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 . 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, 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,  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. It is IFNg which stimulates the macrophages to produce neopterin
in infectious disorders, 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, and this could be causing a
distortion in the results. However, creatinine clearance has a positive linear
correlation with both neopterin and biopterin 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
There is a greater incidence of Alzheimer type changes in Down's
syndrome patients than in the normal population, 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
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
0.1||12.3, 11.8||1.12; 0.55
%||NS||NS||< 0.2 %
|Units Ámol pteridine /mmol crealinine.
1 Jones SA, Armstrong RA, Blair JA, et al. Telrahydrobiopterin
metabolism in senile dementia of the Alzheimer type. Biochem Soc Trans
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.
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
7 Huber C, Batchelor J, Fuchs D. et al. Neopterin: release from
macrophages primarily under the contro of interferon-gamma. J Exp Med
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.