Brain structure and function in primary adrenal insufficiency

Individuals with primary adrenal insufficiency (PAI), i.e., congenital adrenal hyperplasia (CAH) and autoimmune Addison’s disease (AAD), suffer from impaired production of the adrenal gland hormones cortisol and aldosterone, and in the case of AAD, also androgens. Replacement medication for these hormones is sub-optimal due to the difficulties in replicating the natural rhythms of cortisol secretion. The hormones are known to affect brain function via many mechanisms, and both pre- and postnatal hormone dysregulation may affect cognitive functioning, brain structure and brain function. Therefore, studying brain health in PAI is of interest and is needed to optimise treatment and patient wellbeing.

The present thesis investigated brain structure related to cognitive functioning in individuals with CAH, and cognitive functioning, brain structure and resting-state functional connectivity in individuals with AAD. We found that individuals with CAH have impairments in white matter microstructure, as well as cortical thinning of the frontoparietal network that was related to weaker performance on a visuospatial working memory task. On the other hand, individuals with AAD performed equally to control subjects on most measures of cognitive functions assessed with standardized tests during the lab-visit, but they self-reported executive function problems in daily life, which were related to experienced mental fatigue. As opposed to individuals with CAH, those with AAD did not have profound differences in the structure of the brain, apart from smaller total brain volumes. However, they displayed increased resting-state functional connectivity, particularly in primary visual regions and the orbitofrontal cortex. Our results suggest that the effects of adrenal hormone insufficiency affect individuals with CAH and AAD differently. This difference may be related to the onset of the disease, which is from conception for those with CAH and in adolescence or adulthood for those with AAD. Long-term follow-up studies are needed to assess whether the observed differences contribute to increased cognitive decline later in life and how to optimise replacement medication to sustain brain health.

List of scientific papers

I. van’t Westeinde, A., Karlsson, L., Thomsen Sandberg, M., Nordenström, A., Padilla, N. and Lajic, S. (2020). Altered gray matter structure and white matter microstructure in patients with congenital adrenal hyperplasia: relevance for working memory performance. Cerebral Cortex. 30(5):2777-2788.
https://doi.org/10.1093/cercor/bhz274

II. van’t Westeinde, A., Ström, S., Hirvikoski, T., Dahlqvist, P., Wahlberg, J., Gezelius, A., Kämpe, O., Bensing, S. and Lajic, S. (2022). Young adult Swedish patients with autoimmune Addison´s disease report difficulties with executive functions in daily life despite overall good cognitive performance. Psychoneuroendocrinology. 140, 105714.
https://doi.org/10.1016/j.psyneuen.2022.105714

III. van’t Westeinde, A., Padilla, N., Siqueiros Sanchez, M., Fletcher-Sandersjöö, S., Kämpe, O., Bensing, S. and Lajic, S. (2022). Brain structure in autoimmune Addison’s disease. Cerebral Cortex. 1-12.
https://doi.org/10.1093/cercor/bhac389

IV. van’t Westeinde, A., Padilla, N., Fletcher-Sandersjöö, S., Kämpe, O., Bensing, S. and Lajic, S. Increased resting-state functional connectivity in autoimmune Addison’s disease. [Manuscript]