“The Brain for Not-So-Dummies”
Osher Lifelong Learning Institute
NCSU
Eric W. Harris, PhD.
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.com
 Or, hand them to the Class Assistant
Good sources of info about the brain & neuroscience
 The Society for Neuroscience (www.sfn.org) – in particular, “BrainFacts.org”
 The Dana Foundation www.dana.org
 http://faculty.washington.edu/chudler/neurok.html (Neuroscience for Kids)
 http://medicalxpress.com/neuroscience-news/
 The Brain Science Podcast – not for total beginners
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
Follow-up (cont’d): M/F Differences in brain maturation
Blue = Male
Red = Female
Frontal lobe
Parietal lobe
Temporal lobe
Occipital lobe
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)…
…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.
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)
Huntington’s Disease – Pathology in the Basal Ganglia
Striatal “medium spiny neurons” are the most vulnerable
Neuronal Circuitry Change in HD
Normal
HD
Net Loss of
inhibition
from GPi,
more excit.
of Sp.Cord
HD Patholgy not just in striatum, and not all patients the same
Neurons in Primary Motor Cortex (BA4)
Normal
HD Motor Sympt
HD Mixed
HD Mood Sympt
Anterior Cingulate Cortex (BA24)
Normal
HD Motor Sympt
HD Mixed
HD Mood Sympt
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
Huntington’s Disease – Search for the gene
Nancy Wexler
circle =♀; square = ♂; black = had HD; slash = deceased
The HD gene is located on the short (p) arm of chromosome 4 (1983)
What does this gene do? First a few words about genes…
Chains of
Nucleotides
Chain of
Amino acids
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.
CELL NUCLEUS
CELL CYTOPLASM
mRNA
The HD gene (HTT)
DNA sequence
Amino Acid
Sequence
Multiple CAGs
(CAG → glutamine,
abbreviated as “Q”)
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
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
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)
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
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.
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
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.
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