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Brain Damage & Recovery • • • • • Causes of brain damage Some examples of brain damage Effects of brain damage Recovery from brain damage Myelination disorders Causes of Brain Damage • • • • • • • • Genetic (not necessarily hereditary!) Congenital Environmental (toxins) Neoplasms Apoptosis (programmed cell death) Cerebrovascular problems Head impact injuries (closed head) Infections Hereditary Brain Damage • Passed from parent to child through DNA. • Several types: – Faulty chromosome duplication • Rare – Dominant gene disorders • Rare, tend to be self-limiting. – Recessive gene disorders • Not all children express the defect. – Polygenetic disorders • By far the most common. Faulty Chromosome Duplication • Trisomies – Patau’s Syndrome (trisomy 13) • Cleft lip, polydactyly, heart, stillborn or die young. – Edward’s Syndrome (trisomy 18) • Multiple major abnormalities & MR – Down’s Syndrome (trisomy 21) • MR, Alzheimer’s • Others – Turner’s Syndrome (X0) – Klinefelter’s Syndrome (XXY) Dominant Gene Disorders • Normally the disorders prevent their own reproduction, with two exceptions: – Disorder limited to rare environmental conditions. – Disorder manifests itself later in life. • Pubertal changes required for gene expression • Adult onset. • Huntington’s disease (Huntingtin, 4p16.3) • Early-onset Parkinson’s (pre-50, chr. 4 & 6) – (not all Parkinson’s cases are genetic) Recessive Gene Disorders • Single defective gene is passed from parents to children, but only ~25% of children express (or know of) the disorder. • Often affects myelination of cerebral neurons. • Pelizaeus-Merzbacher brain sclerosis – PLP (proteolipid protein), Xq21.3-q22. • Adrenoleukodystrophy (ALD) – Xq28 mutation causes peroxisomes to lose the ability to breakdown very long chain fatty acids (VLCFAs). VLCFAs degrade both myelin and the adrenal gland. Polygenetic Disorders • Requires the presence of multiple defective genes, along with environmental influences. • Most psychological disorders & personality traits. • Genetics can also protect against disorders. Congenital Brain Disorders • In-womb damage – Typically due to maternal toxin exposure – Fetal Alcohol/Narcotic Syndrome (FAS/FNS) – Prescription drugs • Thalidomide – “seal limb” • DES (synthetic estrogen) – 50% vaginal cancer by age 10 • Birth Trauma – Hypoxia due to umbilical strangulation – Forceps damage during delivery – Gonorrhea and herpes infections Environmental • Toxins – Ingested toxins (alcohol, drugs, etc.) – Heavy metal (mercury, lead, etc.) poisoning • Radiation (fallout, exposure, X-rays, etc.) – Radiation can cause genetic mutations. • Drugs – Drugs of abuse – Aspirin – Reye’s Syndrome • Nutritional problems Neoplasms (Cancers) • • • • Mass of new tissue (= “new growth”). Physiologically useless. Growth is usually not controlled. Neoplasms account for a relatively high proportion of neurological disease. • Brain is 2nd only to uterus as tumor area. • Brain tumors typically not from nerves. – Gliomas account for 45% of brain neoplasms Neoplasms • Two types of tumors – Benign (-omas) • Regular, well-defined shape. • Does not intrude into surrounding tissue. • Effects only by pressure on the brain. – Malignant (-carcinomas) • Irregularly shaped. • Intrudes (infiltrates) into surrounding tissue. • Tend to be recurrent. Neoplasms • Astrocytomas – 40%, slow growing, good prognosis • Glioblastomas – 30%, M, >30, highly malignant, < 1 year. • Meduloblastomas – 11%, children only, 1.5-2 years • Meningioma – Most benign of brain tumors, well encapsulated. Glioblastoma Neoplasms • Metastatic Tumors – Cancerous cells migrate from other parts of the body, normally the lung or breast. – It is not uncommon for lung cancers to first be noticed in the brain. – Normally multiple implant sites. – All malignant. – Very hard to treat. Cell Death • Necrosis – – – – – Externally caused Death by injury Cells swell and rupture Death is swift, < 1 hour Surrounding area becomes inflamed – Nucleus not affected until the very end • Apoptosis – – – – – Death by suicide Normal housekeeping Shrivel and waste Slow death, days No inflammation – Nucleus affected from the beginning – More prevalent in early development Cerebrovascular Damage • Brain is wellprotected against vascular problems. • Bilateral independent arterial supply both front and back. • Circle of Willis Cerebrovascular Damage Cerebrovascular Damage • Aneurysms = weakened/expanded blood vessels – Take up space normally occupied by brain. • Ruptured aneurisms = hemorrhage – Stroke / cerebrovascular accident (CVA). • Arteriosclerosis – Hardening/narrowing of arteries. • Cerebral thrombosis – Lodged embolus causes ischemia and infarction. Aneurysm • Weakened and/or expanded blood vessels, or pouches. • Can burst causing hemorrhage, infarction & ischemia. Aneurysm of aortic arch Arteriosclerosis • Arteries get clogged – Fat & cholesterol • Blocks oxygen delivery. • Partial obstructions require increased blood pressure to push blood past obstruction. • Elevated BP can rupture aneurysms. Thrombosis • Floating body lodges in vessel. • A 70-year-old woman presented to the emergency room with an acute onset of left arm weakness, difficulty walking and slurred speech. • DX: Acute cerebral infarct from right MCA thrombosis. Thrombosis Thrombosis Cerebrovascular Damage • Formerly assumed that most damage was due to decreased oxygen and/or glucose. • Now appears that most cerebrovascular damage is due to excess glutamate release by blood-deprived neurons. • Excess Ca++ and Na+ influx, especially through NMDA receptors, kills cells. • Hippocampus is particularly affected. • Ca++ channel & NMDA receptor blockers helpful in preventing post-stroke damage. Head Impact Injuries • Car accidents • Household accidents – Falling down stairs – Bike/scooter/Rollerblade accidents • Shaken baby syndrome • Physical abuse Head Impact Injuries • Contusions (= bruise) – Damage to the vascular system. – Hematomas - localized collections of blood. • Subdural - beneath (inside) the dura • Epidural - on top of (outside) the dura – Many are contrecoup, opposite to blow. Head Impact Injuries • Concussion – Disturbance of consciousness without evidence of contusion or other structural damage. • Common assumption is temporary disruption with no long-term damage. – Punch-drunk syndrome suggests otherwise. – Boxers show cerebral scarring with dementia. Other CNS Injuries • Primarily spinal cord • Slipped disk – Intervertebral disk presses into cord. • Vertebral fracture – Spinal cord can be transected, with varying disabilities. Infections • Bacterial – Streptococcus • Sore throat, OCD, ADHD – Syphilis (shown) • General pariesis – insanity and dementia – Neisseria meningitidis – Campylobacter jejuni • Common intestinal bacteria – Clostridium tetani (tetanus) • Neurotoxin that blocks cholinesterase Infections • Viral – – – – – – – – – Rubella (German measles) Rubeola (measles) Varicella/Zoster (chicken pox/shingles) Mumps Poliomyelitis Cytomegalovirus (CMV) Epstein-Barr virus Rabies Herpes Infections • Encephalitis - inflammation of brain – Bacteria and/or viruses – herpes (shown) measles, chicken pox, mumps, etc. – Sometimes passed by mosquitos or animals. – Can have high mortality rate. Infections • Meningitis - inflammation of the meninges – Bacteria, viruses, funguses, toxins. – Bacterial form (Neisseria meningitidis) most common. – Viral form most deadly. – Often mistaken for flu: fever, aches, stiffness. – Drowsiness, stupor, seizures, then coma. Effects of Brain Damage • Kill neurons – Damage to nerve itself – Damage to glial cells/altered environment – Damage to pre-/post-synaptic nerves • Crowd out or put pressure on the brain • Disable neurons – Often by interfering with myelin Recovery of Function Recovery of Function • What happens after (or during) brain damage? – Degeneration – Regeneration – Reorganization • Can anything be done to aid recovery? Degeneration • Damaged neurons degenerate over days by the process of phagocytosis: • By astroglia in CNS. • By Schwann cells in the PNS. Degeneration • Anterograde – segments distal to soma: – Always die thru Wallerian degeneration. • Swell within hours, fragment within days – Distal neurons can also be affected. • Retrograde – segments proximal to soma: – Might die, might live. • Early swelling = regeneration likely • Early shrinking = degeneration likely – Proximal neurons can also be affected. Regeneration • Damaged neurons may regrow. • Regeneration is well developed in invertebrates. – Accurate in both the CNS and PNS. – Accurate even when not in a myelin channel. • Mammals seem to lose their regeneration capabilities during maturation. – Almost non-existent in mammalian CNS. – Hit-or-miss in mammalian PNS. Regeneration • Regeneration in mammals depends on the balance of two competing factors: – Growth promoting factors (higher in PNS) • Neural growth factor (NGF) • Brain-derived neurotrophic factor (BDNF) – Growth inhibiting factors (higher in CNS) • • • • Nogo Myelin-associated glycoprotein (MAG) Chondroitin sulfate proteoglycan (CSPG) Oligodendrocyte myelin glycoprotein (OMG) Regeneration in PNS • If myelin sheaths remain intact, nerve can regrow at mm/day to original destination. • If nerve sections are separated by more than a couple mm, they can grow back thru the wrong myelin tunnels. • If nerves sections are widely separated, both sections will die, or regenerating axon tips will grow wildly into a spaghetti patch. Regeneration • Collateral sprouting – When axons degenerate, adjacent healthy neurons send out axon branches from terminal end or nodes of Ranvier to sites vacated by the dying neuron. – Appears to be mediated by neurotrophic factors released by the denervated target tissue. Neural Reorganization • aka. Plasticity • The ability of the brain to remap its functioning. • 2 Mechanisms: – Rapid reorganization • Altered synaptic strengths – Gradual reorganization: • Establishment of new connections • Collateral sprouting, etc. • Damage repair Neural Reorganization • The extent and mechanisms of neural reorganization are still being debated. • 3 general conclusions – Bona fide recovery is rare. – Small lesions are more likely to be recovered. – Recovery is more likely when young. Therapeutic Implications • Promotion of recovery by neurotransplantation – PNS neurons secrete NGFs and will cause nearby CNS neurons to grow. – Cheng, Cao & Olson (1996) cut an optic nerve, spliced in a PNS nerve segment, and found retinal axon cells projecting to superior colliculus 4 months later. – NGF injection into human CNS promotes a little growth. Anti-nogo allows ~5% regrowth. Therapeutic Implications • Promotion of recovery by rehabilitative training. – At least in motor cortex, greater use = less loss of function (or greater recovery). – Recovery of monkeys with hand motor cortex lesions improved with hand motor tasks. – Humans with spinal cord injuries learn to walk better with rehabilitative treatment than with just physiotherapy. Therapeutic Implications • Promotion of recovery by genetic engineering. – The promise of the future. – Since CNS nerves do not grow because of lack of neural growth factor (NGF), the idea is to introduce some from stem cells or altered viruses. – Nogo also prevents the growth of nerves. Maybe it can be artificially inhibited. Experimental nogo antagonists have been found. Myelination Disorders Myelination Disorders • Dysmyelination – poor myelin formation – Early in life, mostly genetic. – Many disorders • Many affect connection between myelin layers. • Demyelination – myelin destroyed – Later in life, some genetic, mostly autoimmune. Myelination Diseases • Dysmyelination – leukodystrophies (ALD, PMD, Krabbe) - CNS • Demyelination – Guillan-Barré Syndrome (GBS) - PNS – Acute Disseminated Encephalomyelitis (ADEM) CNS – Multiple Sclerosis (MS) - CNS • Combination – Charcot-Marie-Tooth Disease (CMT) – PNS Adrenoleukodystrophy (ALD) • Rare genetic dysmyelination disorder of the CNS with progressive dysfunction of the adrenal gland made famous in the movie “Lorenzo’s Oil.” • (Lorenzo will be 29 in May, 2007. He can no longer speak, see or move on his own, but he can communicate by finger tapping and eye blinking.) Adrenoleukodystrophy (ALD) • Etiology – A genetic defect on Xq28 causes peroxisomes to lose the ability to breakdown very long chain fatty acids (VLCFAs). The accumulating VLCFAs degrade both myelin and the adrenal gland. • Course – Poor prognosis, typical 1-10 years till death. – Progresses to blind, mute and tetraplegic. • “Treatment” – Lorenzo’s Oil, lovastatin, bone marrow transplant Acute Disseminated Encephalomyelitis (ADEM) • CNS demyelination, especially in corpus callosum and white matter in the brain around veins. – analogous to Guillan-Barré Syndrome in PNS. • Probably autoimmune, often appears 1-3 weeks after an antecedent infection or vaccination. • measles, mumps, rubella, varicella, smallpox, herpes, etc. • Monophasic, 30% mortality or 2 week recovery. • A significant number will later develop MS. • SX: fever, visual neuritis, ataxia, stupor, seizures Charcot-Marie-Tooth Disease • Affects the PNS only. • Most common inherited disorder 1 : 2500 • Characterized by: – Progressive muscle dystrophy, starting with distal extremities. – Loss of proprioception and vibration. – No loss of pain and temperature (no myelin). Charcot-Marie-Tooth Disease • Hereditary – Variety of genes, some dominant, some recessive. • 2 major types: – Demyelinating or hypertrophic type • The myelin dies off or doesn’t form properly. • Includes CMT 1, 3, 4 and most X forms. – Axonal type • The axon dies off, leaving the myelin intact. • Includes CMT 2, 5, 6 and some X forms. CMT-X • Etiology – All are mutations in Connexin-32 gene. – Thin myelin sheaths and “onion bulbs.” – CMT-X1, Xq13.1 • point mutation, duplication, or deletion – CMT-X2, Xp22.2 – CMT-X3, Xq26 Multiple Sclerosis • Autoimmune disease of the CNS causes: – Multiple white matter lesions (plaques). – Multiple episodes of neurological deficits. • 1:1000, F = 2xM, MZ = 25%, onset 20-50 • Most common neurological disorder in young Canadians. • Mild neuritis and paresthesias progress to ataxia and paraplegia, with cognitive problems. Multiple Sclerosis • 5x more prevalent in temperate than tropical zones. • Residence at puberty determines risk. • White>black>asian • Native Eskimos, Bantu, American (N&S) Indians have very low risk, despite area. Multiple Sclerosis • Etiology – Autoimmune attack assumed. – There is some genetic and environmental predisposition. – The DNA of HHV-6 (childhood roseola) has been found in plaques. – Proteins of the coronavirus have been found to mimic the structure of MBP. – Antibodies to nerve cells are often found in MS patients. Multiple Sclerosis Plaques in actual brain slice and MR scan of MS brain