Plasma level in demented subjects with Down syndrome cohorts distinguishes patients who were 60 years or older (born before 1947; n = 88) and those who were younger than 60 years (born after 1947; n = 313) at the reference date January 1, 2007. To deﬁne syndrome speciﬁc differ- ences, the group of subjects with DS (n = 401) was compared with a group of 48 age and sex-matched healthy controls of the general population (source lab data, female 16, male 32, mean age 50.2, SD 9.1 years). For neopterin, data were available for 28 control subjects. Separate analyses were performed comparing individu- als who were demented at baseline (prevalent demented) with those who developed dementia at follow-up (incident demented) and those who remained nondemented during follow-up. Clinical assessment At baseline, assessment included an extensive interview with relatives, caregivers and the responsible physician in order to ascertain the medical history and daily function- ing. In addition, all subjects had a thorough physical and neurological examination. The premorbid level of intellectual disability (ID) was derived from the medical records and classiﬁed according to the ICD-10 (World Health Organisation 1992). In addition, a diagnosis of AD was made based on the ICD-10 criteria and the guidelines of the IASSID (Aylward et al. 1997; Burt and Aylward 2000). All subjects were screened annually with a mean follow-up of 4.5 years. Patients who met the diagnostic criteria of AD at baseline or during follow-up, were monitored every 6 months. A probable diagnosis of depressive disorder was made by the respon- sible physician or the consultant psychiatrist. Epilepsy was diagnosed by a neurologist or the responsible physician. Level of ID and living situation as an expression of general functioning are presented in Table 1. The study population was divided into four subgroups according to the presence of only dementia (n = 84), only depression (n = 38) or only epilepsy (n = 34) and healthy DS persons (n = 130). The ratio for this subclassiﬁcation was that the use of anti-epileptics and antidepressants might bias the results. At baseline, of the 401 DS subjects included in this study, 61 had a diagnosis of dementia, of whom 23 with epilepsy. Of the nondemented persons 64 had a diag- nosis of epilepsy resulting in a group of 276 nondemented subjects without epilepsy at the start of the study. Biochemical analyses Plasma amino acids were analyzed by high-performance liquid chromatography using pre-column derivatization with o-phthaldialdehyde (Fekkes et al. 1995). The trypto- phan-ratio was calculated by dividing the total tryptophan 925 level times 100 by the sum of the other large neutral amino acids, i.e., valine, isoleucine, leucine, tyrosine (Tyr) and phenylalanine (Phe), which compete for the transport of tryptophan through the blood–brain barrier. The Tyr ratio was calculated in the same manner by substituting trypto- phan for Tyr. The value of aromatic amino acids comprises the summed concentrations Phe, Tyr and tryptophan, and the value of BCAA is the sum of the concentrations of leucine, isoleucine and valine. The Phe/Tyr ratio was cal- culated to serve as an estimate of BH4 activity. Plasma concentration of neopterin was determined as described previously (Hoekstra et al. 2001). Amino acids could be measured in 401 subjects and neopterin in 394 subjects Statistical analysis Univariate analyses of variance and Chi-square analyses were used to determine whether missing data were asso- ciated with age, sex and level of ID; no signiﬁcant effects were found. In descriptive analyses, data were reported as mean or numbers. Not all data showed normal distribution, and therefore statistical analyses were made using the nonparametric Mann–Whitney U test for comparison of groups. When analyzed as continuous variables, as in the partial correlation analyses, variables were natural log transformed. P values were corrected for multiple comparisons. Results During the follow-up period a total of 80 subjects died, of whom 61 (76.3%) were demented. As can be inferred from Table 2, plasma concentrations of nearly all biochemical parameters, are signiﬁcantly different between healthy controls and all individuals with DS. Only a few differ- ences are found in the plasma concentration of the amino acids between the four subgroups, i.e., healthy, demented, depressive and epileptic persons. Signiﬁcant differences (P \ 0.05) are found for taurine, phenylalanine and neop- terin in that the levels of these parameters are increased in the demented group as compared to the healthy DS group. The increased level of taurine is present mainly in the incident demented group as can been seen in Table 3. In the epileptic subgroup only the tryptophan ratio is found to be decreased as compared to the other subgroups. From Table 3, it can be inferred that in the group of prevalent demented subjects, excluding those with epilepsy, a signiﬁcantly higher neopterin concentration (P = 0.05) and a lower Cit/Arg ratio (P = 0.006) are found as compared to the group of nondemented subjects. The plasma concentration of taurine is signiﬁcantly higher 123