Heat-related illness and dementia: a study integrating epidemiological and experimental evidence

Abstract

Background: Heat-related illness (HRI) is commonly considered an acute condition, and its potential long-term consequences are not well understood. We conducted a population-based cohort study and an animal experiment to evaluate whether HRI is associated with dementia later in life.

Methods: The Taiwan National Health Insurance Research Database was used in the epidemiological study. We identified newly diagnosed HRI patients between 2001 and 2015, but excluded those with any pre-existing dementia, as the study cohort. Through matching by age, sex, and the index date with the study cohort, we selected individuals without HRI and without any pre-existing dementia as a comparison cohort at a 1:4 ratio. We followed each cohort member until the end of 2018 and compared the risk between the two cohorts using Cox proportional hazards regression models. In the animal experiment, we used a rat model to assess cognitive functions and the histopathological changes in the hippocampus after a heat stroke event.

Results: In the epidemiological study, the study cohort consisted of 70,721 HRI patients and the comparison cohort consisted of 282,884 individuals without HRI. After adjusting for potential confounders, the HRI patients had a higher risk of dementia (adjusted hazard ratio [AHR] = 1.24; 95% confidence interval [CI]: 1.19-1.29). Patients with heat stroke had a higher risk of dementia compared with individuals without HRI (AHR = 1.26; 95% CI: 1.18-1.34). In the animal experiment, we found cognitive dysfunction evidenced by animal behavioral tests and observed remarkable neuronal damage, degeneration, apoptosis, and amyloid plaque deposition in the hippocampus after a heat stroke event.

Conclusions: Our epidemiological study indicated that HRI elevated the risk of dementia. This finding was substantiated by the histopathological features observed in the hippocampus, along with the cognitive impairments detected, in the experimental heat stroke rat model.

Keywords: Amyloid plaque; Apoptosis; Cognitive deficits; Dementia; Epidemiology; Heat related illness; Hippocampus; Neurodegeneration.

Fig. 1

The flowchart of this study. HRI, heat-related illness

Fig. 2

Cumulative incidence rates of dementia in the HRI patients and the non-HRI patients. HRI, heat-related illness

Fig. 3

EHS causes neurobehavioral disorders. The behavioral test battery included two tests for learning and memory (radial maze and passive avoidance) and one motor test (rotarod). These tests were performed before the stress (pre-EHS) and at the onset (Onset), as well as on day 3 (D3), day 7 (D7), and day 14 (D14) of the post-EHS period for both the experimental (EHS) and normal control (NC) groups of rats. Compared to the NC group, the (A) retention time (latency period, seconds), (B) working memory errors, and (C) reference memory errors on the radial-arm maze test were significantly increased in EHS groups. On the passive avoidance test, the retention latency (D) was significantly shorter, and the number of errors (E) was significantly higher in EHS rats than in NC animals from Onset to D14. The EHS groups had significantly decreased (F) the latency (s) in the rotarod test compared to the NC group. Data were presented as mean ± standard deviation

Fig. 4

Histological analysis in NC rats and EHS rats and correlation analysis between cognitive test and histological effects. The histology of the hippocampal regions CA1, CA2, CA3, and the dentate gyrus in NC and EHS rats was examined using HE staining (A and B), NeuN + Fluoro-Jade B staining (C and D), thioflavin-S staining (E and F), and NeuN + TUNEL staining (G and H). A correlation analysis was also conducted between the passive avoidance test and various staining methods, including HE (I), NeuN + Fluoro-Jade B (J), thioflavin-S (K), and NeuN + TUNEL (L). A total of six animals were used for each experimental group. Data presented as mean ± standard deviation