Table 2 Comparing the demented, depressive and epileptic persons with Down syndrome with the healthy persons with Down syndrome Demented Down syndrome n = 84 Depressive Down syndrome n = 38 926 Citrulline (lM) Arginine (lM) Taurine (lM) Tyrosine (lM) Valine (lM) Methionine (lM) Tryptophan (lM) Phenylanaline (lM) Isoleucine (lM) Leucine (lM) Tryptophan ratio Tyrosine ratio Phe/Tyr Cit/Arg Neopterin (nM) BCAA AAA LNAA Healthy controls n = 48 34.23 (8.8) 68.02 (24.3) 42.88 (7.6) 71.04 (17.3) 286.21 (59.7) 32.04 (6.4) 50.38 (9.1) 63.06 (9.9) 82.69 (24.1) 148.48 (31.8) 7.89 (1.5) 11.33 (2.1) 0.91 (0.1) 0.55 (0.2) 17.3 (3.6) 517.37 (111.2) 184.48 (30.2) 701.85 (135.2) All Down syndrome n = 401 44.95 (13.6)a 74.27(21.8) 52.52 (13.0)a 61.77 (16.1)a 232.48 (60.1)a 24.98 (6.2)a 41.70 (10.2)a 60.15 (14.1) 64.13 (17.5)a 125.06 (29.3)a 7.81 (1.5) 11.98 (2.5) 0.99 (0.2)a 0.63 (0.2)a 25.18 (11.0)a 421.67 (104.3)a 163.61 (36.3)a 528.28 (133.8)a Healthy Down syndrome n = 130 45.89 (13.2) 74.49 (21.1) 51.28 (12.0) 61.00 (15.2) 231.76 (60.6) 24.99 (5.4) 42.83 (9.4) 58.68 (12.7) 63.87 (17.0) 125.97 (28.5) 8.07 (1.4) 11.82 (2.4) 0.98 (0.1) 0.64 (0.2) 23.40 (8.7) 421.60 (103.8) 162.51 (34.1) 584.11 (131.6) 46.90 (13.9) 75.26 (19.5) 55.39 (12.3)b 64.02 (15.5) 242.38 (60.4) 25.94 (7.2) 42.89 (9.3) 62.50 (13.1)b 66.31 (18.0) 127.55 (29.2) 7.77 (1.4) 12.01 (2.6) 0.99 (0.1) 0.63 (0.2) 26.35 (12.2)b 436.24 (104.7) 169.42 (34.6) 605.65 (130.0) 45.42 (13.5) 79.89 (30.2) 55.00(14.8) 63.00 (17.1) 230.89 (54.9) 25.45 (6.3) 44.29 (10.1) 62.53 (13.6)b 63.58 (17.7) 127.13 (30.3) 8.26 (1.5) 12.03 (2.4) 1.02 (0.2) 0.62 (0.3) 24.03 (14.9) 421.60 (103.8) 169.81 (36.6) 591.42 (131.5) A. M. W. Coppus et al. Epileptic Down syndrome n = 34 44.50 (12.7) 78.18 (19.1) 54.00 (12.8) 63.35 (18.5) 235.65 (50.3) 25.35 (6.5) 39.79 (9.8) 60.74 (14.9) 66.65 (14.0) 126.47 (23.7) 7.23 (1.4)b 12.12 (3.1) 0.98 (0.2) 0.59 (0.2) 24.22 (11.5) 428.76 (84.9) 163.88 (37.2) 592.64 (114.5) Values are mean (standard deviation) Tryptophan ratio tryptophan/LNAA ratio, tyrosine ratio tyrosine/LNAA ratio, Phe/Tyr phenylanaline/tyrosine ratio, Cit/Arg citrulline/arginine ratio, BCAA summed concentration of Leucine, Isoleucine and Valine lM/l, AAA summed concentration of phenylanaline, tyrosine, tryptophan lM/l, LNAA large neutral amino acids: summed concentration of phenylalanine, tyrosine, tryptophan, valine, leucine and isoleucine lM/l a Mann–Whitney U-test, P \ 0.05 healthy controls compared with the total group of persons with Down syndrome b Mann–Whitney U-test, P \ 0.05 compared with the group of healthy persons with Down syndrome in the incident demented as compared with the nonde- mented (P = 0.002) and as compared with the prevalent demented subjects (P = 0.003). In the group of incident demented subjects, a signiﬁcantly higher Cit/Arg ratio is found as compared to the group of prevalent demented subjects (P = 0.003). After adjusting for age, excluding those with epilepsy, there is a high correlation between neopterin and the Cit/ Arg ratio in the group of prevalent demented subjects (n = 38): q = 0.45; P = 0.006, but not in the incident demented cases (n = 64): q = 0.18; P = 0.16 or in the nondemented (n = 276): q = 0.08; P = 0.24. There is a signiﬁcant correlation between neopterin and the Cit/Arg ratio in the total group of demented subjects (n = 84): q = 0.23; P = 0.04). By comparing the two age subgroups, born before and after 1947, we see that the concentrations of neopterin and the tyrosine ratio are increased with age whereas the levels of BCAA, taurine and tryptophan are decreased in the older group (data not shown). After controlling for dementia only tryptophan (q = -0.11, P = 0.03) and neopterin is sig- niﬁcantly correlated with age (q = 0.18, P \ 0.001). 123 Discussion In the present study, including a large sample of DS sub- jects with or without dementia, plasma concentrations of nearly all biochemical parameters differ signiﬁcantly from healthy controls. The decreased tryptophan ratio is explained most likely by the frequent use of anti-epileptics. Concentrations of neopterin and the tyrosine ratio are increased with age whereas the levels of BCAA, taurine and tryptophan are decreased in the older group. These ﬁndings are consistent with those reported previously in a small group of healthy DS subjects (Coppus et al. 2007). With respect to neopterin, a marked increase is found in the total group as compared to healthy controls, that further increases in the demented group. In the group of prevalent dementia the enhanced concentration of neopterin is sig- niﬁcantly correlated with a decreased Cit/Arg ratio. This ﬁnding is may be explained by an increase in oxidative, inﬂammatory or neurodegenerative processes in dementia. An explanation for a decreased Cit/Arg ratio in this con- dition may be a reduced bioavailability of BH4, which is the cofactor for NO synthesis and also for the conversion of