Diseases Affecting Sensation and Motor Control Nancy Long Sieber, Ph.D. September 20, 2010

Major Neurotransmitters Small Molecules Neuropeptides Acetylcholine Nitric Oxide Biogenic Amines Epinephrine Norepineprine Dopamine Serotonin Histamine Amino Acids Glutamate  Aminobutyric Acid (GABA) Glycine Aspartate Homocysteine Taurine Nucleotides Adenosine Adenosine triphosphate Hypothalamic Releasing Hormones Corticotrophic Releasing Hormone Growth Hormone Releasing Hormone Thyrotrophin Releasing Hormone Pituitary Peptides ß endorphins Oxytoxin Vasopressin Adrenocorticotropic Hormone (ACTH) Thyroid Stimulating Hormone (TSH) Growth Hormone Gastrointestinal Peptides Secretin Substance P Insulin Gastrin Neurotensin Somatostatin Cholecystokinin Others Angiotensin Bradykinin Neuropeptide Y Calcitonin

Sensory neurons can diverge (a) or converge (b) as they ascend towards the brain

The body is “mapped” onto the somatosensory cortex.

Lower Motor Neurons (from spinal cord to muscle) => Upper Motor Neurons (all motor neurons within the CNS) =>

MS is characterized by demyelinization of neurons in the CNS

Disease of Sensory and/or Motor Control Parkinson’s Disease – results from death of dopamine-containing neurons in the substantia nigra. Affects ability to initiate movements. Multiple Sclerosis – affects neurons in the CNS involved in sensation and movement. Some also experience mild cognitive effects. Amyotrophic Lateral Sclerosis – affects motor neurons both in the CNS and in the periphery.

Parkinson’s Disease Substantia nigra cells in the basal ganglia are gradually killed off, but the mechanism of neuronal death is not known These cells normally synapse on cells involved in the initiation of movement. Patient experiences “intention tremor”, and rigidity. Movements become increasingly difficult to carry out. The disease shortens life expectancy. Patients become increasingly frail and immobilized. Some have trouble with swallowing.

Regions of the brain affected by Parkinson’s Disease

Multiple Sclerosis An autoimmune disease that leads to demyelinization of neurons in the CNS Patients usually present with blurred or double vision. They go on to experience abnormal sensations, and muscle weakness. 50% of patients need help with walking within 15 years of diagnosis.

Pathogenesis of MS In patients with MS, T lymphocytes, which are normally excluded from the brain by the blood- brain barrier (BBB) are able to enter. These cells are thought to trigger the damage to myelinated neurons in the CNS. The cause of this opening of the BBB is unknown – it the cause of the problem, or is it just a consequence of inflammation caused by something else?

Blood vessels in the human brain Zlokovic & Apuzzo: Neurosurgery 43(4): , 1998

Many factors are thought to contribute to MS: Intrinsic problems with immune system - probably common to all autoimmune diseases, probably genetic. Problems with the blood-brain barrier, allowing T cells to enter the CNS and promote production of antibodies against myelin A specific Infectious agent – Some have proposed that a virus triggers the autoimmune response that leads to demyelinization. No specific agent has been found Vitamin D deficiency – the geographic distribution supports this. Vitamin D is involved in regulating the immune system, as well as neural function.

Grigoriadis and Hadjigeorgiou Journal of Autoimmune Diseases :1 doi: / Proposed scheme for virus-mediated autoimmunity in multiple sclerosis.

MRI Images help diagnose and monitor MS

Treatments for MS Anti-inflammatory agents – corticosteroids, chemotherapeutic agents, etc. as used to treat lupus. –Drawbacks: These drugs have many side effects. In addition, they generally increase the risk of infection, and viral and bacterial infections have been shown to speed the progression of MS. Supplemental vitamin D has been shown to slow the progression of MS Tysabri – A monoclonal antibody against T cells, which blocks their entry into the CNS. –Drawback: cripples brain defenses against infection. Patients are at risk of deadly brain infections, especially progressive multifocal leukoencephalopathy (PML).

ALS affects both upper (within the CNS) and lower (those that directly innervate muscle) motor neurons.

Genetics and ALS 5-10% of cases are strictly genetic (Familial ALS). Of these about 20% are due to a defect in an enzyme called superoxide dismutase 1 (SOD1), which scavenges free radicals. This finding has led some to speculate that free radical damage may be involved in other forms of the disease. The defective protein may also interfere with movement of ADP into mitochondria, interfering with ATP production.

Possible environmental risk factors Exposure to a dietary toxin called BMAA may account for high incidence in Guam and other places in the western Pacific. US military veterans from both the Pacific and the Gulf War. Exposure to herbicides has long been suspected, as clusters have been seen in athletes and farmers.

Possible Mechanisms of ALS Pathogenesis Oxidant injury, perhaps due to some abnormality in antioxidant systems Glutamate toxicity, perhaps due to a defect in astroglial cells which normally remove this neurotransmitter from the synapse. The resulting “excitotoxicity” leads to neuronal death, causing further release of glutamate.

Treatments for ALS Riluzole, a drug that decreases glutamate release is the only FDA-approved drug for ALS. It is only moderately effective suggesting that other mechanisms are involved in the pathogenesis of ALS. Other drugs are used to treat symptoms of the disease, including muscle cramps, spasms, fatigue, etc.