, Volume 24, Issue 1–2, pp 46–61 | Cite as

Cell death in the human infant central nervous system and in sudden infant death syndrome (SIDS)

  • Natalie Ambrose
  • Michael Rodriguez
  • Karen A. Waters
  • Rita MachaalaniEmail author


The brainstem has been a focus of sudden infant death syndrome (SIDS) research with amassing evidence of increased neuronal apoptosis. The present study extends the scope of brain regions examined and determines associations with known SIDS risk factors. Immunohistochemical expression of cell death markers, active caspase-3 and TUNEL, was studied in 37 defined brain regions in infants (aged 1–12 months) who died suddenly and unexpectedly (SUDI). A semi-quantitative mean score of marker expression was derived for each region and scores compared between three SUDI subgroups: explained SUDI (eSUDI; n = 7), SIDS I (n = 8) and SIDS II (n = 13). In eSUDI, active caspase-3 scores were highest in several nuclei of the rostral medulla, and lowest in the hypothalamus and cerebellar grey matter (GM). TUNEL was highest in regions of the hippocampus and basal ganglia, and lowest in the thalamus and cerebellar GM. TUNEL scores were higher in SIDS II compared to eSUDI in the amygdala (p = 0.03) and 5/9 nuclei in the rostral medulla (p = 0.04 − 0.01), and higher in SIDS II compared to SIDS I in the amygdala (p < 0.01), putamen (p = 0.01), lentiform nucleus (p = 0.03) and parietal (p = 0.03) and posterior frontal (p = 0.02) cortex. Active caspase-3 was greater in the hypoglossal nucleus (p = 0.03) of SIDS I compared to eSUDI infants. Co-sleeping, cigarette smoke exposure and the presence of an upper respiratory tract infection in SIDS infants was associated with differences in marker expression. This study affirms the sensitivity of the brainstem medulla to cell death in SIDS, and highlights the amygdala as a new region of interest.


Apoptosis Caspase-3 Postnatal brain Sudden unexpected death in infancy TUNEL 



Arcuate nucleus


Cornu ammonis


Central nervous system


Cuneate nucleus


Dorsal motor nucleus of the vagus


Explained sudden unexpected death in infancy


Inferior olivary nucleus


Lateral reticular formation


Nucleus of the spinal trigeminal tract


Programmed cell death


Sudden infant death syndrome


Sudden unexpected death in infancy


Terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP-biotin nick end-labelling


Upper respiratory tract infection


Medial and spinal vestibular nuclei combined


Hypoglossal nucleus



The tissue used in this study was provided by the NSW Forensic and Analytical Science Service. The authors acknowledge the contribution of Arunnjah Vivekanandarajah in the staining of hippocampal sections. The authors acknowledge the facilities, and scientific and technical assistance of the Australian Microscopy and Microanalysis Research Faculty at the Australian Centre of Microscopy and Micro Analysis, University of Sydney.


This study was funded by philanthropy (The Miranda Belshaw Foundation, Australia).

Compliance with ethical standards

Conflict of interest

The authors declare they have no conflict of interest.

Ethical approval

Ethical approval was from the NSW health RPAH zone (X13-0038 and HREC/13/RPAH/54) and University of Sydney Ethic committees.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medicine, The Bosch Institute, Medical Foundations BuildingThe University of SydneySydneyAustralia
  2. 2.Department of PathologyThe University of SydneySydneyAustralia
  3. 3.The Children’s HospitalSydneyAustralia

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