiate various CNS infections, thus improving the diagnostic ability.

Changes in serum and cerebrospinal fluid enzyme activity after head injury.

We studied simultaneously in serum (S) and CSF (L) the enzyme activities of GOT, GPT, LDH, ICDH, MDH, ALD, and CPK in 28 patients with head injuries divided into three groups according to the severity of the trauma. We found a correlation between severity of brain lesion and enzyme activity. The best correlation was found for SGOT, SCPK, LGOT, LLDH, LMDH and LCPK. We do not believe that enzyme activity is of prognostic value. We think that further studies should be made of the specific isoenzymes of the Central Nervous System.