Important Points!

1. Important Points! • Website: http://play.psych.mun.ca • Course outline • Course lectures • Study questions • Course info (i.e. change of exam date, class cancelled, assignment info, etc) • Not time in class to cover all material in text, but students are responsible for text and class material for midterms and exams. • Students are responsible for all material covered in class (but not in text).

2. Chapter 15: Neurological Disorders

3. Preview Tumors Seizure Disorders Cerebrovascular Accidents Disorders of Development Degenerative Disorders

4. Tumors Mass of cells whose growth is uncontrolled and that serves no useful function. Malignant Tumor – a cancerous tumor; lacks distinct border and may metastasize. Benign Tumor – a noncancerous tumor; has a distinct border and cannot metastasize. Glioma – a cancerous brain tumor composed of one of several types of glial cells. Meningioma – a benign brain tumor composed of the cells that constitute the meninges.

5. Seizures • Partial seizures– does not involve the whole brain • Generalized seizures– involves the entire brain, widespread. • Simple • Complex • Grand mal – generalized, tonic/clonic • Absence (Petit mal) – generalized, absence of behavior • Causes: • Injury, stroke, developmental abnormality, effect of a growing tumor • Febrile seizures • Infantile fever • Alcohol or barbiturate withdrawal • Genetic factors • Treatment - Anticonvulsant drugs, surgery, diet

6. Cerebrovascular Accidents • Hemorrhagic Stroke - rupture of a cerebral blood vessel • Obstructive Stroke – occlusion of a blood vessel • Thrombus – blood clot that forms within a blood vessel • Embolus – piece of material that forms in one part of the vascular system, breaks off, carried by blood stream until it reaches a smaller artery • Treatment • Clot dissolving drugs • Hypothermia • Constraint-induced movement therapy

7. Preview Tumors Seizure Disorders Cerebrovascular Accidents Disorders of Development Toxic chemicals Inherited metabolic disorders Down Syndrome Degenerative Disorders Disorders Caused by Infectious Diseases

8. Disorders of Development • Toxic Chemicals • During pregnancy, impairs fetal development • Mother contracts rubella (German measles) • Mother ingests alcohol during pregnancy • Inherited Metabolic Disorders • Phenylketonuria (PKU) • Tay-Sachs disease

9. Inherited Metabolic Disorders • Tay-Sachs disease • Causes brain to swell and damage itself against the inside of the skull and dura mater • Metabolic “storage” disease • 1 or more enzymes are missing, waste products cannot be destroyed by lysosomes, accumulation • Lysosomes get larger, cells get larger, brain swells • Symptoms begin around 4 months • Exaggerated startle response, listlessness, irritability, spasticity, seizures, dementia, death

10. Down Syndrome • Genetic accident • ~0.15% of births • Usually occurs during ovulation • Extra chromosome 21 is created in the egg • 3 chromosome 21s in the zygote

11. Down Syndrome • Probability increases with advancing maternal age

12. Genetics of DS • Trisomy 21 • Caused by a nondisjunction event. • a gamete (a sperm or egg cell) is produced with an extra copy of chromosome 21 • Cause of approximately 95% • 88% from nondisjunction in the maternal gamete • 8% from nondisjunction in the paternal gamete. Nondisjunction is the failure of chromosome pairs to separate properly during cell division • The result of this error is a cell with an imbalance of chromosomes

13. Down Syndrome Mosaicism • When some of the cells in the body are normal and other cells have trisomy 21 • This can occur in one of two ways: • Nondisjunction event during early cell division in a normal embryo leads to a fraction of the cells with trisomy 21 • Down syndrome embryo undergoes nondisjunction and some of the cells in the embryo revert to the normal chromosomal arrangement. • Variability in the fraction of trisomy 21, both as a whole and among tissues. • Cause of 1–2%

14. Down Syndrome Robertsonian translocation • The long arm of chromosome 21 is attached to another chromosome, often chromosome 14 or itself (called an isochromosome) • A person with such a translocation is phenotypically normal. • During reproduction, there is a significant chance of creating a gamete with an extra chromosome 21 • Cause of 2–3% of observed cases of Down syndrome. • No maternal age effect, and is just as likely to have come from fathers as mothers.

15. Down Syndrome Duplication of a portion of chromosome 21 • Region of chromosome 21 will undergo a duplication (rare) • Leads to extra copies of some, but not all, of the genes on chromosome 21 • If the duplicated region has genes that are responsible for Down syndrome physical and mental characteristics, such individuals will show those characteristics • Very rare

16. Down Syndrome • Consequences • Disfigurement • Flattened skull and nose • Folds of skin over the inner corners of the eyes • Short fingers • Retarded intellectual development • Often serious medical complications

17. Preview Seizure Disorders CerebrovascularAccidents Disorders of Development Degenerative Disorders variant Creutzfeldt-Jackob (BSE) Parkinson’s Disease Huntington’s Disease Alzheimer’s Disease Multiple Sclerosis Disorders Caused by Infectious Diseases

18. Degenerative Disorders: vCJD • Transmissible Spongiform Encephalopathies • Contagious brain disease whose degenerative process gives the brain a sponge-like appearance. • Bovine Spongiform Encephalopathy (BSE) • Creutzfeldt-Jakob Disease (CJD) • Fatal familial insomnia • Kuru (humans) • Scrapie (sheep) • Prions– protein that can exist in two forms that differ only in their 3-D shape. • Stanley Prusiner (discovered 1986) • Nobel Prize (1997) • Normal prion protein (synaptic protein) • Development and learning and memory • Accumulation of misfoldedprion protein is responsible for TSE.

19. PRION DISEASES • PrPc (normal) and PrPsc (prion infected) • PrPSC-protease-resistant (prion protein also heat resistant) • Abnormal protein taken up into neuron by retrograde transport PrPSC PrPC

20. Transmissible Spongiform Encephalopathies • Encephalopathies • Encephalopathy gives the brain a ‘swiss cheese’-like appearance • Once introduced into the cell thePrPsc can cause the PrPc (normal) to become misfolded • APOPTOSIS: programmed cell death • Caspases: enzymes generated by the cell initiating cell death • BSE: caspase 12

21. Transmissable Spongiform Encephalopathy

22. Creutzfeldt-Jakob Disease (CJD) NEURODEGENERATIVE DISEASE • Rapidly progressive dementia, memory loss, personality changes and hallucinations • Physical problems such as speech impairment, jerky movements, balance and coordination dysfunction (ataxia), changes in gait, rigid posture, and seizures • Death

23. Creutzfeldt-Jakob Disease (CJD) Three recognized methods of affliction • Familial • Sporadic • Acquired • Iatrogenic • Variant (a.k.a. New Variant) • Long incubation periods (4-40 years) • Species Barrier and multiple exposures

24. FOOD FOR THOUGHT 50,000 BSE-infected cattle are estimated to have entered the human food chain before its recognition in 1986 “You’re sick, Jessy!…Sick, sick, sick!”

25. vCJD: Age of Onset British Medical Journal 2001; 322 : 841

26. Preview Seizure Disorders CerebrovascularAccidents Disorders of Development Degenerative Disorders variant Creutzfeldt-Jackob (BSE) Parkinson’s Disease Huntington’s Disease Alzheimer’s Disease Multiple Sclerosis

27. Degenerative Disorders Lewy Body • Parkinson’s Disease • A disease caused by degeneration of the nigrostriatal system – the dopamine-secreting neurons of the substantianigra (send axons to BG) • Lewy Body – abnormal circular structures with a dense core consisting of -synucleinprotein (presynaptic protein); found in dopaminergicnigrostriatal neurons of Parkinson’s patients.

28. DA pathways

29. Parkinson’s Disease • 1% of people over 65 • Symptoms: • Muscular rigidity • Slowness of movement • Resting tremor • Postural instability • Difficulties with handwriting or making facial expressions

30. Genetic causes of PD • Gene mutations • Mutation on chromosome 4 • Gene that codes for alpha-synuclein (SNCA) – located in presynaptic terminal of DA cells • Toxic gain of function • Dominant • Abnormal SNCA becomes misfolded, forms aggregations - make up lewy bodies Toxic gain of function – genetic disorder caused by a dominant mutation that involves a faulty gene that produces a protein with toxic effects

31. Genetic causes of PD • Mutation on chromosome 6- produces an abnormal Parkin protein • Recessive disorder • Loss of function • Normal Parkin plays a role • Trafficking defective/misfolded proteins to proteasomes for destruction (recycling) • Defective Parkin: • Allows abnormally high levels of defective proteins to accumulate in dopaminergic neurons • Fails to ubiquinate abnormal proteins • Ubiquitination – targets the abnormal proteins for destruction by the proteasomes • Kills the cell Fig. 15.16

32. Sporadic PD • ~95% of cases are sporadic (occur in the absence of family history) • Causes: • Toxins present in environment • Insecticides • Faulty metabolism • Unidentified infectious disorder • Toxic chemicals inhibit mitochondrial functions which leads to the aggregation of misfolded alpha-synuclein, in DA neurons, kills the cell

33. Why the Nigrostriatal Pathway? • Ca2+ channels – regulate spontaneous activity of DA cells in NGS pathway • Na+ channels – regulate spontaneous activity of DA cells in other pathways • Animal models – SNCA, increased Ca2+, increased DA = kill cells • DA cells in other pathways don’t contain increased Ca2+, neurons are spared

34. Treatment for PD • L-DOPA – precursor of DA • Increased level of L-DOPA in brain causes remaining DA neurons to secrete more DA, alleviates symptoms • Short-term • Number of nigrostriatal DA neurons decline – symptoms become worse • High levels of L-DOPA produce side effects – acting on DA systems other than nigrostriatal • Hallucinations and delusions

35. Treatment for PD http://www.youtube.com/watch?v=d64iAcaK69M MPTP – 1-methyl-4-phenyl-1,2,3-6-thrahydropyridine • Nonhuman primates respond to MPTP the same as humans • Cell loss in substantia nigra • Level of DA is greatly reduced • Gross motor symptoms • Deprenyl (monamine agoinst) – blocks the effects of MPTP in the animal model • Inhibits the activity of the enyzme MAO-B • Intracellular breakdown of DA by MAO-B causes the formation of H202 – damages the cell • Increases mitochondrial function in the brains of mice • Administration in early Parkinson’s slows the progression of the disease

36. Treatment for PD • Stereotaxic surgery • Transplantation of fetal tissue/neural stem cells • Pallidotomies – surgical destruction of the internal division of the globuspallidus • Electric stimulation or lesion of subthalamic nucleus • Genetically modified virus into the subthalamic nucleus, delivered a gene for GAD (synthesis of GABA) • Causes some of the glutamate neurons into GABA-producing neurons • Symptoms improved

37. Treatment for PD Transplantation of fetal tissue • Re-establish the secretion of DA in the neostriatum • Tissue is obtained from the SN of aborted human fetuses and implanted into the caudate nucleus and putamen • Fetal cells grow in their new host and secrete DA, reducing symptoms (initially) • Develop severe dyskinesias (involuntary movements) • Misfolded SNCA is transferred from the recipient's own neurons to the grafted neurons • No longer recommended

38. Treatment of PD Transplantation of neural stem cells – undifferentiated cells with potential to develop into DA neurons • Transplantation of large number of cells – increasing the numbers of surviving cells • Remond et al., 2007 • MPTP injections in monkeys destroyed nigrostriatal DA neurons • Implanted neural stem cells in the caudate • Stem cells differentiated into DA neurons, astrocytes and other cells that protect and repair neurons • Motor behavior improved

39. GPi - Output of BG • Output, directed through the thalamus to motor cortex, is inhibitory • Decrease in activity of DA input to caudate nucleus and putamen causes an increase in activity of GPi • Damage to GPi might relieve the symptoms of PD

40. Treatment of PD Pallidotomies • MRI to determine location of GPi • low intensity, high-frequency stimulation through electrode GPi, temporarily disabling it • If patients rigidity stopped (patient is awake) • Metabolic activity in premotor and supplementary motor areas returns to normal levels • Release the motor cortex from inhibition

41. Treatment of PD Lesions of subthalamic nucleus • Subthalamic nucleus has an excitatory effect on GPi • Damage to subthalamus decreases the activity of this region and removes some of the inhibition on motor output • Normal people – damage to subthalamus causes involuntary jerking and twitching • PD patients – damage to subthalamus causes normal motor activity (normally depressed)

42. Treatment of PD • Stimulation of subthalamus (deep brain stimulation) • Implant electrodes in subthalamic nucleus and attach a device that permits PD patient to electrically stimulate the brain • Fewer side effects (compared to surgery) • How can stimulation and lesions of the same area produce the same effect???

43. Gene Therapy as a Treatment of PD • Genetically modified virus into the subthalamic nucleus of PD patients • Delivered a gene for GAD (enzyme that makes GABA) • Production of GAD turned some of the glutamate neurons into inhibitory, GABA neurons • Activity of GPi decreased, activity of supplementary motor area increased, symptoms improved

44. Preview Seizure Disorders CerebrovascularAccidents Disorders of Development Degenerative Disorders variant Creutzfeldt-Jackob (BSE) Parkinson’s Disease Huntington’s Disease Alzheimer’s Disease Multiple Sclerosis

45. Huntington’s Disease • Degeneration of caudate nucleus and putamen • Uncontrollable movements, jerky limb movements • Progressive, cognitive and emotional changes • Death (10-15 years)

46. HD • The disease can affect both men and women. • HD is caused by an autosomaldominantmutation in either of an individual's two copies of a gene called Huntingtin, which means any child of an affected person typically has a 50% chance of inheriting the disease. • Physical symptoms of Huntington's disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. • About 6% of cases start before the age of 21 years with an akinetic-rigid syndrome; they progress faster and vary slightly.

47. Huntington’s Disease • Neurodegeneration in the putamen • First: Inhibitory neurons (GABAergic) • Removes inhibitory control of motor areas in cortex (hyperkinetic) • As the disease progresses, neural degeneration occurs in many other regions

48. Huntington’s Disease • GENETICS • Dominant gene on chromosome 4 • Gene that codes the huntingtinprotein (htt) • Repeated sequence of bases that code for the amino acid glutamine • Abnormal httbecomes misfolded and forms aggregates in nucleus • Cell death: apoptosis

49. Huntington’s Disease • Normal Huntingtin (htt) • Forms complex with clatherin, Hip1 and AP2 • Involved in endocytosis and neurotransmitter release • Huntington’s Disease • Htt protein has abnormally long glutamine tract • May lead to abnormal endocytosis and secretion of neurotransmitters • Striatal death by apoptosis • Caspase-3 Nature 415, 377-379 (2002) • Another study: Li et al. 2000 • HD mice with caspase inhibitor lived longer • Inhibits apoptosis

50. Huntington’s Disease • Normal htt facilitates the production and transport of brain derived neurotropic factor (BDNF) • BDNF: neurotropic factor critical for the survival of neurons • BDNF produced in cortex and transported to basal ganglia • Abnormal htt interferes with BDNF in 2 ways: • Inhibits the expression of the BDNF gene • Interferes with the transport of BDNF from the cerebral cortex to the BG