Neurodegenerative and Neurobehavioral Diseases

 Neurodegenerative diseases are chronic degenerative diseases of the Central Nervous System that often cause dementia.  Although for the most part the causes and mechanisms of this collection of brain diseases are not well known, they are increasing in incidence in the developed as well as the underdeveloped world and are often found in the aging population.  These diseases are characterized by molecular changes in nerve cells that result in nerve cell degeneration and ultimately nerve dysfunction and cell death, resulting in neurological signs and symptoms and in extreme cases dementia.  There appears to be a genetic link to neurodegenerative diseases, but the genetic changes that occur and the changes in gene expression that are found in these diseases are complex.  One of the types of change found in essentially all neurological degenerative diseases is the over-expression of oxidative free radical compounds (oxidative stress) that cause lipid, protein and genetic structural changes.  In addition to genetics and changes in gene expression, it is thought that nutritional deficiencies, head trauma, environmental toxins, chronic bacterial and viral infections, autoimmune immunological responses, vascular diseases, accumulation of fluid in the brain, changes in neurotransmitter concentrations and other causes are involved in various neurodegenerative diseases.

 Amyothrophic Lateral Sclerosis (ALS)

 ALS, also known as Lou Gehrig’s Disease, in a progressive neurodegenerative disease of the upper and lower motor neurons located in the mid-brain, brainstem and spinal cord.  In ALS the motor neurons in these areas become dysfunctional and slowly die, and when this occurs the muscles can no longer receive nerve impulses from the brain.  The muscles then weaken and atrophy, resulting eventually in muscle paralysis.  ALS patients progress rather quickly, and only 5% of ALS patients survive beyond 5 years after their diagnosis.  The diagnosis of ALS is performed by neurologists and generally follows a set of signs and symptoms, but there are atypical ALS cases that do not follow the usual clinical course and do not show all of the typical signs and symptoms of classical ALS.

 The cause(s) of ALS remain unknown, but there are several new avenues of research that could be important in the development of new treatments for ALS.  One theory of ALS is that an important neurotransmitter, glutamate, is over-expressed resulting in damage to motor neurons and eventually death.  There are drugs that can reduce the damage caused by excess glutamate, but these usually only result in a 2-3 month increase in life span.  Newer drugs are being investigated that could slow the effects of glutamate on motor neurons.

 Chronic bacterial and viral infections that invade the brain have been found at high incidence in ALS patients, and these may play an important role in nerve cell death.  For example, investigations at the Institute for Molecular Medicine have found that 85% of ALS patients (and 100% of Gulf War veterans with ALS) have bacterial infections caused by Mycoplasma species (see the publications below).  In addition, other bacteria, such as the Lyme Disease Borrelia burgdorfii may also be involved in some patients.  These small intracellular bacteria may cause nerve cell death by increasing the cellular concentration of Reactive Oxygen Species (ROS), free radicals that can damage nerve membrane lipids and proteins and DNA, resulting in apoptosis or programmed cell death.  Studies on ALS have shown that a major defect in ALS is the reduction or change in an enzyme called superoxide dysmutase (SOD) that is involved in reducing the concentration of ROS.  In addition, other studies have shown the reduction over time of of the body’s antioxidant defense system in ALS patients.  Methods are being developed to treat these infections and also reduce the generation of ROS by administration of antioxidants and replacing damaged membrane lipids (Lipid Replacement Theray).  In addition, neurotrophic viruses such as the Echo-7 enteroviruses are found in most ALS patients, and these viruses could cause cell death to infected cells.

 In addition to neurotransmitters and infections, chemical toxins and heavy metals, such as lead, mercury and aluminum may damage nerves and contribute  to neurodegeneration.  Although ALS is not generally thought to be an autoimmune disease, several studies have found antibodies to motor neuron membrane components in ALS patients.  These autoantibodies may damage nerve cells similar to MS. 

Alzheimer’s Disease (AD)

 Alzheimer’s Disease (AD), the most common cause of dementia, is a collection of brain disorders, usually in older people, characterized by slow progressive loss of brain function, especially notable by lapses in memory, disorientation, confusion, mood swings, changes in personality, language problems, such as difficulty in finding the right words for everyday objects, loss of behavioral inhibitions, loss of motivation, and paranoia.  The prognosis and course of AD varies widely, and the duration of illness can be a few years up to over 20 years in duration.  During this time parts of the brain that control memory and thinking are first affected, followed by other brain changes that ultimately result in brain cell death.

 AD is characterized by distinct neuropathological changes in the brain.  Among the most notable are the appearance of plaques and tangles of neurofibrils within brain nerves that affect nerve synapses and nerve-nerve cell communication.  Both of these structures involve the deposition of altered amyloid proteins, called Ab proteins, and scientists in the Department of Immunology at the Institute for Molecular Medicine are developing new immunological methods to prevent the deposition of Ab proteins and increase their removal from nerve cells so that the nerve damaging structures are reduced or prevented from forming.

 Although the cause of AD is not known to any certainty, formation of the amyloid plaques and neurofiber tangles may be due to genetics and changes in the structure of Ab proteins, neurotoxicity caused by chemicals or other toxic events, imflammatory responses, oxidative stress and increases in ROS, loss of nerve trophic factors that are important in nerve physiology and loss of nerve cell transmission.  Treatments for AD are generally only palliative and only slow progression of the disease.  As mentioned above, newer approaches at the Institute for Molecular Medicine’s Department of Immunology have focused on preventing the formation of amyloid plaques and neurofibril tangles using unique molecular vaccines primed to specific segments on the Ab proteins.  These vaccines are currently being studied in animal models of AD, and clinical trials are being planned to test their effectiveness in patients with AD.

 

Multiple Sclerosis (MS)

  Multiple Sclerosis is a disease of the nerves of the central nervous system, and it can occur in young as well as older people.  The nerves in various parts of the brain are covered by a protective insulation made up of the protein myelin and other proteins imbedded in a lipid sheath so that the electrical impulses that cause nerve conduction are protected.  In MS, inflammation and the presence of autoimmune antibodies against myelin and other antigens causes the protective sheath to break down and lose their protective capacity (demyelination), resulting in decrease or loss of electrical impulses along the nerve.  In progressive MS the nerve cells are damaged by demyelination and deposition of plaques on the nerve cells to the point where nerve cell death occurs.

 The signs and symptoms of MS include visual disturbances, muscle weakness, fatigue, numbness, difficulty in coordinating movement and balance, tremors, dizziness, loss of hearing, memory loss, impairment in judgment, behavioral changes and pain.  The symptoms may cycle or relapse-remit initially and later on become progressive and degeneration occurs in a steady decline.  MS may affect virtually any myelinated nerve, sensory or motorneuron, and it can cause widespread signs and symptoms.

 Since MS is a genetic and an autoimmune disease; however, most treatments are specifically directed at symptom relief and some have focused on suppressing the immune response to nerve cell proteins such as myelin basic protein.  Corticosteroids, such as prednisone, are often used, but their non-specific nature can cause side effects related to loss of immune function.  Other approaches have utilized interferons, such as interferon-b1, protein messengers that immune and other cells use to communicate with each other, in an effort to regulate the immune system and prevent attacks on nerve cell proteins like myelin.

 Recent research at the Institute for Molecular Medicine and elsewhere has shown that some of the autoimmune response to nerve cell proteins may be caused by intracellular infections.  As many as 50% of MS patients may be infected with intracellular bacterial infections caused by Mycoplasma species.  Other bacterial infections, such as Borrelia burgdorfii (Lyme Disease), Chlamydia pneumoniae and other intracellular bacterial infections may also be involved in some MS cases.  Viruses may also be involved in MS, because certain viruses have been found at high incidence in MS patients.  Infections can stimulate immunological responses, and the presence, in particular, of intracellular bacterial infections in nerve cells can stimulate autoimmune responses when these intracellular bacteria are released from nerve cells carrying nerve cell antigens.

 

Autistic Spectrum Disorders (ASD)

 Autism patients are young children to teens who generally suffer from an inability to properly communicate, form relationships with others and respond appropriately to their environments.  Autism patients often display repetitive actions and develop troublesome fixations with specific objects, and they are often sensitive to certain sounds, tastes and smells.  Autism patients do not all share the same signs and symptoms but tend to share certain social, communication, motor and sensory problems that affect their behavior in predictable ways.  Autism and related disorders have been recently placed into a multi-disorder category called Autistic Spectrum Disorders (ASD), which includes autism, Attention Deficit Disorder (ADD) Attention Deficit Hyperactivity Disorder (ADHD), Asperger Syndrome and other disorders.

 ASD patients, in general terms, share the presence of a triad of impairments in social interaction, communication and imagination, which are thought to be due to abnormalities in brain function or structure and are thought to have a genetic basis.  The incidence of ASD is currently estimated at 1 in 1,000 children, and in genetically predisposed families the disorder is ~100-times higher in incidence than in the general population.  In some patients there are also a number of other less specific chronic signs and symptoms. Among these are fatigue, headaches, gastrointestinal and vision problems and occasional intermittent low-grade fevers and other signs and symptoms that are generally excluded in the diagnosis of ASD.  These suggest that a subset of ASD patients may suffer from bacterial and/or viral infections.  There are several reasons for this, including the nonrandom or clustered appearance of ASD, sometimes in immediate family members or particular regions, the presence of certain signs and symptoms associated with infection, the cyclic course of the illness and in some cases its response to anti-microbial therapies.

 

At the Institute for Molecular Medicine we have identified systemic infections, such as those produced by Mycoplasma species, Chlamydia pneumoniae and Human Herpes Virus-6 (HHV-6), in a high percentage of ASD patients, and these infections are likely to be important in determining the treatment strategies for many ASD patients.  These infections can penetrate the CNS and are associated with other neurological diseases.  In addition, heavy metal contamination, chemical and environmental exposures also appear to be important in ASD.

 Since these infections can cause neurological signs and symptoms, they may be important in ASD.  Previously we found that children of Mycoplasma-positive Gulf War veterans were over 18-times more likely to come down with Mycoplasma fermentans than the general population and high rates of ASD diagnoses were found in their children.  In addition, examination of a group of autism patients from civilian families revealed that there was a high incidence of mycoplasmal infections, including M. fermentans, M. pneumoniae and M. hominis  as well as co-infections with C. pneumoniae or HHV-6, suggesting that chronic infections are common in ASD patients and should be effectively treated.