Sir: Urinary neopterin:biopterin ratios are elevated in senile dementia
of the Alzheimer type (SDAT) compared with age matched controls, due to a
reduced conversion of dihydroneopterin triphosphate to tetra-hydrobiopterin.[1,
2] There is a similar elevated neopterin:biopterin ratio in Down's syn-drome, a
condition producing a similar dementia to SDAT.
Morning urines were collected into ascor-bic acid (2% final
concentration) from a group of 53 Downs sufferers of mixed sex aged between 1
to 70 years without any other disease and, following storage at - 20°C, the
neopterin and biopterin levels were determined by HPLC after acid iodine
oxidation [3]. Compared with a group of 35 healthy con-trols of mixed sex and
aged 23 to 93 years, the neopterin:biopterin ratio was significantly elevated
3.44, 1.73 vs 1.12, 0.55 (mean, SD) p < 0.2% (table). Against a creatinine
baseline biopterin levels were unaffected but the urin-ary neopterin levels
were significantly increased (Table). No age trend was observed suggesting that
these metabolic effects precede dementia onset. The elevated
neopterin:biopterin ratio could be due to a disease related immune response
causing stimulation of neopterin biosynthesis,[4] alth-ough all disease states
known to produce such were absent and the rise is less pronoun-ced that in such
conditions. It is known that there are disturbances in the immune system of
Down's patients, [5] and it could be sugges-ted that these disturbances are
causing the rise in urinary neopterin in a similar manner to viral and
malignant disorders. However, it has been found that interferon gamma (IFNg)
production is lower in Down's patients than in normal patients with
infec-tion.[6] It is IFNg which stimulates the macrophages to produce neopterin
in infectious disorders,[7] so any decrease in IFNg levels should result in
similar or reduced levels of urinary neopterin and not the increased levels
observed. A second possibility is the presence of greater levels of guanosinc
triphosphate in the purine pool from an increased biosynthesis of purines as a
result of the extra chromosome 21, which has the locus for some of the enzymes
for purine biosynthesis.
The levels of neopterin and biopterin are measured against a creatinine
baseline. In the Downs subjects creatinine clearance is repor-tedly lower,
reflecting a reduced glomerular nitration rate,[8] and this could be causing a
distortion in the results. However, creatinine clearance has a positive linear
correlation with both neopterin and biopterin[9] so any reduction in the
baseline will be compensated for by reduced pterin excretion. This would also
account for the elevated levels of biopterins in the plasma of such
subjects.[10]
There is a greater incidence of Alzheimer type changes in Down's
syndrome patients than in the normal population,[11] and Down's syndrome has
been suggested as a model for accelerated ageing.[12) However, there is no
correlation between age and urinary N/B ratio in Down's syndrome from birth and
not one acquired with age.
Table Neopterin and biopterin levels in Down's subjects and
healthy controls
| N | Neopterin/Creatinine (mean,
SD) | Biopterin/Creatinine (mean, SD) | Creatinine (mmol/l) (mean,
SD) | N:B (mean, SD) |
|---|
| Downs syndrome | 53 | 0.47, 0.32 | 0.17,
0.14 | 8.22, 5.3 | 3.44, 1.7 |
|---|
| Control | 32 | 0.14, 0.17 | 0.11,
0.1 | 12.3, 11.8 | 1.12; 0.55 |
|---|
| P | | < 0.2
% | NS | NS | < 0.2 % |
|---|
| Units µmol pteridine /mmol crealinine. |
|---|
Haut
References
1 Jones SA, Armstrong RA, Blair JA, et al. Telrahydrobiopterin
metabolism in senile dementia of the Alzheimer type. Biochem Soc Trans
1987;15:713-4.
2 Andersen JM, Hamon CGB, Armstrong RA, Blair JA. Tetrahydrobiopterin
metabolism in normal brain, senile dementia of the Alz-heimer type and Down's
syndrome. In: Cooper BA, Whitehead V. eds. Chemistry and Biology of Pteridines.
Berlin: Walter de Gruyter, 1986:327-30.
3 Fukushima T, Nixon J. Analysis of reduced forms of biopierin in
biological tissues and fluids. Anal Biochem 1980;102:176-88.
4 Huber C, Lang A, Niederwieser D, et al. Immune response associated
production of neopterin. In: Pfleiderer W, Wachter H. Curtius H Ch, eds.
Biochemical and Clinical Aspects of Pteridines. Vol 3. Berlin: W de Gruyter.
1984:245-50.
5 Levine S. The immune system and susceplibility to infections in
Down's syndrome. Proc Clin Biol Res 1987;246:143-62.
6 Nair MP. Schwartz S. Association of decreased t-cell mediated
natural cytotoxicity and interferon production in Down's syndrome, Immunol
Immunopathol 1984;33:412-24.
7 Huber C, Batchelor J, Fuchs D. et al. Neopterin: release from
macrophages primarily under the contro of interferon-gamma. J Exp Med
1984:160:310-6.
8 Coburn SP, Seidenberg M, Menz ET. Clearance of uric acid, urea and
creatinine in Down's syndrome. J Appl Physiol 1967;23:579-80.
9 Fink M. Jhen U, Wilmanns W, Ziegler I. Blood levels of biopterin and
AGPM during kidney and bone marrow transplantation. Biochemical and
Clinical Aspects of Pteridines 1982;1:241-50.
10 Aziz AA. Blair JA, Leeming RJ. Sylvester PE. Telrahydrobiopterin
metabolism in Down's syndrome and in non-Down's syndrome mental retardation. J
Ment Deficit Res 1982;26:67-71.
11 Wisniewski HM, Brucc ME. Fraser H. Infec-tious etiology of neurotic
(senile) plaques in mice. Science 1975; 190:1108-10.
12 Walford R, Barnett E. Fahey J. Gatti R. Grossman H. Hibrawi H,
Motola M. Immunological and Biochemical Studies of Down's Syndrome as a Model
of Accelerated Aging. In: Segre D, Smith L. eds. Immunological Aspects of
Aging. New York: Marcel Dekker, 1981:479-532.
|