ALS is a degenerative neurological disease that causes motor neuron cell death leading to paralysis and death from respiratory failure. Free radicals, excess glutamate, calcium release, and genetic mutations contribute to motor neuron cell death. The disease progresses through corticomotor neuron death followed by spinal motor neuron denervation atrophy. Epidemiological studies show organophosphate pesticides and heavy metal exposures increase ALS risk by causing oxidative stress and gene imbalances that further damage cells. Electrophysiology shows abnormal cortical excitability occurs in sporadic ALS patients but not all genetic mutation cases, and excitability worsens with disease progression.

1. ALS is a degenerative neurological disease of motor neurons which leads to eventual end paralysis and death from respiratory failure Free radicals, excess glutamate, and excess calcium release contribute to the motor neuron cell death. There is the ‘die forward’ model of corticomotor neuron cell death where corticomotor neurons die first followed by denervation atrophy of the spinal motor neurons. The cortical innervations theory suggests that loss of muscular coordination and control occurs earlier than progressive weakness and denervation atrophy. The retrograde neuronal cell death theory applies to several more situations where backwards atrophy is the rule rather than the exception to the case.<br />Free radicals generated from singlet oxygen and free radical water species can cause cellular membrane and mitochondrial cell damage, causing cell death spontaneously. Apoptosis is genetically programmed cell death caused presumably by a redox balance fallout. Mutants such as the superoxide dismutase one mutation in mice (SOD1) exhibit motor neuron disease. The mutants, interestingly, demonstrate another genetic abnormality in abnormal prion gene expression. Prions are infective protein particles which are responsible for prion spongiform encephalopathies, such as Creutzfeldt Jakob Disease or CJD. The prions are approximately 120 amino acids in length and are the only protein thought to be infectious in the central nervous system or otherwise. The prions do not have any nucleic acid but are associated with wild type genes within the human, yeast, and and mammalian genomes.<br />The epidemiologists have shown that organophosphate pesticides predispose to ALS in human studies involving Veterans and non-veterans. The epidemiology of ALS is characterized by redox gene imbalances and and oxidant stresses both leading to abnormal prolonged oxidant stress. Lead and other heavy metals can be chronic exposures leading to free radical damages which lead to other gene abnormalities. These gene changes in turn cause further abnormal prion gene expression or oxidant stress mitochondrial and or cellular membrane damage.<br />Electrophysiology has shown that abnormal cortical excitability occurs in sporadic but not homozygous SOD1 mutants. Most of these studies have used transcranial magnetic stimulation to excite or depolarize the cerebral motor cortex. The Nardone et al group showed that as ALS progresses the cortical responses become more abnormal and diminish in responsivity. The hyperexcitability seen in animal models is also observed in humans, where disease progression indicates worsening function. There does not appear to be epileptic seizures associated with this hyperexcitability. <br />References: (to follow)<br />Limviphuvadh V, Tanaka S, Goto S, Ueda K, & M Kanehisa (2007) “Systems Biology, the Commanlity of Protein Interaction Networks Determined in Neurodegenerative Disorders (NDDs)” Bioinformatics 23, 2129-2138.<br />Nardone R, Buffone E, Florio I, & F Tezzon (2005) Changes in Motor Cortex Excitability during Muscle Fatigue in Amyotrophic Lateral Sclerosis” J Neurology, Neurosurgery, & Psychiatry 76: 429-431.<br />Schmidt S. et al. (2008) “Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis : The GENEVA Study” Methods in Neuroepidemiology 30: 191-204.<br />Turner MR, et al. (2005) “Abnormal Cortical Excitability in Sporadic but not Homozygous D90A SOD1 ALS” J Neurology, Neurosurgery, & Psychiatry 76, 1279-1285.<br />Vucic S, & MC Kiernan (2006) “Novel Threshold Tracking Techniques Suggest that Cortical Hyperexcitability in an Early Feature of Motor Neuron Disease” Brain 129, 2436-2446.<br />