Background/Purpose:  Cognitive dysfunction including depression-like symptoms is a frequent comorbidity of rheumatoid arthritis (RA)¹. Mechanisms that have been linked to cognitive impairments in the general population such as endothelial dysfunction, systemic inflammation or functional limitations have particular relevance for RA. Brain-derived neurotrophic factor (BDNF) is abundantly expressed by endothelial cells and neurons in the brain, where it plays a crucial role in cognition. Surprisingly, the impact of RA on BDNF is poorly documented. Available studies reported higher circulating BDNF levels in RA patients than controls². In order to gain further insights into the interplay between RA, cognitive dysfunction and BDNF, we explored brain and circulating BDNF levels in a rat model of RA.

Methods:

Adjuvant-induced arthritis (AIA) was used as a rat model of RA. Using Western blot analysis, BDNF expression were measured in two brain regions involved in cognition (frontal cortex and hippocampus) and in the microvasculature isolated from the whole cortex. BDNF levels were measured in serum and peripheral blood mononuclear cells (PBMC) and serum TNFα and IL-1β levels were measured in serum using ELISA and the Magpix® Luminex kit, respectively. Disease activity was assessed from the arthritis score, depression-like symptoms from the sugar preference test and physical limitations from mobility in activity chambers. All the parameters were evaluated on day 29-32 post-immunization (n=40) and in corresponding non-AIA control rats (n=28). Data were analyzed using non parametric tests. P<0.05 was considered statistically significant.

Results:

AIA resulted in physical limitations and depression-like symptoms. These alterations coincided with a significant decrease in BDNF levels in the frontal cortex (- 70%) and hippocampus (-50%) as well as in the cerebrovasculature (-40%). Conversely, BDNF levels in serum and in PBMC were higher in AIA than in controls (+30% and +75%, respectively). Serum but not brain BDNF levels were positively associated with the arthritis score and circulating TNF alpha levels. No association was observed with IL-1β.

Conclusion:  The present results support the involvement of brain BDNF depletion in AIA-induced impaired cognition and identify TNFα as a potential actor in AIA-induced rise in circulating BDNF levels. From a clinical perspective, our data refute serum BDNF level as a reliable marker of brain BDNF levels or impaired cognition in RA. Given the evidence of low cerebrovascular BDNF levels in AIA interactions between cerebral endothelial dysfunction, cerebrovascular BDNF and cognition should be explored further. References:

1. Shin SY, Katz P, Wallhagen M, Julian L (2012) Cognitive impairment in persons with rheumatoid arthritis. Arthritis care & research 64:1144-1150. 2. Grimsholm O, Rantapaa-Dahlqvist S, Dalen T, Forsgren S (2008) BDNF in RA: downregulated in plasma following anti-TNF treatment but no correlation with inflammatory parameters. Clinical rheumatology 27:1289-1297.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impaired-cognition-is-linked-to-brain-depletion-in-brain-derived-neurotrophic-factor-levels-in-a-rat-model-of-rheumatoid-arthritis/