~Amyotrophic Lateral Sclerosis (ALS) - Lou Gehrig's Disease

~Amyotrophic Lateral Sclerosis (ALS) - Lou Gehrig's Disease
Reprinted with permission of Life Extension®. Introduction
  • Symptoms
  • Epidemiology
  • Course
Amyotrophic lateral sclerosis (ALS) is also known as Lou Gehrig's disease. Lou Gehrig was one of baseball's greatest players and earned the nickname "Iron Horse" for his record of 2130 consecutive games. His outstanding career was ended by ALS.

ALS is a rapidly progressive neuromuscular disease caused by the destruction of nerve cells in the brain and spinal cord. This causes the loss of nervous control of voluntary muscles, resulting in the degeneration and atrophy of the muscles. Eventually the respiratory muscles are affected which leads to death from an inability to breathe.

Symptoms

ALS symptoms vary from one person to another according to which group of muscles is affected by the disease. Tripping, dropping things, abnormal fatigue in the arms and/or legs, slurred speech, difficulty in talking loudly, uncontrollable bouts of laughing or crying, and muscle cramps and twitches are all symptoms of ALS. The disease usually starts first in the hands and will cause problems in dressing, bathing, or other simple tasks. It may progress more on one side of the body and generally proceeds up the arm or leg. If it starts in the feet, walking will become difficult. ALS can also start in the throat, causing difficulty with swallowing.

People afflicted with ALS do not lose their ability to see, hear, touch, smell, or taste. The bladder, sexual drive and function, and muscles of the person's eyes are not affected. The disease does not affect the person's mind.

Epidemiology

Men make up the majority of those who contract ALS, although women also get the disease. Race, ethnicity, or socioeconomic boundaries make no difference as to who will come down with ALS. Most of those who get the disease are usually between the ages of 40 and 70, but people in their 20s and 30s can also get it. In most societies, there is an incidence of five in every 100,000 people (Fauci 1998; Onion 1998).

Course

The rate of progression of the symptoms of ALS varies for each person. The average life expectancy for a newly diagnosed person is 2-5 years, although improved medical care is resulting in longer life. ALS frequently takes its toll before being diagnosed, causing the people who have the disease to be significantly debilitated before they learn they have it.

Causes
  • Glutamate Toxicity
  • Oxidative Stress
  • Mitochondrial Dysfunction
  • Autoimmune Disease
  • Infectious Disease
  • Toxic Chemical Exposure
  • Calcium and Magnesium Deficiency
  • Growth Factor Deficiency
  • Carbohydrate Metabolism
There are three types of ALS: sporadic, familial, and Guamanian. The most common form is sporadic. A small number of cases are inherited genetic disorders (familial). A large number of cases, however, occur in Guam and other Pacific territories.

The familial type of ALS is caused by a genetic defect in superoxide dismutase, an antioxidant enzyme that continuously removes the highly toxic "superoxide" free radical. The causes of sporadic and Guamanian ALS are unknown. Several hypotheses have been proposed including:
  • Glutamate toxicity
  • Oxidative stress
  • Mitochondrial dysfunction
  • Autoimmune disease
  • Infectious disease
  • Toxic chemical exposure
  • Exposure to heavy metals such as lead, mercury, aluminum, and manganese
  • Calcium and magnesium deficiency
  • Carbohydrate metabolism
  • Growth factor deficiency
Glutamate Toxicity. Glutamate is the main excitatory neurotransmitter in the brain. It has been calculated that glutamate is responsible for 75% of excitatory neural transmissions. Glutamate is unique in that it can produce such marked stimulation that neurons die. It has been proposed that the neuronal damage following ischemia (deficiency of blood, for example, after a stroke) is due to the action of glutamate rather than a lack of oxygen (Ganong 1995).

ALS is highly linked with glutamate. One proposed mechanism is a defective glutamate transport system that permits neurotoxic levels to build up (Onion 1998). A study showed significant elevations (by about 70%) of plasma levels of glutamate in ALS patients as compared to controls (Plaitakis et al. 1993).

Oxidative Stress. Oxidative stress refers to a shift in the ratio of oxidants to antioxidants in the body. Free radicals are molecules that have an unpaired electron. Most free radicals react with molecules that contain oxygen to form reactive oxygen species, such as nitric oxide (NO), superoxide (O2-), and hydroxyl ( OH- ). Free radical damage is associated with many degenerative conditions, including neurological disorders (Jenner 1994).

Antioxidants inhibit oxidation by free radicals. There are many types of antioxidants, including:
  • Detoxification enzymes such as superoxide dismutase (SOD) catalase, glutathione peroxidase, and glutathione transferase
  • Enzymes such as glutathione reductase, albumin, transferrin, ceruloplasmin, and metallothionein.
  • Nutritional supplements including tocotrienols, coenzyme Q10, vitamins C and E, lycopene, cysteine, glutathione, alpha lipoic acid, and melatonin.
Inflammation represents a major source of oxidants. Inflammation is often caused by bacterial or viral infections, toxic exposure, and aging-related cytokine changes. The continuous production of reactive oxidant species during chronic inflammation may deplete the store of antioxidants, eventually resulting in a spiral from health to disease (Jenner 1994).

Mitochondrial Dysfunction. Mitochondria are the power-generating units of the cell and are most developed abundant where energy-requiring processes take place (for example, in muscles). The outer membrane of the mitochondria is studded with oxidative enzymes that provide raw materials for the reactions occurring inside. In the interior, the citric acid cycle converts fats and carbohydrates into energy - releasing carbon dioxide. The energy produced by this reaction is used to form the high-energy phosphate bonds in compound adenosine triphosphate (ATP) in a process called oxidative phosphorylation. ATP is the principal energy source for both plants and animals. Mitochondrial DNA is transmitted genetically, solely from the mother (Ganong 1995).

Mitochondrial dysfunction has been linked to neurodegenerative diseases (Beal 1996; Beal 1999b). Defects in mitochondrial DNA have also been proposed as a causative mechanism in sporadic ALS (Murphy et al. 1999; Beal 2000; Manfredi et al. 2000).

One study explored the role of mitochondrial dysfunction by transferring mitochondrial DNA from ALS subjects to normal human neuroblastoma cells (embryonic cells that form nervous tissue) with their mitochondrial DNA removed. The resulting hybrid cells exhibited abnormal electron transport chain functioning, increases in free radical scavenging enzyme activity, perturbed calcium homeostasis, and altered mitochondrial structure.

The nickname "Iron Horse" given to Lou Gehrig is quite appropriate in a biochemical sense. The energy forming process of oxidative phosphorylation relies heavily upon transferring electrons between several iron molecules that form the electron transport chain. The oxidative phosphorylation process also requires coenzyme Q10, nicotinamide or niacinamide adenine dinucleotide (NAD), and flavin adenine dinucleotide (FAD). Niacin (vitamin B3) is used to form NAD, and riboflavin (vitamin B2) is used to form FAD.

Autoimmune Disease. Autoimmunity may play a role in ALS. In this disease, the immune system becomes confused and begins attacking tissues in the body. Under normal conditions, the body's immune system produces proteins called immunoglobulins which attach to their target antigen. An antigen is a substance that produces an immune response and is usually something foreign to the body. The immunoglobulins attach to and surround the target antigen, forming an antigen-antibody complex. This complex is then ingested by phagocytes, such as macrophages, in a process called phagocytosis.

In autoimmune disease, antibodies are produced that attach to the tissues of the body, instead of foreign substances. The following are examples of diseases with an autoimmune basis:
  • In autoimmune hemolytic anemia, the body produces autoantibodies to red blood cell membrane proteins.
  • In diabetes mellitus, autoantibodies are formed against insulin receptors.
  • Graves's disease is associated with autoantibodies to thyroid stimulating hormone (TSH) receptors.
  • Pernicious anemia can be caused when autoantibodies are formed against intrinsic factor which is needed for vitamin B12 absorption.
Researchers have proposed that ALS may have an autoimmune basis. The following are the bases for their hypotheses:
  • Analyses of ALS patient sera have identified circulating antibodies secreted by denervated muscle. These antibodies inhibit the stimulation of the sprouting of axons, the long arms of neurons which conduct nervous impulses to other neurons throughout the body (Onion 1998).
  • Researchers have found an immunoglobulin that affects the conductance of neuronal voltage-activated calcium channels which may induce an excessive release of glutamate from nerve endings (Onion 1998).
  • Several studies of ALS patients found the presence of antibodies that interact with motor neurons (Pestronk et al. 1988a; Pestronk et al. 1988b; Pestronk et al. 1989; Niebroj-Dobosz et al. 1999).
  • Immune complexes have been found in spinal cords of patients with ALS.
It has been proposed that T cells, activated microglia, and immunoglobulin G (IgG) within the spinal cord lesions may be the primary event that leads to tissue destruction in ALS.

The increased prevalence in Guam is associated with a decreased delayed hypersensitivity. The secondary response, which occurs with the second exposure to the antigen, is normally quicker and usually produces more antibodies than the primary response. The major reason for the enhanced secondary response is the formation of B memory cells during the primary response (Onion 1998). In an early study, a family history of thyroid disease was present in 19% of ALS patients, and an additional 21% of patients described family members with other possible autoimmune disorders. In 19% of the patients with ALS, either past or present thyroid disease was documented. Eleven of 47 additional patients with ALS had significant elevations of microsomal and/or thyroglobulin antibody levels (Appel et al. 1986).

Infectious Disease. ALS was once thought to be caused by persistent viral infection (Salazar-Grueso et al. 1995). This hypothesis fell out of favor when researchers could not isolate a single causative agent. Recently, however, many researchers are reconsidering infectious agents because many neurodegenerative disorders are associated with chronic infections, particularly latent viruses. Support for the continued investigation of infectious agents in ALS include the knowledge that:
  • It is well-known that excess free radical activity is associated with chronic infection (Racek et al. 2001).
  • Both Lyme disease and poliomyelitis have chronic states that resemble the symptoms of ALS (Garcia-Moreno et al. 1997).
  • HIV infection is associated with a variety of neurological problems (Dalakas et al. 1988; Cruz Martinez et al. 1989).
  • Tertiary syphilis affects the nervous system (neurosyphilis) causing tabes dorsalis, a syndrome marked by degeneration of the posterior columns and posterior roots and ganglia of the spinal cord.
Toxic Chemical Exposure
  • Heavy Metals
People with a history of exposure to agricultural chemicals, including fertilizers and pesticides used in gardening and lawn care, may be at twice the risk for developing ALS (Baker 1996; McGuire et al. 1997).

Chemicals foreign to the body are called xenobiotics. They include toluene, xylene, hexanes, benzene, trichloroethane, styrene, phytates, and pesticides. Most xenobiotics are lipophilic, which means that they are attracted to the fats (lipids) which make up cell membranes. Because the brain is full of lipids, xenobiotics are able to rapidly diffuse across cell membranes into the brain and cause neurological problems.

Many pesticides are specifically designed as neurotoxins (toxins that affect the nervous system). Pesticides are generally odorless and can cause progressive symptoms weeks after an exposure (Prazmo 1978; Ames et al. 1995; Keifer et al. 1997).

Xenobiotics are removed from the body by a process called detoxification, which takes place in two phases. Phase I takes place inside the cell and changes the toxic chemicals into less toxic forms by means of the chemical processes of oxidation, reduction, and hydrolysis. Phase II detoxification then attaches molecules such as glutathione, methionine, and sulfur compounds in a process called glucuronidation. The body is then able to excrete these modified toxins in stool, urine, or sweat.

The process of detoxification requires several nutritional cofactors including magnesium, zinc, and manganese. The glutathione, methionine, and sulfur molecules are a component in the Phase II detoxification process and are used up in the process. As the detoxification pathways become overloaded, any further toxic challenge, however slight, can cause symptoms. This is often referred to as chemical sensitivity.

Chemically sensitive people experience symptoms to a variety of chemical insults. Caffeine (the active component of coffee), aspirin, and acetaminophen (Tylenol) are often used to assess the functional capacity of the detoxification system. Alcohol is metabolized in Phase I by aldehyde dehydrogenase. Gasoline fumes, deodorizers, rubber, and solvents are sources of benzene. Trichloroethylene, if blocked from the normal Phase I pathway, will form a toxic secondary metabolite called chloral hydrate, the so-called "Mickey Finn," which causes disorientation and dizziness.

Toxic chemical exposure may be one reason why there is a higher incidence of ALS diagnosed in soldiers who participated in Operation Desert Storm. On April 6, 2000, the Associated Press reported that the Veterans Administration announced a year-long study to determine whether there is a higher incidence of Lou Gehrig's disease (ALS) among the veterans of the Gulf War. At least 28 Gulf veterans have been diagnosed with this deadly disease. Researchers are interested in locating other veterans, diagnosed with ALS or other motor neuron diseases, who were actively serving duty between August 2, 1990, and July 31, 1991, regardless of location. Those who did not go to the Persian Gulf will serve as part of the control group. Eligible veterans may call 1-877-342-5257 (Smith et al. 2000).

Heavy Metals
  • Lead
  • Mercury
  • Aluminum
  • Manganese
Because there are high numbers of ALS patients in Guam, Western New Guinea, and Japan, there is a theory that ALS might be caused by environmental problems. These areas have large amounts of heavy metals such as lead, mercury, and aluminum. These metals can poison the body and cause ALS symptoms (Conradi et al. 1976; Adams et al.1983; Armon et al. 1991).

Lead. Lead was used as an additive to gasoline and in many paints. Absorption of lead is enhanced by dietary deficiencies in calcium, iron, and zinc. Lead toxicity is most likely related to lead's affinity for cell membranes and mitochondria, where it interferes with several important enzymes.

In adults, systemic lead poisoning causes abdominal and joint pain, fatigue, anemia, and neurologic al symptoms, including headaches, irritability, peripheral motor neuropathy, short-term memory loss, and an inability to concentrate. Chronic subclinical lead exposure affects the kidneys, causing interstitial nephritis, renal tubular damage (with tubular inclusion bodies), hyperuricemia (with an increased risk of gout), and a decline in glomerular filtration rate and chronic renal failure. Armon et al. (1991) suggest that there may be an association between ALS in men and exposure to lead vapor.

Mercury. Mercury exposure is thought to occur from ingestion of contaminated fish (particularly tuna and swordfish, which can contain high levels of methyl mercury), inhalation of mercury vapor from dental amalgams, and possibly from drinking water contaminated by toxic waste sites.

Chronic mercury exposure produces a characteristic intention tremor and a constellation of findings, including excitability, memory loss, insomnia, timidity, and sometimes delirium. The neurotoxicity resulting from organic mercury exposure is characterized by paresthesia (an abnormal touch sensation often in the absence of external stimulus), impaired peripheral vision, hearing, taste, and smell, slurred speech, unsteadiness of gait and limbs, muscle weakness, irritability, memory loss, and depression. Dentists with occupational exposure to mercury score below normal on neurobehavioral tests of motor speed, visual scanning, verbal and visual memory, and visual-motor coordination ( Harrison 1998).

ALS was diagnosed in one patient after accidental injection of mercury (Schwarz et al. 1996).

It is well-known that selenium decreases the toxicity of mercury in the human body. After measuring the mercury and selenium content in the hair of 13 ALS cases, one study concluded that mercury in the body with a low content of selenium may be one of the environmental factors involved in producing ALS (Mano et al. 1989; Khare et al. 1990; Mano et al. 1990).

Aluminum. High levels of aluminum are found in the delicate threads running through the cytoplasm of nerve cells (neurofibrillary tangles) in the cerebral cortex and hippocampus of patients with Alzheimer's disease. High levels of aluminum have also been found in the drinking water and soil of areas with an unusually high incidence of Alzheimer's disease (Harrison 1998).

Aluminum and calcium deposits were found in the neurons of patients with ALS from Guam (Garruto et al. 1985).

Manganese. Manganese toxicity can cause a syndrome similar to Parkinson's within 1-2 years, including gait disorders, postural instability, a masked, expressionless face, tremor, and psychiatric symptoms.

Manganese is emitted from the tail pipes of motor vehicles (Aschner 2000). Occupational exposure can occur in miners, dry-battery manufacturers, and arc welders (Harrison 1998).

A study showed that the nitrated manganese-SOD level was strikingly elevated in ALS patients. The authors also proposed that nitration of manganese SOD in cerebrospinal fluids is a marker for oxidative stress in neurodegenerative diseases (Aoyama et al. 2000).

Calcium and Magnesium Deficiency. It is proposed that chronic environment deficiencies of calcium and magnesium may result in increased intestinal absorption of toxic metals and lead to the mobilization of calcium and metals from the bone and the deposition of these elements in nervous tissue. This hypothesis, called metal-induced calcifying degeneration of central nervous system (CNS), has been supported by experimental studies using several animal species (Van den Bergh et al. 1977).

Low calcium/magnesium intake with excess amounts of aluminum and manganese are associated with the incidence of ALS in the Western Pacific. The authors conclude that the high incidence of ALS in the Western Pacific may be due to calcium/magnesium metabolism dysfunction, resulting in excess deposition of aluminum (Yasui et al. 1991a; Yasui et al. 1991b).

Carbohydrate Metabolism. Over the last 30 years glucose intolerance has been reported in a significant percentage of patients with ALS. Currently, a controversy exists in determining whether the carbohydrate abnormality is disease-specific or secondary to the decreased glucose utilization caused by muscle atrophy. One study showed that the glucose infusion rate, an estimate of in vivo insulin sensitivity, was significantly diminished in ALS patients compared to both normal and disease controls, which suggests that ALS may be associated with a dysfunction in carbohydrate metabolism (Van den Bergh et al. 1977; Nagano et al. 1979; Reyes et al. 1984).

Growth Factor Deficiency. A lack of trophic (growth) factors support has been hypothesized as a probable cause of ALS. Several growth factors have been identified, including insulin-like growth factor I (IGF-I), nerve growth factor (NGF), leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNF). Specific information can be found about these growth factors in the Drug Research section.

Continued . . .


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