Teodoro Bottiglieri Ph.D.

Posted October 31st 2020

Novel biomarkers and age-related metabolite correlations in plasma and dried blood spots from patients with succinic semialdehyde dehydrogenase deficiency.

Teodoro Bottiglieri, Ph.D.

Teodoro Bottiglieri, Ph.D.

Kirby, T., Walters, D.C., Shi, X., Turgeon, C., Rinaldo, P., Arning, E., Ashcraft, P., Bottiglieri, T., DiBacco, M., Pearl, P.L., Roullet, J.B. and Gibson, K.M. (2020). “Novel biomarkers and age-related metabolite correlations in plasma and dried blood spots from patients with succinic semialdehyde dehydrogenase deficiency.” Orphanet J Rare Dis 15(1): 261.

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BACKGROUND: Previous work has identified age-related negative correlations for γ-hydroxybutyric acid (GHB) and γ-aminobutyric acid (GABA) in plasma of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD). Using plasma and dried blood spots (DBS) collected in an ongoing natural history study, we tested the hypothesis that other biomarkers would follow a similar age-related negative correlation as seen for GHB/GABA. Samples (mixed sex) included: patients (n = 21 unique samples, 1-39.5 yrs) and parallel controls (n = 9 unique samples, 8.4-34.8 yrs). Archival control data (DBS only; n = 171, 0.5-39.9 yrs) was also included. RESULTS: Metabolites assessed included amino acids (plasma, DBS) and acylcarnitines, creatine, creatinine, and guanidinoacetate (DBS only). Age-related negative correlations for glycine (plasma, DBS) and sarcosine (N-methylglycine, plasma) were detected, accompanied by elevated proline and decreased levels of succinylacetone, argininosuccinate, formaminoglutamate, and creatinine. Significantly low acylcarnitines were detected in patients across all chain lengths (short-, medium- and long-chain). Significant age-dependent positive correlations for selected acylcarnitines (C6-, C12DC(dicarboxylic)-, C16-, C16:1-, C18:1-, C18:2OH-carnitines) were detected in patients and absent in controls. Receiver operating characteristic (ROC) curves for all binary comparisons revealed argininosuccinate and succinylacetone to be the most discriminating biomarkers (area > 0.92). CONCLUSIONS: Age-dependent acylcarnitine correlations may represent metabolic compensation responsive to age-related changes in GHB and GABA. Our study highlights novel biomarkers in SSADHD and expands the metabolic pathophysiology of this rare disorder of GABA metabolism


Posted June 24th 2020

Relationship of Cerebrospinal Fluid Vitamin B12 Status Markers With Parkinson’s Disease Progression.

Teodoro Bottiglieri, Ph.D.

Teodoro Bottiglieri, Ph.D.

Christine, C. W., P. Auinger, N. Saleh, M. Tian, T. Bottiglieri, E. Arning, N. K. Tran, P. M. Ueland and R. Green (2020). “Relationship of Cerebrospinal Fluid Vitamin B12 Status Markers With Parkinson’s Disease Progression.” Mov Disord May 14. [Epub ahead of print].

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BACKGROUND: Using blood specimens from untreated early Parkinson’s disease (PD) patients from the DATATOP trial, we found that subjects in the low serum vitamin B12 tertile experienced greater annualized change in ambulatory capacity score, whereas those with moderately elevated (>15 μmol/L) total homocysteine had greater annualized declines in the Mini-Mental State Exam. METHODS: In this this study we sought to determine whether levels of cerebrospinal fluid (CSF) B12 markers were also associated with progression of PD. RESULTS: The annualized change in the UPDRS “walking” item, a component of the ambulatory capacity score, was worse in the low B12 tertile. No association with change in the Mini-Mental State Exam was seen for those 7% with the highest baseline CSF total homocysteine. CONCLUSIONS: In these untreated early-PD subjects, low CSF B12 predicted greater worsening of the UPDRS “walking” item, whereas CSF total homocysteine was not associated with progression of cognitive impairment. These findings extend and partially support our findings in serum.


Posted May 15th 2020

Impact of the MTHFR C677T polymorphism on one-carbon metabolites: Evidence from a randomised trial of riboflavin supplementation.

Teodoro Bottiglieri, Ph.D.

Teodoro Bottiglieri, Ph.D.

Rooney, M., T. Bottiglieri, B. Wasek-Patterson, A. McMahon, C. F. Hughes, A. McCann, G. Horigan, J. J. Strain, H. McNulty and M. Ward (2020). “Impact of the MTHFR C677T polymorphism on one-carbon metabolites: Evidence from a randomised trial of riboflavin supplementation.” Biochimie Apr 21. pii: S0300-9084(20)30074-2. [Epub ahead of print].

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Homozygosity for the C677T polymorphism in MTHFR (TT genotype) is associated with a 24-87% increased risk of hypertension. Blood pressure (BP) lowering was previously reported in adults with the TT genotype, in response to supplementation with the MTHFR cofactor, riboflavin. Whether the BP phenotype associated with the polymorphism is related to perturbed one-carbon metabolism is unknown. This study investigated one-carbon metabolites and their responsiveness to riboflavin in adults with the TT genotype. Plasma samples from adults (n 115) screened for the MTHFR genotype, who previously participated in RCTs to lower BP, were analysed for methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), betaine, choline and cystathionine by liquid chromatography tandem mass spectrometry (LC-MS/MS). The one-carbon metabolite response to riboflavin (1.6 mg/d; n 24) or placebo (n 23) for 16 weeks in adults with the TT genotype was also investigated. Plasma SAM (74.7 +/- 21.0 vs 85.2 +/- 22.6 nmol/L, P = 0.013) and SAM:SAH ratio (1.66 +/- 0.55 vs 1.85 +/- 0.51, P = 0.043) were lower and plasma homocysteine was higher (P = 0.043) in TT, compared to CC individuals. In response to riboflavin, SAM (P = 0.008) and cystathionine (P = 0.045) concentrations increased, with no responses in other one-carbon metabolites observed. These findings confirm perturbed one-carbon metabolism in individuals with the MTHFR 677TT genotype, and for the first time demonstrate that SAM, and cystathionine, increase in response to riboflavin supplementation in this genotype group. The genotype-specific, one-carbon metabolite responses to riboflavin intervention observed could offer some insight into the role of this gene-nutrient interaction in blood pressure.


Posted April 17th 2020

Betaine restores epigenetic control and supports neuronal mitochondria in the cuprizone mouse model of multiple sclerosis.

Teodoro Bottiglieri, Ph.D.

Teodoro Bottiglieri, Ph.D.

Singhal, N. K., S. Sternbach, S. Fleming, K. Alkhayer, J. Shelestak, D. Popescu, A. Weaver, R. Clements, B. Wasek, T. Bottiglieri, E. J. Freeman and J. McDonough (2020). “Betaine restores epigenetic control and supports neuronal mitochondria in the cuprizone mouse model of multiple sclerosis.” Epigenetics Mar 9:1-16. [Epub ahead of print].

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Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programmes. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate gene expression that supports neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability.


Posted April 17th 2020

Post-mortem tissue analyses in a patient with succinic semialdehyde dehydrogenase deficiency (SSADHD). I. Metabolomic outcomes.

Teodoro Bottiglieri, Ph.D.

Teodoro Bottiglieri, Ph.D.

Kirby, T., D. C. Walters, M. Brown, E. Jansen, G. S. Salomons, C. Turgeon, P. Rinaldo, E. Arning, P. Ashcraft, T. Bottiglieri, J. B. Roullet and K. M. Gibson (2020). “Post-mortem tissue analyses in a patient with succinic semialdehyde dehydrogenase deficiency (SSADHD). I. Metabolomic outcomes.” Metab Brain Dis Mar 14. [Epub ahead of print].

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Metabolomic characterization of post-mortem tissues (frontal and parietal cortices, pons, cerebellum, hippocampus, cerebral cortex, liver and kidney) derived from a 37 y.o. male patient with succinic semialdehyde dehydrogenase deficiency (SSADHD) was performed in conjunction with four parallel series of control tissues. Amino acids, acylcarnitines, guanidino- species (guanidinoacetic acid, creatine, creatinine) and GABA-related intermediates were quantified using UPLC and mass spectrometric methods that included isotopically labeled internal standards. Amino acid analyses revealed significant elevation of aspartic acid and depletion of glutamine in patient tissues. Evidence for disruption of short-chain fatty acid metabolism, manifest as altered C4OH, C5, C5:1, C5DC (dicarboxylic) and C12OH carnitines, was observed. Creatine and guanidinoacetic acids were decreased and elevated, respectively. GABA-associated metabolites (total GABA, gamma-hydroxybutyric acid, succinic semialdehyde, 4-guanidinobutyrate, 4,5-dihydroxyhexanoic acid and homocarnosine) were significantly increased in patient tissues, including liver and kidney. The data support disruption of fat, creatine and amino acid metabolism as a component of the pathophysiology of SSADHD, and underscore the observation that metabolites measured in patient physiological fluids provide an unreliable reflection of brain metabolism.

Correction to: Treatment of Psoriasis with Secukinumab in Challenging Patient Scenarios: A Review of the Available Evidence.

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Upon publication, it was noted that five of the on-line supplementary figures had incorrect figure: figure legend associations. These were supplementary Figs. 6, 7, 14, 15, and 23.