daguerreotype

Brain Damage

The Boston Post for September 21, 1848

Phineas P. Gage
(July , 1823 May 21, 1860)
1st case widely cited in medicine to infer that brain function can alter personality
 ~1850
Pattern of injury is very localized
-blood vessels spared

- only frontal cortex damaged

- loss of 1 eye

Consciousness regained in days

- personality/behavior dramatically altered

- child-like, profane, disinhibited, inappropriate, inability to control anger and

emotions.

Referred to today as classic hypofrontality

-common with traumatic injury to the frontal lobes

Social Recovery Until 2008, commonly thought that he demonstrated these

symptoms until his death, 12 years later. But this was not true
Brain Damage

1. Traumatic brain injury

2. Strokes
3. Alzheimers Disease
4. Parkinsons Disease

Other neurological disorders discussed in the book will

NOT be subject to test questions
Traumatic Brain Injury
FACTS:

1.4 million who sustain a TBI each year in the United States (0.5% of people in U.S.)

50,000 die;
235,000 are hospitalized; and
1.1 million are treated and released from an emergency department.

What causes TBI?

Falls (28%)
Motor vehicle-traffic crashes (20%)
Struck by/against (19%)
Assaults (11%)

Who is at highest risk for TBI?

Males are about 1.5 times as likely as females to sustain a TBI.1

The two age groups at highest risk for TBI are 0 to 4 year olds and 15 to 19 year olds
Certain military duties (e.g., paratrooper) increase the risk of sustaining a TBI
Langlois JA (2006)
Types of Traumatic Brain Injury

Closed Head Injury

Concussion. Concussions are the most common type of TBI. A concussion is

damage to nerves or blood vessels in the brain often caused by an impact to the head.

Contusions. A contusion is a bruise or bleeding on the brain that can be caused

by an impact.

Diffuse Axonal Injury. This is tearing of nerve tissue or blood vessels when the
brain is jostled in the skull. It can result from shaking (for instance, shaken baby syndrome)
or whiplash

Coup-countrecoup Injury. impact not only injures the site of impact, but causes
the brain to impact with the skull, causing injury to the opposite side of the brain.

Symptoms:
acute: confusion, visual disturbance, unconsciousness if severe
long-term: memory problems, sensory problems .
- dementia pugalistica
 How does traumatic brain injury develop ?
-direct, mechanical injury to neurons (axons, dendrites or soma)

- damage to blood supply deprives neurons and glia of nutrients

-Overactivity of glutamate receptors

-Activation of NMDA-type glutamate receptors

-Inflow of too much Ca2+ into neurons

- activates death enzymes that break down

neuron

-Impairs neuron ability to meet energy

requirements
-Triggers cell death

A little bit of Ca2+ inflow is good at the right time, too much is toxic
Strokes
disruption of blood flow in brain
3rd leading cause of death in adults
1. Hemorrhage: bleeding in brain, blood vessel ruptures

- can be from traumatic injury to blood vessel

- can be from aneurysm

weakening of blood vessel wall, balloonlike

dialation forms and can burst

caused by some infections, toxins like cigarette

Smoke. Can also be develomental abnormality.
2. Ischemia: blood flow to a brain region is blocked

- a blockage that comes from another part

of the body is an embolism (vs. thrombosis)

for example, a blood clot in leg, can travel to brain

and cause ischemia is gets stuck in a smaller artery.

arteriosclerosis: fat deposits in brain blood vessels grow

over time and block blood flow. (can become embolism)

How does a loss of blood supply kill neurons ?

-deprived neurons become overexcited, release glutamate
-glutamate activates NMDA receptors
- and because no blood supply=no energy, no reuptake of glutamate
Dementias deterioration of intellectual abilities due to disease
*memory, judgment, concentration
*usually w/ personality changes, emotional
instability
What causes dementia ??
12-15% stroke
12-15% Huntingtons, Parkinsons Diseases (motor diseases)
* other similar disease that are rare

>5% Korsakoffs syndrome

severe anterograde amnesia

Alzheimers Disease (leading cause of severe dementia in U.S.)

- +1% of population, most over 65 yrs old
The severity and type of symptoms observed is directly related to death of
neurons in several brain regions.
 Causes ?

We do NOT know what causes Alzheimers Disease !

But, we know that:

1. Risk of developing it is heritable
there is a genetic factor involved
2. Some AD patients have a specific genetic problem
That can cause early-onset and severe form (~45 yrs old)

3. But, many other AD patients dont have family members

with AD and dont have an identified genetic problem

Alzheimers Disease is probably just 1 term used to describe

the symptoms of lots of different diseases that cause
brain damage and similar symptoms.
 I. Plaques: most AD patients have plaques in
parts of the brain that show cell loss

in early AD: medial temporal lobe areas

(hippocampus) and cortex
(all areas that produce or receive acetylcholine)

in late AD: lots of areas

Key to understanding plaques:

1. Plaques are made of a protein called beta-amyloid

2. Beta amyloid come from a normal protein that neurons need to function normally,
called Amyloid Precursor Protein (APP)

3. but, APP is cut by enzymes into abnormal amounts of beta amyloid.

-neurons can get rid of a small amount of beta amyloid, but

if there is too much, beta amyloid clumps together to form plaques inside of neurons.
Neurons dont function normally and die-off
II. Tangles: Many AD patients also have tangles in
neurons

Microtubules are long string-like structures that transport

things from the cell body to the end of the axon and dendrites

Tau proteins (like rungs of a ladder)

In AD, these microtubules break apart and

collapse into a tangles mess and neurons dont function normally,
so they die-off.
 Normal Human

Gross Pathology:

Ventricles larger

gray matter loss

Human with Alzheimers Disease

white matter loss

Drug Treatment of Dementias
Drugs approved by the U.S. Food and Drug Administration

Cognex
Aricept
Reminyl YOU DONT NEED TO KNOW THESE
Exelon
Namenda
All are inhibitors of acetylcholinesterase, except Namenda

1. Acetylcholine is release from presynaptic neuron, and then re-absorbed

lots of it in hippocampus and cortex

2. Acetylcholinesterase is an enzyme that breaks down acetylcholine

3. That means that more acetylcholine is present in synaptic cleft to stimulate

receptors on neurons in learning/memory areas
Key facts about acetylcholinesterase inhibitors:

some improvement in daily living skills

some delay in progression of disease

BUT, typically a small effect and occurs in a small % of patients

Can be very toxic to the liver

Namenda FDA approved to treat late-stage Alzheimers

the newest approved drug (2004)

Namenda - blocks the NMDA receptor for a very short period of time

-Based on theory that over activity of NMDA receptors contribute

to neuron death in Alzheimers disease

Does it work ?: small effects in a small # of patients

But, these small effects have a dramatic effect on quality of life

Parkinsons Disease

mentioned in the Ayurveda, the system of

medicine practiced in India as early 7,000 years
ago , and in the first Chinese medical text, Nei
Jing, which appeared 2500 years ago

"An Essay on the Shaking Palsy," published in

1817 by a London physician named James
Parkinson,
Symptoms
Difficulty initiating movement
Shuffling gait
Cogwheel rigidity
Tremor at rest
Advanced stages may include psychiatric complications
depression
hallucinations http://www.youtube.com/watch?v=13ftfmYwfaw
Paranoia
Cognitive decline
Incidence
Onset usually appears after age of 40 years
but can begin at any time including childhood when
it is termed juvenile parkinsonism

affects 1% aged 50 years and over

10% aged 60 years and over may have undiagnosed,

early stages of the disease

about 1 times more common in men than in

women
Subtypes
Primary (idiopathic- most common)
unknown origin but not induced by obvious stimulus

Secondary (parkinsonism)
related to drugs, stroke, or trauma, other stimuli

Familial
genetically linked
accounts for < 20% of the diagnosed cases
Progression: identified too late ?
Considerable dopamine loss must occur before the
disease is apparent

clinical diagnosis is usually made after 80% loss in

basal ganglia dopamine content

symptoms may emerge after a 60% reduction in basal

ganglia dopamine content

The disease is probably present > 20 years before

diagnosis
 Meso-Striatal Dopamine system
COMPONENTS OF THIS SYSTEM

1. Substantia Nigra- in midbrain

- send fibers to Basal Ganglia
- releases dopamine = movement

2. Basal Ganglia (part of striatum)-

-sends fibers to motor cortex
-receives fibers from sensory
cortex and substantia Nigra
In Parkinsons Disease
Substantia Nigra neurons die
= reduced excitatory input
into basal ganglia

The two parts of the basal

ganglia (Caudate and
Putamen) also die
Postmortem Analysis

brain photographs courtesy of the

University of Utah Medical School
Shrunken Substantia Nigra
Roberta J. Seidman, M.D., SUNY
PET Scan

Loss of cellular activity in the Basal Ganglia

 Pathology in Parkinsons Disease

Lewy body pathology: these bodies are circular structures

found in cytoplasm.

-Dense core of protein called -synuclein

- normally aids in synaptic vesicle function

Abnormality in gene that makes this protein is a

significant risk for Parkinsons disease

Many environmental toxins lead to clumping of

-synuclein too (pesticides, drugs of abuse ?)
Parkin abnormalities ? (familial PD)
gene mutation that is a risk factor for Parkinsons Disease

Parkin: a protein found in neurons that transport abnormal proteins

to a proteosome and tag these proteins with a death flag
called ubiquitin.

Ubiquitination of a protein signals the proteosome to degrade the

protein into its amino acid subparts.

Overactivity of Parkin in brain regions controlling motor function can

cause over-activation of the proteosome

neuronal death
Treatment

Levodopa (L-dopa) therapy (L-dopa is a dopamine precursor)

generally very effective for the first 2 to 5 years of
treatment after which the on-off effect develops

Direct-acting dopamine receptor agonists

Experimental brain surgery

lesions of nuclei that inhibit basal ganglia
- remove inhibition of dying neurons, they may be more active = motor
control
neural tissue implants (e.g., fetal dopamine cells)
 Substantia nigra cells were surgically implanted into the right putamen. Note
the continued degeneration seen on the contralateral (left) side revealed by the
PET.

PET images courtesy of the UCLA School

of Medicine, Division of Brain Mapping

Recently, Deep Brain stimulation - indwelling electrodes

implanted in some of the dying neurons. Patients can stimulate
electrodes , provides a brief pulse to these neurons, which
rapidly restores some control of motor activity.