Cerebrospinal Fluid Biopterin Is Decreased in Alzheimer's Disease

Kay, Arthur D.; Milstien, Sheldon; Kaufman, Seymour; Creasey, Helen; Haxby, James V.; Cutler, Neal R.; Rapoport, Stanley I.

doi:10.1001/archneur.1986.00520100018008

Cited by 41 publications

(21 citation statements)

References 52 publications

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“…These results are in general agreement with those reported previously in adults (19,20) and with in vitro studies in which alteration of BH4 concentration has been shown to influence monoamine metabolism (2 1-23). In the multiple regression model, we found that much of the variability in CSF HIAA was explained by age and BH4, yet a similar proportion of the variability in CSF HVA was explained by HIAA only.…”

Section: Discussionsupporting

confidence: 93%

Cerebrospinal Fluid Concentrations of Pterins and Metabolites of Serotonin and Dopamine in a Pediatric Reference Population

Hyland¹,

Surtees²,

Heales³

et al. 1993

Pediatr Res

122

105

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ABSTRACT. Accurate diagnosis and management of in-group of conditions and not all are associated with characteristic born errors of monoamine neurotransmitter and tetrahy-findings. Indeed, some affected subjects are symptomless. In drobiopterin metabolism depend on reliable reference addition, there are a variety of conditions that may mimic the ranges of key metabolites. Cerebrospinal fluid (CSF) was clinical and/or biochemical picture but that are not due to a collected in a standardized way from 73 children and young primary defect in biopterin metabolism. adults with neurologic disease, with strict exclusions. InIn clinical practice, differential diagnosis, decisions on maneach specimen, concentrations of homovanillic acid (HVA), agement, and monitoring of therapy for the patients with the 5-hydroxyindoleacetic acid (HIAA), total neopterin, 7,8-inborn errors of BH4 metabolism are dependent on the correct dihydrobiopterin, and tetrahydrobiopterin (BH4) were choice and interpretation of biochemical investigations and remeasured using HPLC. There was a continuous decrement quire that reliable reference ranges are available for key metabin CSF HVA, HIAA, and BH4 during the first few years olites. The present article documents such ranges for the followof life; this was independent of height (or length). Age-ing metabolites in CSF: HVA, HIAA, BH4, BH2 (a metabolite related reference ranges for each metabolite are given. of BH4), and NEO (neopterin plus 7,8-dihydroneopterin, derivExtensive correlations between HVA, HIAA, 7,8-dihydro-atives of the BH4 precursor dihydroneopterin triphosphate). biopterin, and BH4 were further analyzed by multiple Although pediatric reference ranges have been established for regression. Age and CSF BH4 were significant explanatory CSF amine metabolites (3-7) and for total biopterins and neopvariables for CSF HIAA, but CSF I-IVA had only HIAA terins (8-12), these have never been generated using the same as a significant explanatory variable. (Pediatr Res 34: 10-CSF samples; therefore, close study of the relationship between 14,1993) these variables has not been possible. These relationships are carefully examined in the present article. Abbreviations MATERIALS AND METHODS

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Section: Discussionsupporting

confidence: 93%

Cerebrospinal Fluid Concentrations of Pterins and Metabolites of Serotonin and Dopamine in a Pediatric Reference Population

Hyland¹,

Surtees²,

Heales³

et al. 1993

Pediatr Res

122

105

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“…The aerobic oxidation of (6R)BH4 was allowed to go to completion under the conditions listed. The resulting products were analyzed by MASDS as described in Table 1 or by HPLC [34]. The concentrations of the buffers were all 0.1 M. The halftimes ( t i / , ) listed for the oxidation reactions were estimated from semilogarithmic plots of the change in absorbance at either 243 nm or 229 nm.…”

Section: -)mentioning

confidence: 99%

“…The stability of 7,s-dihydrobiopterin under various conditions Solutions of 7,8-dihydrobiopterin were incubated under the specified conditions. The product distribution was then analyzed by MASDS as described in Table 2 or by HPLC [34]. The numbers in parentheses are the estimated half-times (min) for the auto-oxidation of (6R)BH4 under the same reaction conditions.…”

Section: -)mentioning

confidence: 99%

“…The tl,* values were obtained graphically from the semilog plot of the change of absorbance at either 229nm or 243nm versus time. The concentrations of PH2 and BH2 were determined from MASDS as described in Table 2 or by HPLC [34]. BH2 percentages are defined in Table 2 MASDS Table 6.…”

Section: -)mentioning

confidence: 99%

“…The enzymatic oxidation was performed at 25°C in the buffers listed, in the presence of 1 mM phenylalanine and 50 pg/ml catalase and was monitored at 330 nM. Following the completion of the reaction, the products were analyzed by HPLC [34]. The non-enzymatic values were compiled from Table 1 and Table 2 for the aerobic oxidation of (6R)BH4.…”

Section: -)mentioning

confidence: 99%

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The auto‐oxidation of tetrahydrobiopterin

Davis

Kaufman

Milstien

1988

European Journal of Biochemistry

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The product of the aerobic oxidation of tetrahydrobiopterin, quinonoid dihydrobiopterin, is unstable and rapidly rearranges to form a 7,s-dihydropteridine. Kaufman [Kaufman, S. (1967) J. Biol. Chem. 242,3934-39431 identified the stable product produced in 0.1 M phosphate pH 6.8, as 7,s-dihydrobiopterin. However, Armarego et al. [Armarego, W. L. F., Randles, D. and Taguchi, H. (1983) Eur. J. Biochem. 135 393-4031 questioned this assignment because they found that the dihydroxypropyl group on C-6 was eliminated and 7,s-dihydropterin was the predominant product when the aerobic oxidation was performed in 0.1 M Tris pH 7.6. In the present study we demonstrate that the rearrangement of the unstable quinonoid dihydrobiopterin results in a mixture of these two 7,8-dihydropteridines at neutral pH, 25 "C. Furthermore, we find that the loss or retention of the alkyl sidechain is not solely dependent on the pH of the reaction mixture, as was previously assumed by Armarego et al., but rather is strongly influenced by the temperature and the type of buffer. In addition, we describe a new method for quantifying the relative amounts of these two 7,8-dihydropteridines in mixtures of unknown concentrations. This method relies on multicomponent analysis of second derivative spectra and results in values which agree with the concentrations determined directly by HPLC.A reduced pteridine cofactor is necessary for phenylalanine hydroxylase to catalyze the conversion of phenylalanine to tyrosine [l]. The natural cofactor for this enzyme (as well as for tyrosine hydroxylase [2-51 and tryptophan hydroxylase [6, 71 is tetrahydrobiopterin, (BH,) [S]. During the hydroxylation reaction at neutral pH, there is a stoichiometric oxidation of BH4 to quinonoid dihydrobiopterin (qBH2) [9, 101. This latter species can then be reduced back to BH4 by the NADH-dependent enzyme, dihydropteridine reductase [ l l -151. qBH2 is unstable and, in the absence of the reductase, rapidly rearranges to a 7,s-dihydropteridine [9]. It was concluded that 7,s-dihydrobiopterin (BH,) was the product of the tautomerization of qBH2 [16,17] because when the auto-oxidation of BH4 was performed in 0.1 M phosphate pH 6.8 at ambient temperature, the ultraviolet spectrum of the product was identical to that of authentic BH2 [16]. This conclusion was also strongly supported by the finding that one of the products of the aerobic oxidation of BH4 in phosphate buffer was a substrate for sepiapterin reductase, an enzyme that catalyzes the NADP-dependent oxidation of the 2'-hydroxyl group on the side-chain of BH2 [16].However, it has become apparent that the unstable qBH2 does not always isomerize to BH,. Whereas the oxidation of Correspondence to

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CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome

2001

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PURPOSE To evaluate the role of CNS dopaminergic systems in Restless Legs Syndrome (RLS), homovanillic acid (HVA), tetrahydrobiopterin (BH4), and neopterin (NEOP), were assayed in CSF from RLS patients. The serotonin metabolite, 5‐hydroxyindoleacetic acid (5‐HIAA), was also measured. METHODS CSF was taken from 16 RLS patients after 2 weeks off medication and from 14 control subjects. The CSF metabolites were determined using HPLC techniques. RESULTS There was no significant difference in HVA or 5‐HIAA, but NEOP and BH4 were higher in RLS patients. The RLS group was significantly older than the control group (64.2 ± 9.2 years vs. 51.4 ± 6.3 years; P < 0.001). A multiple regression analysis showed a strong correlation between age and 5‐HIAA (r = 0.46, P = 0.04) and between age and NEOP (r = 0.61, P < 0.01). To eliminate the potential error created by the age difference between groups, an age‐adjusted subgroup of RLS and control subjects were compared. There was still no difference found for HVA; however, 5‐HIAA was now significantly lower (P < 0.01) in the RLS subgroup. Age‐adjustment eliminated the differences previously found for NEOP, (P = 0.12), but BH4 continued to remain higher in the RLS group (P < 0.01). CONCLUSION Differences in CSF HVA concentrations were not found. The changes in 5‐HIAA and BH4 are of unclear clinical significance and require further assessment with appropriate age‐matched controls. Mov. Disord. 16:144–149, 2001. © 2001 Movement Disorder Society.

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Cerebrospinal Fluid Biopterin Is Decreased in Alzheimer's Disease

Cited by 41 publications

References 52 publications

Cerebrospinal Fluid Concentrations of Pterins and Metabolites of Serotonin and Dopamine in a Pediatric Reference Population

Cerebrospinal Fluid Concentrations of Pterins and Metabolites of Serotonin and Dopamine in a Pediatric Reference Population

The auto‐oxidation of tetrahydrobiopterin

CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome

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