A neuroimaging proof of principle study of Down's syndrome and dementia: ethical and methodological challenges in intrusive research.

BACKGROUND: Research into specific illnesses and the development of new treatments may only become possible as new technologies become available. When used for research, such technologies may best be described as 'intrusive', in that they require a considerable willingness and commitment on the part of the participants. This has increasingly been the case for brain disorders and illnesses where novel neuroimaging techniques, often combined with clinical and psychological assessments, have the potential to result in new understanding. People with intellectual disabilities (ID) have a history of under-representation as participants in research using such technologies and are therefore at risk of not receiving equal access to state-of-the-art treatments. We propose that 'intrusive' biomedical research is both possible and ethical in ID, and explore some of the methodological challenges by reference to a recent proof of principle study that used a relatively new ligand-based brain scanning technique in a group of volunteers with Down's syndrome. METHODS: Five overlapping stages of the study methodology were identified and evaluated for their acceptability to volunteers with mild to moderate ID through discussion, reflection, and analysis of structured feedback in the context of key policy documents, ethical guidelines and relevant legislation. RESULTS: Identification of key ethical and methodological challenges from reflective practice and participant feedback facilitated the emergence of strategies that permitted continual refinement of the study design. Important areas considered included (1) being clear about the purpose and scientific justification for the study; (2) reconciling the potential risks and benefits with relevant ethical guidelines and legislation; (3) identifying and implementing effective recruitment strategies; (4) optimising and assessing capacity to consent; and (5) making the 'intrusive' procedures as acceptable as possible to people with ID. CONCLUSION: We were able to demonstrate that a proof of principle study incorporating a novel brain scanning technique in a group of volunteers with ID was feasible, safe and well tolerated, despite the vulnerabilities of the study cohort and the intrusive nature of the research. We consider the study within an ethical and historical discourse about the principles that define current 'best practice' in ID research and propose a number of key recommendations for making intrusive research acceptable in people with ID.

Age-related changes in plasma dehydroepiandrosterone levels in adults with Down's syndrome and the risk of dementia.

People with Down's syndrome (DS) are at high risk of developing early onset dementia. Recent studies suggest a link between age-related decreases in dehydroepiandrosterone (DHEA) concentrations and dementia in the general population. The present study investigates the relationship between DHEA serum levels and age and the risk of dementia in adults with DS. The DHEA plasma concentrations of 67 adults with DS and 65 age-matched controls were determined. Participants with DS were assessed for the presence of dementia using the CAMDEX informant interview. The DHEA plasma concentrations decreased with age in subjects with DS as well as in controls. Age significantly predicted DHEA levels in both groups (B = -0.06, t = -4.536, P < 0.001 in the DS group and B = -0.04, t = -2.928, P < 0.005 in control participants). The mean ± SD DHEA level was 3.47 ± 1.41 µmol/l in controls and 2.79 ± 1.24 µmol/l in participants with DS. This difference was significant (t = -2.981, P < 0.01). Within the DS population, ancova revealed a significant relationship between DHEA concentrations and dementia (F(1,65) = 4.348, P < 0.05). We found that DHEA levels declined significantly with age in people with DS and controls and were lower, in comparison to age-matched controls, in people with DS across all ages studied. Those with DS and evidence of dementia have lower DHEA concentrations than those with DS (controlling for age) but without dementia.

Urinary excretion of N-nitrosoproline in relation to consumption of raw and cooked vegetables in a Danish rural population.

Several recent case-control studies of gastric cancer have demonstrated the protective effect of consumption of vegetables. According to Correa's model of gastric carcinogenesis, the initiating agent is N-nitroso compounds either ingested or formed in vivo. In our study of endogenous nitrosation, we measured intragastric formation of N-nitroso compounds in 285 individuals by the nitrosation of proline; in this presentation we analysed the effect of consumption of vegetables on urinary excretion of N-nitrosoproline (NPRO). When adjustment was made for the dominating determinants of NPRO excretion (total nitrate intake and tobacco smoking), a marked difference in the effects of consumption of raw and cooled vegetables was seen: consumption of cooked vegetables increased endogenous nitrosation of proline, while consumption of raw vegetables had only a marginal effect. We suggest that the difference between raw and cooked vegetables is due to destruction of ascorbate in the cooking of the vegetables. The lack of a protective effect of consumption of raw vegetables on the rate on endogenous nitrosation of proline indicates, however, that the determinants of nitrosation of proline and the determinants of gastric cancer risk may be different.

Endogenous nitrosation in relation to nitrate exposure from drinking water and diet in a Danish rural population.

Increasing levels of nitrate in drinking water is of concern due to the possibility of an associated increase in long-term exposure to endogenously formed carcinogenic N-nitroso compounds. Excretion of N-nitrosoproline in 12-h overnight urine after intake of 500-mg L-proline was used to quantify the rate of endogenous nitrosation in 285 individuals in an area in northern Denmark with large variation in nitrate concentration of the drinking water. Nitrate intake was measured in a 24-h duplicate diet sample. The crude association between nitrate concentration in drinking water and rate of endogenous nitrosation in individuals is only weakly positive and not quite statistically significant (P = 0.08). The risk of having detectable nitrosation increases significantly with total nitrate intake and tobacco smoking. In nonsmokers, nitrosation is determined by nitrate intake. Smokers have increased nitrosation which does not depend on nitrate intake. Effect modification through dietary factors was evaluated and indicated a protective effect of tea consumption, while the effect of eating vegetables was not clear-cut. The experimental design (12-h urine sample; proline dose taken in the evening) is likely to underestimate the effect of nitrate in drinking water relatively to nitrate in the diet.

Nitrate exposure from drinking water and diet in a Danish rural population.

Increasing levels of nitrate (NO3-) in drinking water in Denmark is of concern due to the possibility of an associated increase in long-term exposure to endogeneously formed N-nitroso compounds. Using a duplicate portion technique in combination with a qualitative description of diet and other background variables, the total nitrate intake in a Danish rural population and the contribution of drinking water to the total nitrate exposure is estimated. People drinking nitrate-free water have an intake of 37 mg NO3- per day. At 47 mg NO3- per litre, the exposure is increased to 89 mg, about 60% of which originates from the water. At 84 mg NO3- per litre, the daily exposure is 123 mg, 70% of which originates from the drinking water. These crude comparisons between three groups of people are supplemented with quantitative modelling of nitrate exposure at individual level. Apart from drinking water, consumption of vegetables is a major source of nitrate in this population. Using nitrate in overnight urine samples to quantify exposure is less accurate than the duplicate dietary portion technique and tends, in the present study, to underestimate the contribution of water-derived nitrate to total nitrate intake.

Pancreatic islet metabolism and redox state during stimulation of insulin secretion with glucose and fructose.

The mechanism of potentiation of insulin secretion by fructose was investigated. Twenty mM fructose + 3 mM glucose stimulated insulin secretion in a biphasic manner similar to what is found during stimulation with 20 mM glucose, whereas 20 mM fructose alone did not affect secretion. Fructose utilization was measured as formation of tritiated water from 5-3H-fructose. At 27.8 mM fructose the utilization rate was 258 pmol/2 h/10 islets, which is less than the utilization rate of 2.8 mM glucose. 20 mM glucose increased the islet NADH/NAD+ and NADPH/NADP+ redox ratios as well as islet concentration of ATP and PEP. 20 mM fructose + 3 mM glucose did not affect the concentration of ATP and PEP or the NADH/NAD+ redox ratio. The NADPH/NADP+ ratio was significantly decreased (60%) after 2.5 min incubation with .20 mM fructose + 3 mM glucose. It is concluded that fructose potentiation of insulin secretion is not primarily dependent on fructose metabolism and that any conceivable effect on plasma membrane ion fluxes as caused by a reduction of plasma membrane disulfides, may be caused by mechanisms other than a mere increase in the pyridine nucleotide substrates for the transhydrogenation process.