924 active molecule NO is formed by the conversion of L-arginine to L-citrulline, a reaction catalyzed by the enzyme NO synthase. In this process tetrahydrobiopterin (BH4) is a necessary cofactor. We have shown that the ratio of the plasma concentrations of citrulline (Cit) and arginine (Arg), the so-called Cit/Arg ratio, can be regarded as an index of NO synthesis (Fekkes et al. 2007). One of the key players in the production of NO in AD may be the inﬂammation and immune activation that characterize the pathology of AD. These processes may play an important role in the development and progression of dementia (McGeer and McGeer 2004). Brain inﬂam- mation is mainly caused by activation of glia cells that produce a variety of pro-inﬂammatory and neurotoxic factors, including free radicals such as NO (Bernstein et al. 2005; Sharma et al. 2007). These processes may also be relevant for persons with DS. We recently found that neopterin, which is an indicator for systemic inﬂammation and immune activation, increases with age in these subjects and is associated to the risk of dementia (Coppus et al. 2009). Others have found that neopterin is increased in the brain and the plasma of patients with AD and other neu- rodegenerative disorders (Hull et al. 2000; Murr et al. 2003). It has become clear that amino acids are not only essential for various metabolic pathways such as the syn- thesis of the major neurotransmitters. In addition, amino acids are involved in immune responses (Li et al. 2007; Mircher et al. 1997). Probably of special relevance are the so-called branched-chain amino acids (BCAA) that A. M. W. Coppus et al. comprise the three essential amino acids: L-leucine, L-iso- leucine and L-valine. In experimental conditions, adminis- tration of BCAA was found to improve immune function (Kakazu et al. 2007). In our previous study in healthy DS persons, wide spread differences in nearly all amino acids were found as compared to healthy control subjects with signiﬁcant lower levels of the essential amino acids (Coppus et al. 2007). The present study was designed to assess the putative differences in plasma levels of amino acids and neopterin in a large cohort of DS individuals with and without dementia. Methods Study population Over a period of 4 years a community based sample of 401 individuals with DS, age 45 years and older, from the Southern and South-Western part of the Netherlands was composed. Recruitment procedures and the ethical protocol are described in detail elsewhere (Coppus et al. 2006, 2007). The sample comprises 151 women and 250 males with a mean age of 52 ± 5.1 years (Table 1). In 232 subjects, the diagnosis DS was conﬁrmed by cytogenetic analysis. In the remaining, the diagnosis was based on the characteristic phenotype. The study population was divided into two birth cohorts based on the subject’s age at the reference date. The birth Table 1 General characteristics All Sex n (%) Women Men Age start, mean (±SD) Level of ID, n (%) Severe/profound Moderate/mild Living situation Institutionalized Community living Dementia status, n (%) Demented at the start New demented at follow-up All 401 persons 151 (37.7) 250 (62.3) 51.6 (5.1) 138 (34.4) 216 (53.9) 247 (61.6) 154 (38.4) 61 (15.2) 79 (19.7) a Healthy persons, without dementia, or symptoms of depression and/or epilepsy b Demented persons without symptoms of depression and/or epilepsy c Depressive persons without symptoms of dementia and/or epilepsy d Persons with epilepsy, without dementia and/or depressive symptoms 123 Healthya 130 41 (31.5) 89 (68.5) 49.9 (3.9) 40 (30.8) 68 (52.3) 79 (60.8) 51 (39.2) Dementedb 84 32(38.1) 52 (61.9) 53.2 (5.7) 34 (40.5) 46 (54.8) 50 (59.5) 34 (40.5) 30 (35.7) 54 (64.3) Depressionc 38 19 (50) 19 (50) 50.3 (3.3) 15 (39.5) 18 (47.4) 32 (84.2) 6 (15.8) Epilepticd 34 11(32.4) 23 (67.6) 51.3 13 (38.2) 17 (50) 22 (64.7) 12 (35.3)