Brainstem Serotonergic Deficiency in Sudden Infant Death Syndrome
- Jhodie R. Duncan, PhD;
- David S. Paterson, PhD;
- Jill M. Hoffman, BS;
- David J. Mokler, PhD;
- Natalia S. Borenstein, MS;
- Richard A. Belliveau, BA;
- Henry F. Krous, MD;
- Elisabeth A. Haas, BA;
- Christina Stanley, MD;
- Eugene E. Nattie, MD;
- Felicia L. Trachtenberg, PhD;
- Hannah C. Kinney, MD
- Author Affiliations: Department of Pathology, Children's Hospital Boston, and Harvard Medical School, Boston, Massachusetts (Drs Duncan, Paterson, and Kinney, Mss Hoffman and Borenstein, and Mr Belliveau); Department of Biochemical Sciences, University of New England College of Osteopathic Medicine, Biddeford, Maine (Dr Mokler); Rady Children's Hospital San Diego and University of California, San Diego, School of Medicine, La Jolla (Dr Krous and Ms Haas); San Diego County Medical Examiner's Office, San Diego, California (Dr Stanley); Department of Physiology, Dartmouth School of Medicine, Lebanon, New Hampshire (Dr Nattie); and New England Research Institutes, Watertown, Massachusetts (Dr Trachtenberg). Dr Duncan is currently affiliated with the Howard Florey Institute, University of Melbourne, Parkville, Victoria, Australia.
Abstract
Context Sudden infant death syndrome (SIDS) is postulated to result from abnormalities in brainstem control of autonomic function and breathing during a critical developmental period. Abnormalities of serotonin (5-hydroxytryptamine [5-HT]) receptor binding in regions of the medulla oblongata involved in this control have been reported in infants dying from SIDS.
Objective To test the hypothesis that 5-HT receptor abnormalities in infants dying from SIDS are associated with decreased tissue levels of 5-HT, its key biosynthetic enzyme (tryptophan hydroxylase [TPH2]), or both.
Design, Setting, and Participants Autopsy study conducted to analyze levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA); levels of TPH2; and 5-HT1A receptor binding. The data set was accrued between 2004 and 2008 and consisted of 41 infants dying from SIDS (cases), 7 infants with acute death from known causes (controls), and 5 hospitalized infants with chronic hypoxia-ischemia.
Main Outcome Measures Serotonin and metabolite tissue levels in the raphé obscurus and paragigantocellularis lateralis (PGCL); TPH2 levels in the raphé obscurus; and 5-HT1A binding density in 5 medullary nuclei that contain 5-HT neurons and 5 medullary nuclei that receive 5-HT projections.
Results Serotonin levels were 26% lower in SIDS cases (n = 35) compared with age-adjusted controls (n = 5) in the raphé obscurus (55.4 [95% confidence interval {CI}, 47.2-63.6] vs 75.5 [95% CI, 54.2-96.8] pmol/mg protein, P = .05) and the PGCL (31.4 [95% CI, 23.7-39.0] vs 40.0 [95% CI, 20.1-60.0] pmol/mg protein, P = .04). There was no evidence of excessive 5-HT degradation assessed by 5-HIAA levels, 5-HIAA:5-HT ratio, or both. In the raphé obscurus, TPH2 levels were 22% lower in the SIDS cases (n = 34) compared with controls (n = 5) (151.2% of standard [95% CI, 137.5%-165.0%] vs 193.9% [95% CI, 158.6%-229.2%], P = .03). 5-HT1A receptor binding was 29% to 55% lower in 3 medullary nuclei that receive 5-HT projections. In 4 nuclei, 3 of which contain 5-HT neurons, there was a decrease with age in 5-HT1A receptor binding in the SIDS cases but no change in the controls (age × diagnosis interaction). The profile of 5-HT and TPH2 abnormalities differed significantly between the SIDS and hospitalized groups (5-HT in the raphé obscurus: 55.4 [95% CI, 47.2-63.6] vs 85.6 [95% CI, 61.8-109.4] pmol/mg protein, P = .02; 5-HT in the PGCL: 31.4 [95% CI, 23.7-39.0] vs 71.1 [95% CI, 49.0-93.2] pmol/mg protein, P = .002; TPH2 in the raphé obscurus: 151.2% [95% CI, 137.5%-165.0%] vs 102.6% [95% CI, 58.7%-146.4%], P = .04).
Conclusion Compared with controls, SIDS was associated with lower 5-HT and TPH2 levels, consistent with a disorder of medullary 5-HT deficiency.
