1. “The Brain for Not-So-Dummies” Osher Lifelong Learning Institute NCSU Eric W. Harris, PhD.

2. Requests  Silence cell phones etc.  Please do interrupt me with “clarifying questions” about anything I’ve said today  Please save general questions, speculations, stories etc. until the end of class  Please give feedback, suggestions, questions  Send to ask.eric.about.neuro@gmail.comask.eric.about.neuro@gmail.com  Or, hand them to the Class Assistant

3. Good sources of info about the brain & neuroscience  The Society for Neuroscience (www.sfn.org) – in particular, “BrainFacts.org”www.sfn.org  The Dana Foundation www.dana.orgwww.dana.org  http://faculty.washington.edu/chudler/neurok.html (Neuroscience for Kids) http://faculty.washington.edu/chudler/neurok.html  http://medicalxpress.com/neuroscience-news/ http://medicalxpress.com/neuroscience-news/  The Brain Science Podcast – not for total beginners

4. Follow-up Acetaminophen and NSAIDs are not effective against phantom limb pain Not surprising, as they tend to act at the site of injury However, use of NSAIDs pre- and post-operatively during amputation seems helpful in reducing subsequent phantom limb pain

5. Follow-up (cont’d): M/F Differences in brain maturation Frontal lobe Parietal lobe Temporal lobe Occipital lobe Blue = Male Red = Female

6. Week 3- Pathophysiology of selected brain disorders  There are many types/causes of neuro/psychc disorders:  Genetics (e.g., Down’s Syndrome)  Development (e.g., schizophrenia)  Chemical exposure (e.g., parkinsonism)  Physical trauma (e.g., Traumatic Brain Injury)  Emotional trauma (e.g., Post-Traumatic Stress Disorder)  Lifestyle (sleep deprivation)  Age (Alzheimer’s Disease)  Cardiovascular disease (e.g., stroke)…

7. …But, we have only 90 minutes  For this course I’ve selected:  Huntington’s Disease  Interesting and increasingly common type of genetic problem  variant Creutzfeld Jacob Disease  Interesting new transmissibility mechanism  Autism  Interesting insights into the dangers of bad science and the difficulties of good science  Next week, when discussing treatments, I’ll cover Pain, Parkinson’s, Epilepsy.

8. Huntington’s Disease “Chorea” = abnormal dance-like movements Initial symptoms are typically apathy, irritability, depression, mood alterations Usually presents 35 - 45 years of age, progressive deterioration over 15 - 20 years Rare (~6/100,000 in North America)

9. Huntington’s Disease – Pathology in the Basal Ganglia Striatal “medium spiny neurons” are the most vulnerable

10. Neuronal Circuitry Change in HD Normal Net Loss of inhibition from GPi, more excit. of Sp.Cord HD

11. HD Patholgy not just in striatum, and not all patients the same Neurons in Primary Motor Cortex (BA4) Anterior Cingulate Cortex (BA24) Normal HD Motor Sympt HD Mixed HD Mood Sympt

12. HD is a very curious genetic disorder  HD is an autosomal dominant disease, affects men and women  Children of affected individuals have a 50/50 chance of getting the disease  More common in people of Western European descent Asian or African  Usually begins between 35 and 44 years of age  Can present as early as infancy  Children of unaffected people have developed HD  So-called “sporadic HD” (3% of cases) Woody Guthrie

13. Huntington’s Disease – Search for the gene circle = ♀ ; square = ♂ ; black = had HD; slash = deceased Nancy Wexler The HD gene is located on the short (p) arm of chromosome 4 (1983)

14. What does this gene do? First a few words about genes… DNA has 4 “Letters” = A, T, C, G RNA has 4 “Letters” = A, U, C, G Each has a match: DNA RNA A -> U T -> A C -> G G -> C The “words” in DNA and RNA are 3-letters long, each word “translates” to an amino acid: UUG → leucine, GCG → alanine CAG → glutamine, etc. Chain of Amino acids Chains of Nucleotides

15. mRNA CELL NUCLEUS CELL CYTOPLASM

16. The HD gene (HTT) Multiple CAGs (CAG → glutamine, abbreviated as “Q”) DNA sequence Amino Acid Sequence

17. HD – a “polyglutamine-repeat” disorder  In normal individuals, there are 10 to 35 CAG-repeats.  If >35 CAGs, HD is likely; if >40, HD is certain.  >60 CAGs causes a severe form of HD known as ”juvenile HD”.  As the altered gene is passed from one generation to the next, the number of the CAG repeats can increase (due to errors in gene copying), especially when it is inherited from the father.  This explains “sporadic” HD

18. Role of the Huntington protein (Htt)  Htt is expressed throughout the body  Highly expressed in neurons and testes  Very similar across many species (so, an “old” protein)  Is not similar to any other protein in humans  Htt is primarily associated with vesicles and microtubules.  May be important for cytoskeletal anchoring, transport for mitochondria?  Htt has been implicated in regulating “selective autophagy”  Normally, a process for the cell to degrade/recycle proteins  Intriguing hypothesis that Htt may be an brain complexity promoting protein  Numbers of repeats increases as species brain complexity increases  Preliminary evidence of increased brain gray matter with increased #CAGs

19. HD – Prognosis  Is invariantly progressive and fatal  Palliative treatments are generally only somewhat effective, have limiting side-effects  Drugs for dyskinesia, depression, etc.; physical therapy, speech therapy etc.  No treatments shown to change the course of the disease  Have known the gene for >20 years!  Recently, a large study of creatine showed no benefit.  There is a test for the gene for people at risk, if they want it  Can be used for “pre-implantation genetic diagnosis” (i.e., use only those embryos without the HD gene)

20. Creutzfeld-Jacob Disease (CJD)  CJD is a rare, rapidly progressing, invariably fatal neurodegenerative disorder.  The disease is found most frequently in patients 55–65 years of age, but cases can occur in people older than 90 years and younger than 55 years of age.  In more than 85% of cases, the duration of CJD is less than 1 year after onset of symptoms.  Very curious disease, that has revolutionized our understanding of disease… George Ballanchine

21. CJD is a “Spongiform encephalopathy” CJD is characterized by rapidly progressive dementia. Initially, individuals experience muscular incoordination personality changes, impaired memory, judgment, and thinking impaired vision People with the disease also may experience insomnia, depression, or unusual sensations.

22. CJD Subtypes  There are 4 recognized subtypes:  Sporadic CJD: the person has no known risk factors for the disease; 85 % of cases.  Hereditary CJD: family history of the disease and/or tests positive for a genetic mutation associated with CJD. About 5 to 10 % of CJD cases in the US are hereditary. Hereditary CJD is autosomal dominant (i.e., 50% chance of getting from an affected parent)  Variant CJD – caused by exposure to tissue from cows with “Mad Cow Disease”  Iatrogenic CJD: transmitted by a medical procedure that caused exposure tissue from a patient with CJD. About 1% of CJD cases

23. Iatrogenic CJD has unusual transmissibility  A case of CJD associated with a corneal transplant was reported. Animal experiments showed that corneas of infected animals could transmit CJD, and the causative agent spreads along visual pathways.  CJD transmission was caused by silver electrodes previously used in the brain of a person with CJD. Transmission occurred despite decontamination of the electrodes with ethanol and formaldehyde.  In some cases, the exposure occurred weeks after the instruments were used on a person with CJD.

24. CJD has unusual transmissibility – (Continued)  Reminiscent of “kuru”  Transmitted by cannibalism and/or handling of human brain tissue  Can be transmitted only to primates  Does not appear to involve any inflammation, fever  Found that heritable CJD could be transmitted to primates!?  Reminiscent of the sheep disease scrapie  infectious agent was not bacteria, nor virus, nor involved DNA or RNA!?...  For both, transmission more effective the more closely-related the species, and symptoms can take a year to develop!?... Carlton Gajdusek 1976 Nobel Prize