Moon Han

Parkinson’s disease (PD) is a complex neurodegenerative disorder influenced by age, genetic predispositions, and environmental exposures, with a growing global incidence. This review aims to summarize findings from ATSDR Toxicological Profiles, EPA Risk Assessments, and other sources of peer-reviewed literature to examine the potential associations between PD and select metals, pesticides, and chlorinated organic compounds. Additionally, it explores using computational toxicology methods to elucidate the interactions between specific chemicals, associated genes, and their possible roles in PD. A total of 29 substances were identified to be neurotoxic with direct or probable association with PD. Risk of disease onset or symptom exacerbation of PD has been linked to exposures to neurodegenerative metals, pesticides, chlorinated organic compounds, and other environmental toxicants, alongside intrinsic factors such as genetic predisposition and aging. Supporting evidence from neurotoxicological studies directly or possibly associated with PD are summarized in referenced toxicological profiles and EPA risk assessments. Genotoxic endpoints evaluated in exposure-induced neurodegeneration including oxidative stress, DNA strand breaks, mitochondrial dysfunction, impaired DNA repair, and telomere alterations may play a critical role in linking environmental exposures to PD pathogenesis. Although these endpoints represent imperative data gaps between environmental and genetic risk factors for PD, isolating individual substances may not be necessary for prevention, as many co-occur at contaminated sites or within certain occupations. Further research is needed to clarify causal relationships between environmental exposure and genotoxic endpoints seen in neurodegenerative processes that can also be seen in PD for consideration in the development of preventive and therapeutic strategies.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease that typically results in death within 3–5 years from symptom onset. However, little is known about the environmental exposures, clinical aspects, or social determinants of health factors that may be associated with the disease. Multistep modeling has been previously applied to cancer research, demonstrating a linear relationship between logs of incidence and age. This method may help to understand the mechanisms involved in the development of ALS in the United States (e.g., environmental exposures, genetic mutations). We aim to assess whether ALS is a multistep process among patients enrolled in the largest ALS registry in the world—the United States' National ALS Registry.Methods: Incident ALS cases, defined as confirmed and likely, cases between 2012 and 2019 were obtained from the National ALS Registry. Age‐standardized incidence was calculated for all cases and by sex. The log incidence of ALS was regressed against the log of age (years) at case determination, on average, for each year and by sex.Findings: Between 2012 and 2019, there was a mean of 5253 incident ALS cases (confirmed or likely) per year. We identified a linear relationship between the log of the average incidence and log age overall (r² = 0.99), for men (r² = 0.99), and for women (r² = 0.98). The incidence slope estimates were 4.8 (95% CI: 4.4–5.1) overall, 4.7 (95% CI: 4.4–5.1) for men, and 5.0 (95% CI: 4.5–5.5) for women.Interpretation: The linear relationships observed overall, for men, and for women are consistent with a multi‐step process. The slope estimates, on average, are approximately 5.0, which suggests that the development of ALS is a six‐step process. Further investigation of these steps can elucidate potential risk factors and treatments for ALS.

Metal exposure is a potential risk factor for amyotrophic lateral sclerosis (ALS). Increasing evidence suggests that elevated levels of DNA damage are present in both familial (fALS) and sporadic (sALS) forms of ALS, characterized by the selective loss of motor neurons in the brain, brainstem, and spinal cord. However, identifying and differentiating initial biomarkers of DNA damage response (DDR) in both forms of ALS remains unclear. The toxicological profiles from the Agency for Toxic Substances and Disease Registry (ATSDR) and our previous studies have demonstrated the influence of metal exposure-induced genotoxicity and neurodegeneration. A comprehensive overview of the ATSDR’s toxicological profiles and the available literature identified 15 metals (aluminum (Al), arsenic (As), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), mercury (Hg), nickel (Ni), selenium (Se), uranium (U), vanadium (V), and zinc (Zn)) showing exposure-induced genotoxicity indicators associated with ALS pathogenesis. Genetic factors including mutations seen in ALS types and with concomitant metal exposure were distinguished, showing that heavy metal exposure can exacerbate the downstream effect of existing genetic mutations in fALS and may contribute to motor neuron degeneration in sALS. Substantial evidence associates heavy metal exposure to genotoxic endpoints in both forms of ALS; however, a data gap has been observed for several of these endpoints. This review aims to (1) provide a comprehensive overview of metal exposure-induced genotoxicity in ALS patients and experimental models, and its potential role in disease risk, (2) summarize the evidence for DNA damage and associated biomarkers in ALS pathogenesis, (3) discuss possible mechanisms for metal exposure-induced genotoxic contributions to ALS pathogenesis, and (4) explore the potential distinction of genotoxic biomarkers in both forms of ALS. Our findings support the association between metal exposure and ALS, highlighting under or unexplored genotoxic endpoints, signaling key data gaps. Given the high prevalence of sALS and studies showing associations with environmental exposures, understanding the mechanisms and identifying early biomarkers is vital for developing preventative therapies and early interventions. Limitations include variability in exposure assessment and the complexity of gene–environment interactions. Studies focusing on longitudinal exposure assessments, mechanistic studies, and biomarker identification to inform preventative and therapeutic strategies for ALS is warranted.

To summarize amyotrophic lateral sclerosis (ALS) incidence in all 50 states and the District of Columbia from 2012 to 2019. In 2010, the Agency for Toxic Substances and Disease Registry (ATSDR) launched the congressionally mandated National ALS Registry (Registry) to determine the incidence and prevalence of ALS within the United States, characterize demographics, and identify potential risk factors. This is the first analysis of state-level ALS incidence estimates for all 50 states and the District of Columbia. ALS is not a notifiable disease in the United States. As such, the Registry identifies cases using existing national administrative databases (Medicare, Veterans Health Administration, and Veterans Benefits Administration), and a secure web portal that identifies cases not included in the national databases. Confirmed and likely cases are deduplicated and counted as incident cases for the first year they are identified using a validated algorithm. Incident counts, incident rates, and rate ratios were then calculated. State-level age-adjusted overall incidence rates for 2012 to 2019 ranged from 0.65 per 100,000 persons (Alaska) to 2.25 per 100,000 persons (Vermont), with an overall incidence of 1.44 per 100,000 persons in the United States. New England and the upper Midwest regions had higher incidence rates than national rates. These findings summarize the incidence of ALS for all 50 states from 2012 to 2019. This is a continuing effort to identify ALS cases nationally. The establishment of the Registry allows for epidemiological analyses of ALS data and the assessment of potential risk factors.

Objective: To characterize the participant demographics in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database compared with the web-portal National Amyotrophic Lateral Sclerosis (ALS) Registry (the Registry). Methods: Demographics and ALS symptom information were compared between the self-reported registrant data in the Registry web portal (2010–2021) and the latest available PRO-ACT data (updated August 2022), which is a collection of clinical trials data. Results: Greater percentages of younger (≤ 59 years old) but smaller percentages of older (60 + years old) participants were represented in PRO-ACT compared to Registry. Enrollment for minority race groups was greater in the Registry portal data, but race information was largely missing/unknown in PRO-ACT database. Median age at the time of diagnosis and age at the time of symptom onset were significantly higher for Registry enrollees compared to the participants of PRO-ACT. Symptom onset sites were similarly reported, but duration between self-noted symptom onset and diagnosis was slight, but significantly longer for the Registry enrollees (11 vs. 9 months). Hispanic were as likely as non-Hispanic to participate in research studies, based on the Registry data. Conclusion: There was a notable difference in the age distribution and minority representation of enrollees between the PRO-ACT and Registry study populations. Age distribution in the PRO-ACT database skewed to a younger and less diverse cohort. Despite the clinical heterogeneity and complex disease mechanism of ALS, identifying the underrepresented demographic niche in the PRO-ACT and Registry study populations can help improve patient participation and criteria for patient selection to enhance generalizability.

Objective: To summarize the prevalence of ALS in all 50 states and Washington, DC in the United States from 2011 to 2018 using data collected and analyzed by the National ALS Registry. In October 2010, the federal Agency for Toxic Substances and Disease Registry (ATSDR) launched the congressionally mandated Registry to determine the incidence and prevalence of ALS within the USA, characterize the demographics of persons with ALS, and identify the potential risk factors for the disease. This is the first analysis of state-level ALS prevalence estimates. Methods: ALS is not a notifiable disease in the USA, so the Registry uses a two-pronged approach to identify cases. The first approach uses existing national administrative databases (Medicare, Veterans Health Administration, and Veterans Benefits Administration). The second method uses a secure web portal to gather voluntary participant data and identify cases not included in the national administrative databases. Results: State-level age-adjusted average prevalence from 2011-2018 ranged from 2.6 per 100,000 persons (Hawaii) to 7.8 per 100,000 persons (Vermont), with an average of 4.4 per 100,000 persons in the US. New England and Midwest regions had higher prevalence rates than the national average. Conclusions: These findings summarize the prevalence of ALS for all 50 states from 2011 to 2018. This is a continuing effort to identify ALS cases on a national population basis. The establishment of the National ALS Registry has allowed for epidemiological trends of this disease and the assessment of potential risk factors that could cause ALS.

Background: Researchers face challenges in patient recruitment, especially for rare, fatal diseases such as amyotrophic lateral sclerosis (ALS). These challenges include obtaining sufficient statistical power as well as meeting eligibility requirements such as age, sex, and study proximity. Similarly, persons with ALS (PALS) face difficulty finding and enrolling in research studies for which they are eligible. Objective: The aim of this study was to describe how the federal Agency for Toxic Substances and Disease Registry’s (ATSDR) National ALS Registry is linking PALS to scientists who are conducting research, clinical trials, and epidemiological studies. Methods: Through the Registry’s online research notification mechanism (RNM), PALS can elect to be notified about new research opportunities. This mechanism allows researchers to upload a standardized application outlining their study design and objectives, and proof of Institutional Review Board approval. If the application is approved, ATSDR queries the Registry for PALS meeting the study’s specific eligibility criteria, and then distributes the researcher’s study material and contact information to PALS via email. PALS then need to contact the researcher directly to take part in any research. Such an approach allows ATSDR to protect the confidentiality of Registry enrollees. Results: From 2013 to 2019, a total of 46 institutions around the United States and abroad have leveraged this tool and over 600,000 emails have been sent, resulting in over 2000 patients conservatively recruited for clinical trials and epidemiological studies. Patients between the ages of 60 and 69 had the highest level of participation, whereas those between the ages of 18 and 39 and aged over 80 had the lowest. More males participated (4170/7030, 59.32%) than females (2860/7030, 40.68%). Conclusions: The National ALS Registry’s RNM benefits PALS by connecting them to appropriate ALS research. Simultaneously, the system benefits researchers by expediting recruitment, increasing sample size, and efficiently identifying PALS meeting specific eligibility requirements. As more researchers learn about and use this mechanism, both PALS and researchers can hasten research and expand trial options for PALS.

BACKGROUND Researchers face challenges in patient recruitment, especially for rare, fatal diseases such as amyotrophic lateral sclerosis (ALS). These challenges include obtaining sufficient statistical power as well as meeting eligibility requirements such as age, sex, and study proximity. Similarly, persons with ALS (PALS) face difficulty finding and enrolling in research studies for which they are eligible. OBJECTIVE The aim of this study was to describe how the federal Agency for Toxic Substances and Disease Registry’s (ATSDR) National ALS Registry is linking PALS to scientists who are conducting research, clinical trials, and epidemiological studies. METHODS Through the Registry’s online research notification mechanism (RNM), PALS can elect to be notified about new research opportunities. This mechanism allows researchers to upload a standardized application outlining their study design and objectives, and proof of Institutional Review Board approval. If the application is approved, ATSDR queries the Registry for PALS meeting the study’s specific eligibility criteria, and then distributes the researcher’s study material and contact information to PALS via email. PALS then need to contact the researcher directly to take part in any research. Such an approach allows ATSDR to protect the confidentiality of Registry enrollees. RESULTS From 2013 to 2019, a total of 46 institutions around the United States and abroad have leveraged this tool and over 600,000 emails have been sent, resulting in over 2000 patients conservatively recruited for clinical trials and epidemiological studies. Patients between the ages of 60 and 69 had the highest level of participation, whereas those between the ages of 18 and 39 and aged over 80 had the lowest. More males participated (4170/7030, 59.32%) than females (2860/7030, 40.68%). CONCLUSIONS The National ALS Registry’s RNM benefits PALS by connecting them to appropriate ALS research. Simultaneously, the system benefits researchers by expediting recruitment, increasing sample size, and efficiently identifying PALS meeting specific eligibility requirements. As more researchers learn about and use this mechanism, both PALS and researchers can hasten research and expand trial options for PALS.

Various diets and food components have been implicated as one of the environmental factors associated with inflammatory bowel disease (IBD). Patients are often recommended nutritional guidelines to manage disease symptoms. However, the current food consumption pattern of US adults with IBD that are nationally representative is unclear. A secondary analysis of National Health Interview Survey 2015 was performed to characterize the estimated US adults with IBD and their food intake and consumption frequency using bivariate and multivariate logistic regression. Fries were consumed by a greater number of people with IBD. IBD population drank less 100% fruit juice and ate more cheese and cookies than non-IBD population. Intake of fries (OR 1.60, 95% CI 1.14–2.25) and sports and energy drinks (OR 1.46, 95% CI 1.07–1.97) and more frequent drinking of regular soda were significantly associated with the likelihood of having been told one have IBD, while popcorn (OR 0.73, 95% CI 0.548–0.971) and milk (OR 0.70, 95% CI 0.497–0.998) were associated with smaller odds, adjusting for covariates. Foods typically labeled as junk food were positively associated with IBD. Nonetheless, of the assessed 26 foods, we found eating patterns between IBD and non-IBD population to be mostly analogous. It is unclear whether the results reflect potential change in food intake in IBD population long before the survey interview. Understanding the role of food intake in IBD risk/prevalence would benefit from identifying other environmental factors (i.e. food desert), food processing (i.e. frying), and potential bioactive food components that can induce intestinal inflammation that can increase the individual’s susceptibility to IBD.