Link to original article in JAMA
Tumor Necrosis Factor (TNF) Inhibitor use Associated with Increased Risk for Central Demyelinating Diseases
Researchers from the Mayo Clinic have published an article in JAMA about the results of a recent case-control study of 212 patients (106 patients with inflammatory CNS events and 106 control participants without such events) suggesting that exposure to tumor necrosis factor inhibitors is associated with an increased risk of inflammatory central nervous system events such as optic neuritis, transverse myelitis and multiple sclerosis, and neuromyelitis optica spectrum disorder. The authors discuss some possible mechanisms to account for this paradoxical response including upregulation of TNF expression within the CNS. Patients with central demyelinating disease may want to discuss these findings with their neurologist before using tumor necrosis factor inhibitors.
Link to original article in JAMA
Occupational exposures to solvents, pesticides and metals associated increased risk for sporadic ALS
The results of a recently published peer-reviewed population-based case-control study by Filippini and colleagues (2020) who looked at the risk for sporadic Amyotrophic Lateral Sclerosis (ALS) among people living and working in four Italian provinces (Catania, Modena, Novara, and Reggio Emilia) has revealed increased risks for ALS among persons with histories of occupational exposure to paint thinners, fungicides and metals including lead and mercury. A longer duration of working in the agricultural sector was also associated with an increased of developing ALS. Subjects reporting a history of ALS in their relatives were excluded from the study.
These findings add to the growing body of literature implicating occupational exposures to neurotoxicants in the onset of sporadic ALS.
Link to original article in PubMed
Dickerson and colleagues (Eur J Epidemiol, 2020) have shown that among ALS patients from the Danish National Patient Registry men exposed to mixtures of solvents are an increased risk for developing ALS. These findings add to the growing body of evidence suggesting solvent exposure is a disease modifying risk factor in ALS.
Link to original article
Colbeth and colleagues (2019) analyzed questionnaire data gathered from Fire Department of the City of New York (FDNY) World Trade Center (WTC)-exposed firefighters and emergency medical service (EMS) workers to evaluate the risk for peripheral neuropathy based on Diabetic Neuropathy Symptom scores. While these questionnaire data do not provide objective measures they do nevertheless suggest that working at the WTC site increases an individual's risk for developing peripheral nervous system dysfunction with aging 15 years after these workers were exposed to particulates and gases while working at the WTC after 9/11.
Future studies are needed to ascertain if these symptoms of peripheral nerve damage are associated with the increased risk for cognitive deficits and increased accumulation of amyloid and tau pathology in the brain observed by Clouston and colleagues.
Link to Colbeth et al 2019 in PubMed
Link to Alzforum article reporting on Clouston et al findings
A new study by Cacciottolo and colleagues indicates that J20-APPswe mice exposed to nano-sized traffic-related particulate matter (nPM) for 150 hours have increased markers of lipid oxidation (4-HNE) and increased the pro-amyloidogenic processing of APP in lipid raft fractions in cerebral cortex but not in the cerebellum a find which parallels that seen for selectivity of Aβ deposits in Alzheimer's disease (AD). In addition, in vitro, studies showed that nPM induced similar oxidative responses in N2a-APPswe cells, which showed dose-dependent production of NO, oxidative damage (4-HNE, 3NT), and lipid raft alterations of APP with increased Aβ peptides. Furthermore, treatment with the antioxidant N-acetyl-cysteine (NAC) attenuated nPM-induced oxidative damage and alterations of APP processing.
These findings provide additional evidence of the mechanisms via which exogenous toxicants found in the environment and workplace interact with neuropathological mechanisms implicated in the onset and progression of AD.
Link to orignal article in PubMed
A group of researchers from Hawaii (Ross et al., 2019) investigating subjects from the Honolulu-Asia Aging Study (HAAS) has obsevered that the prevalence of Lewy neuropathology is nearly doubled in the presence versus the absence of heptachlor epoxide. Similar but slightly weaker associations were observed with two other organochlorine compounds such as hexachlorobenzene and α-chlordane which are both metabolized to heptachlor epoxide. These results were significant after exclusion of subjects with Parkinson's disease (PD). These findings implicate organochlorine compounds in the severity of Lewy neuropathology in subjects without PD. These findings also reveal a potential point of interaction between organochlorine exposure and a neuropathological process implicated in PD.
Link to citation in PubMed
A new study by Gamache and colleagues (2019) indicates that exposure to pesticides and toxic metals were both associated with an earlier onset of Parkinson's disease. This effect was greater with higher levels of exposure, both in terms of frequency and proximity.
These findings are strikingly to similar to the observations of Ratner and colleagues 2014 who also observed a younger age at onset of sporadic PD among subjects occupationally exposed to metals and pesticides.
Both studies used the same exposure history questionnaire and the Ward and Gibb diagnostic criteria for selection of subjects for research in PD. While the Ratner study looked at duration of exposure, the Gamache study looked at proximity and frequency. These two complimentary studies provide important insight into the role of chemical exposure duration and intensity in the age at onset of PD. Another related study using the same inclusion criteria by Wilk and colleagues (2006) found a younger age at onset of PD among subjects with familial PD exposed to herbicides who also had a single nucleotide polymorphism in a gene that codes for the enzyme glutathione-S-transferase (GST). Future studies designed to further elucidate the relationships between genetic factors that influence drug metabolism and exposure history are needed.
Based on recent observations by Harischandra and colleagues (2019) showing that exosomes isolated from serum of welders have a higher seeding capacity and misfolded α-synuclein protein content compared to exosomes isolated from healthy controls, we have proposed that future research should be designed to evaluate the link between age at onset of idiopathic PD and exosomal α-synuclein in the serum of welders (see Rutchik and Ratner, 2019).
Dr. Ratner's commissioned work for the Workplace Safety Insurance Board (WSIB) of Ontario, Canada (a.k.a. "the Ratner Paper") set the standard used by the Workplace Safety Insurance Appeals Tribunal (WSIAT) for occupational chemical exposure claims related to age at onset of PD.
Link to Gamache et al 2019 article.
Link to Ratner et al. 2014 article.
Link to Harischandra et al 2019 article.
Link to Wilk et al 2006 article.
Link to Rutchik and Ratner 2019 article.
LInk to WSIAT ruling based opt "the Ratner Paper".
New data supports connection between mitochondrial CYP2D6 activation of chemicals to toxic intermediates and Parkinson's disease risk
A new study by Narayan Avadhani and Mrittika Chattopadhyay, published in the Journal of Biological Chemistry, suggests that the enzyme, mitochondrial cytochrome P4502D6, plays a role in Parkinson's disease.
Previous studies have implicated MPTP and similar toxic compounds in Parkinson's disease risk. Earlier work by Avadhani and colleagues has shown that CYP2D6 plays a role in metabolizing MPTP to the toxic metabolite MPP. The results of their new study indicate that toxicants resembling MPTP found in tobacco smoke, alcohol, and some foods are also activated by CYP2D6. This route of metabolic activation was shown in a mouse model, to result in neuronal damage and oxidative stress, and symptoms akin to Parkinson's. "CYP2D6 is known to play a role in influencing the activity of a number of drugs," said Avadhani.
To learn more about the connection between neurotoxicant metabolism and PD risk and age at onset of this disease read my review on the topic here.
Link to original news story here
Link to article in JBC
Maureen Salamon from WebMD is reporting on the results of a new study indicating that patients younger than age 65 years old who have previously been diagnosed with bipolar disorder are at an increased risk for developing Parkinson's disease. It is well recognized that many of the medications used to treat bipolar disorder can cause iatrogenic drug-induced parkinsonism suggesting that there may be a point of mechanistic interaction between these medications and age at onset of Parkinson's disease.
Link to story on WedMD
Link to original article in Neurology.
Tauopathy is neuropathological finding associated with Alzheimer's disease. A new study from a group of researchers at the MD Anderson Cancer Center suggests that the neurotoxic side effects of the chemotherapy agent cisplatin accelerates formation of Tau-1 clusters and decreases levels of the post-synaptic marker PSD95 and of the presynaptic marker synaptophysin in the hippocampus. These findings demonstrate for the first time that certain neurotoxic chemotherapy agents can accelerate development of tauopathy and loss of synaptic integrity in the hippocampus. This finding demonstrates how neurotoxic chemicals can modify the subclinical and clinical course of a neurodegenerative disease associated with memory dysfunction. These results are of importance to patients diagnosed with cancer who also have a family history of Alzheimer's disease. If you have any concerns about these findings please discuss these with your treating physician.
Link to publication
Dr. Marcia Ratner shares and reviews the news.