Presymptomatic geographical distribution of ALS patients suggests the involvement of environmental factors in the disease pathogenesis

Abstract

Background Given that the pathogenetic process of ALS begins many years prior to its clinical onset, examining patients’ residential histories may offer insights on the disease risk factors. Here, we analyzed the spatial distribution of a large ALS cohort in the 50 years preceding the disease onset. Methods Data from the PARALS register were used. A spatial cluster analysis was performed at the time of disease onset and at 1-year intervals up to 50 years prior to that. Results A total of 1124 patients were included. The analysis revealed a higher-incidence cluster in a large area (435,000 inhabitants) west of Turin. From 9 to 2 years before their onset, 105 cases were expected and 150 were observed, resulting in a relative risk of 1.49 (P = 0.04). We also found a surprising high number of patients pairs (51) and trios (3) who lived in the same dwelling while not being related. Noticeably, these occurrences were not observed in large dwellings as we would have expected. The probability of this occurring in smaller buildings only by chance was very low (P = 0.01 and P = 0.04 for pairs and trios, respectively). Conclusions We identified a higher-incidence ALS cluster in the years preceding the disease onset. The cluster area being densely populated, many exposures could have contributed to the high incidence ALS cluster, while we could not find a shared exposure among the dwellings where multiple patients had lived. However, these findings support that exogenous factors are likely involved in the ALS pathogenesis.

Update on recent advances in amyotrophic lateral sclerosis

“…There are weaker or conflicting data for other putative environmental risk factors [ 1 ]. Nevertheless, a recent study on the geographical distribution of presymptomatic ALS patients revealed higher-incidence cluster areas, supporting the idea that exogenous factors may be involved in the ALS pathogenesis [ 86 ]. This hypothesis is in line with the results of another recent study focused on ALS incidence among immigrants in Sweden, which found that the risk of ALS was the same as native Swedish only in second-generation individuals, while it was lower in first-generation people [ 87 ].…”

Hereditary Transthyretin Amyloidosis (hATTR) with Polyneuropathy Clusters Are Located in Ancient Mining Districts: A Possible Geochemical Origin of the Disease

“…Finally, we compare the geochemistry at the different hATTR clusters and attempt to find common features that could be related to hATTR pathogenesis. It has previously been argued that some neurodegenerative diseases could be related to metal exposure [14][15][16][17], possibly of geochemical origin [18,19]. Here, we investigate and discuss if such metal exposure could be a potential contributing factor for hATTR onset.…”

“…Even though significant progress has been made in understanding-and treating-hATTR at the molecular level, the mechanism of pathogenesis and the overall origin of the disease remain unclear [12,13]. It has previously been argued that some neurodegenerative diseases could be related to metal exposure [14][15][16][17], possibly of geochemical origin [18,19]. Here, we investigate and discuss if such metal exposure could be a potential contributing factor for hATTR onset.…”

“…It has previously been argued that some neurodegenerative diseases could be related to metal exposure [ 14 , 15 , 16 , 17 ], possibly of geochemical origin [ 18 , 19 ]. Here, we investigate and discuss if such metal exposure could be a potential contributing factor for hATTR onset.…”

Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

“…Finally, we discuss the known environmental risk factors and highlight how they participate in protein aggregation and their relevance to copper and protein aggregation. This is a key point as much of the cause of SALS appears to be environmental, as demonstrated by hotspots of increased ALS incidence or ALS risk-associated occupations in many countries ( Caller et al, 2009 ; Henry et al, 2015 ; Goutman et al, 2022 ; Vasta et al, 2023 ). In this regard the most notable risk factors seem to be related with contamination of food or water sources with plant and algal toxins, and also heavy metals ( Newell et al, 2022 ), all of which either enhance protein aggregation or interact with copper or cuproproteins in a detrimental manner ( Dunlop et al, 2013 ; Jaishankar et al, 2014 ; Sheykhansari et al, 2018 ; Balali-Mood et al, 2021 ; Diaz-parga et al, 2021 ).…”