Dr. Marcia Ratner of Neurotoxiants.com and Dr. James Hendrix of LuMind IDSC were recently interviewed by Dr. Hackie Reitman of DifferentBrains about their thoughts on the state of the art in Alzheimer's research.
Geospatially Estimating of Exposure to Crop-Applied Pesticides finds Increased Risk for Amyotrophic Lateral Sclerosis
A large study by Andrew and colleagues looking at the risk for Amyotrophic Lateral Sclerosis (ALS) based on geospatially estimating exposure to crop-applied pesticides has found an association with several neurotoxic herbicides, insecticides, and fungicides. The study looked at residence at diagnosis of approximately 26,000 nationally distributed ALS patients, and matched non-ALS controls. The he residency data was then related to pesticide exposure risk based on county-level U.S. Geological Survey data on applications of 423 pesticides. The authors concluded that's their findings are consistent with the hypothesis that certain pesticides have neurotoxic effects that increase risk of neurodegenerative disease. Although this study did not look at duration or magnitude of pesticide exposure as this relates to age at onset of ALS, it nevertheless provides additional support for neurotoxic chemical exposures as risk factors for this neurodegenerative disease.
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Altered Hippocampal Response to Systemic Administration of an α5 type GABA-A Receptor Modulator in a Rat Model of Alzheimer’s disease
α5 subunit containing GABA type A receptors (a5GABAARs) are highly expressed in the hippocampus of humans and animals. The functioning of these receptors is altered in neurodevelopmental disorders including autism and by neuroinflammation and injuries to the brain (reviewed by Jacobs 2019). Ratner and colleagues (Heliyon, 2021) show for the first time that systemic administration of a5IA, a selective negative modulator of a5GABAARs, increases peak ripple amplitudes in wild type adult rats but has no effect on peak ripple amplitudes in the TgF344-AD rat model of Alzheimer's disease which also shows elevated plasma concentrations of AB42 and AB40 during the prodromal state of the disease when memory function is still intact. These findings demonstrate the selective sensitivity of the healthy versus diseased hippocampus to chemicals that modulate inhibitory neurotransmission. These findings also indicate that tonic inhibitory neurotransmission is altered in this highly translational rat model of Alzheimer's disease.
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Alzheimer's patients treated with ANVS401 showed significant improvement in cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog11). ANVS401 also significantly increased speed, coordination and motor function in Parkinson's patients enrolled in in this trial. ANVS401acts by improving axonal transport. Neurotoxic chemicals that disrupt axonal transport such as n-hexane are implicated in Parkinson's (see Pezzoli et al., 1995). Reducing exposure to these chemicals is associated with an increase in the age at onset of PD (see Pezzoli et al., 2014). These findings add additional support to the role of chemical exposures as disease modifiers in neurogenerative disease.
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I am pleased to share our most recent publication which appears in the America Journal of Industrial Medicine titled "A rare case of Holmes tremor in a worker with occupational carbon monoxide poisoning". In this report we present a rare case of toxic encephalopathy and Holmes-type tremor, in a previously healthy 53-year-old man who was exposed to carbon monoxide while using a concrete saw in a small unventilated space. Holmes tremor is characterized by resting, as well as postural and kinetic/intentional components. Specific lesions sites associated with Holmes tremor include the cerebellum, red nucleus, thalamus, and globus pallidus. The globus pallidus is also vulnerable to carbon monoxide poisoning. This patient's symptoms were ameliorated with the D2 preferring dopamine receptor agonist ropinirole. This case report serves as reminder of the dangers associated with exposure to carbon monoxide in occupational settings.
Link to citation in PubMed
Working as a mechanic, painter and construction worker associated with 2-fold increased risk of Amyotrphic Lateral Sclerosis.
A new report appearing in Muscle and Nerve by Angeline Andrew and other members of Elijah Stommel's team at Dartmouth indicates that exposure to the heavy metal neurotoxicant lead and working as a mechanic, painter or construction worker (jobs with increased risk for exposure to industrial chemicals) are associated with greater risk for ALS. Head injury and electrical burns were also associated with an increased risk for ALS.
Although this study, which was funded by the Centers for Disease control (CDC) and the Agency for Toxic Substances and Disease Registry (ATSDR) did not look at duration or intensity of exposure in relationship to age at onset of symptoms, it nevertheless adds to the growing body of literature implicating prior exposure to neurotoxic chemicals such a lead and industrial solvents found in paints in the risk for developing ALS.
Link to original article in Muscle and Nerve
A new prospective cohort study by Diana Younan and colleagues published in the journal Neurology has found that older women without dementia who are exposed later in life to air pollution consisting of microscopic particles of chemicals, smoke, dust and other pollutants < 2.5 μm in diameter have an increased risk for neuroanatomical changes associated with Alzheimer's disease (AD). The study used MRI data combined with supervised machine learning to measure brain atrophy in areas vulnerable to AD. The observed increased risk could not be explained by geographic region; race; ethnicity; highest education level obtained; smoking or alcohol use; physical activity; BMI scores; diabetes; use of hormone replacement therapy nor by an MRI-measure of cerebrovascular damage.
These data add to the growing body of literature implicating exposure to neurotoxicants in the neuropathogenesis of neurodegenerative diseases such as AD.
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A new cast report out of Sweden by Roos and colleagues 2020 suggests that subcutaneous exposure to manganese may be associated with a rapidly progressing form of ALS. This case report is about a 56 year old man who developed ALS in close chronological relationship to his exposure to manganese that was administered as a traditional Kenyan medical practice call Ogosaraka via cuts in the skin of his back near his spinal cord. Within four months the man began to develop neurological symptoms which included symmetrical muscle weakness in his legs, arms, and neck. Neurophysiological testing revealed fibrillation potentials indicative of denervation. The patient died from respiratory failure 10 months post exposure. Although the results of neuroimaging studies showing manganese accumulation n brain nor of post-mortem neuropathological studies confirming the involvement of upper motor neurons in this case were not provided by the authors, this rapidly progressing case of unusual manganese neurotoxicity nevertheless raises concerns about potential risks for interactions between traditional medicine and the onset and progression of latent ALS in vulnerable individuals.
Link to original article in PubMed
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
Dr. Marcia Ratner shares and reviews the news.