Evidence of Climate Change Impact on Parkinson’s Disease

We have investigated the link between climate change and Parkinson’s diseases (PD) by contrasting variations between 1990 and 2016 of PD patients’ indices (prevalence, deaths, and disability-adjusted life years) and climate indices (warming and annual average temperature) for 185 countries. Countries have been clustered in four categories, depending on whether they had higher-than-median warming and higher-than-median temperature, and for each cluster variations in PD patients’ and climate indices have been studied. In the cluster of the 25 countries (home to about 900 million people) characterized by higher-than-average warming and higher-than-average temperature, we have found evidence of a correlation between more intense warming and higher variations. This statistical result is discussed and linked to other evidence reported in literature. To our knowledge, this is the rst time that a statistically-sound link between climate change and the epidemiological data of PD patients has been found and documented.


Parkinson's Disease And Climate Change
The Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder characterized classically by tremor, bradykinesia-akinesia, rigidity and balance de cit, and eventually by depression, cognitive and neurovegetative dysfunctions (Kalia and Lang, 2015). In 2016, PD worldwide affected more than 6 million subjects, while they were only 2. From such premises, an important question is whether there is any evidence that climate change can lead to an increase in PD cases. If this is the case, we should expect that countries with highest temperature increases have an enhanced prevalence of PD. Human beings as living endothermic organisms have indeed several features that can compensate for temperature changes, which are however altered in elderly or sick people (Grosiak et al., 2020). In particular, PD patients may exhibit a spectrum of thermoregulatory dysfunctions, which can be exacerbated by heat stress and heat waves (Coon et al., 2020). Although the increase in PD prevalence is well documented by literature reports (Vos et al., 2020), the link between global warming and the enhanced PD prevalence remains elusive. To our knowledge, it has not yet been reported a relationship between the mean temperature in these last years and the prevalence of neurodegenerative diseases. This could be due to the di culty or inappropriateness of collecting data (considering the quality of life in most poor world countries); moreover, data are still too recent and there is too much variability. Dorsey et al. (2018) listed the global, regional, and country-speci c variations, between 1990 and 2016, of 3 epidemiological indices related to PD patients: prevalence, deaths, and disability-adjusted life years (DALYs). They reported an increase in all 3 indices, and concluded that 'the global burden of PD has more than doubled'. Starting from Dorsey et al., and contrasting their PD data with climate data covering the same period (1990-2016), we aim to assess whether there is any relationship between the 1990-2016 PD patients' epidemiological variations and climate change-induced warming. Since we would expect that global warming could have a major effect on warmer countries, we have decided to compute, for each country, two climate indices: the warming between 1990 and 2016, and the country average temperature in 2016 as indicator of each country's climate. Standard, robust statistical methods are going to be applied to assess whether diachronic PD patients' epidemiological variations are more evident in warmer countries that had been exposed to more intense warming.    show that for all indices but deaths, the probability that the two distributions are similar is less than 2%, while for deaths it is 4.8%. In other words, at the 95% level we can reject the null hypothesis that there is not any difference between the distribution of the HT-HW countries, and the countries of the other 3 categories.

Methods
Epidemiological and climate data. Epidemiological data analysed (prevalence, deaths and DALYs) were -The 1990-2016 warming index, which is a function of the slope of the linear regression curve that tted the monthly 2-meter temperature data from January 1990 to December 2016; more precisely, it has been de ned as the 26-year warming, between 1990 and 2016, computed from the linear-tted curve (we used this index, rather than the difference between the annual average temperatures of 2016 and 1990, to represent in a more correct way the 26-year warming, and avoid the impact of annual variations).
According to these indices, countries with warmer climate have a higher value of T2016, and countries more affected by climate change have a higher warming index.

Discussion
The average age of the world population is increasing and with it all the diseases linked to aging. Environmental temperatures are increasing too, and therefore we are wondering more and more if there is a relationship between these events. In our work we, indeed, have found evidence of a link between climate change-induced temperature variations and PD patients' epidemiological data between 1990 and 2016. We show that for the countries characterized by warmer than average climate and by more intense warming between 1990 and 2016, there is a signi cant correlation between the warming index and the variations in the PD patients' epidemiological indices.
Considering the HT-HW countries, we nd both developing countries (e.g., Ethiopia, Somalia) and others with a high standard of living limited to the wealthiest social classes (e.g., Guatemala, Venezuela, Brazil, Kuwait, Oman), in which the majority of the population can be directly exposed to the effects of environmental heating. An average warming of few degrees implies that there is a higher probability of more intense and longer heat waves. So, if we consider the observed global average warming of about 1.2 degrees (from the pre-industrial level) in many countries, this has implied more frequent, longer and more intense heat waves that can have major impact on human health. For example, it is worth reminding the impact that the extended heat wave that hit Europe in the summer of 2003 had on mortality rates. For the future, a further warming of another 1-2 degrees could mean more frequent summer-2003-type of summers, and thus more heat-induced deaths.
From our ndings, it appears that chronic exposure to higher temperatures in environments that are already warmer than others correlate with the onset of neurodegenerative events of clinical relevance. It can be hypothesized that populations already exposed to higher temperatures have a thermoregulation system more prone to develop neuroin ammatory events (Bongioanni et al., 2021). A plethora of both molecular and metabolic features related to organ homeostasis (e.g., hypothalamus control, hormonal networks, heat shock proteins) is activated in living endothermic organisms that can compensate for temperature changes. However, some of those features can be altered during aging, diseases or excessive heat exposure leading to a greater predisposition to aggravation of neurodegenerative disease. Moreover, when the external temperature varies by even one degree due to enhanced global warming, an acclimatization process begins (Lim, 2020)  people, whose thermoregulation is compromised.
Our results are particularly important since the HT-HW countries are home of about 912 million people, which is about 12% of the world population (based on 2020 data). With the climate-induced warming projected to double in the next decades (IPCC 2014) unless a drastic reduction in greenhouse gas emissions is achieved, these and the other countries that will experience warmer climates could be affected by even larger increases than the one documented in this work.
Our ndings deserve to be con rmed by further studies using possibly larger diachronic databases relating to both climatic variations and epidemiological parameters of PD patients and other subjects suffering from neurodegenerative diseases. Work along these lines should be encouraged.   Table in Appendix A). The horizontal and vertical lines divide the countries in the 4 categories high/low temperature, high/low warming. The dotted inclined line shows the linear t of the warming index with respect to T2016 (y=-0.0011 x+0.052).

Figure 2
Warming index and DALYs correlation. HT-HW countries relationship between 1990-2016 variations of the PD indices and climate warming, for PD patients' deaths (top panel), prevalence (middle panel) and DALYs (bottom panel). Each dot represents one of the 25 HT-HW countries.