(July, 1823 – May 21, 1860) Phineas P. Gage The Boston Post for September 21, 1848 1 st case widely cited in medicine to infer that brain function can.

(July , 1823 – May 21, 1860)(July , 1823 – May 21, 1860)Phineas P. GagePhineas P. Gage

The Boston Post for September 21, 1848

11stst case widely cited in medicine to infer that brain function can case widely cited in medicine to infer that brain function can alter personalityalter personality

daguerreotypedaguerreotypeBrain DamageBrain Damage

~1850Pattern of injury is very localizedPattern of injury is very localized

-blood vessels spared

- only frontal cortex damaged

- loss of 1 eye

Consciousness regained in days

- personality/behavior dramatically alteredpersonality/behavior dramatically altered

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

Referred to today as classic “hypofrontality”

-common with traumatic injury to the frontal lobes

““Social RecoverySocial Recovery”” Until 2008, commonly thought that he demonstrated these Until 2008, commonly thought that he demonstrated these symptoms until his death, 12 years later. But this was not true…symptoms until his death, 12 years later. But this was not true…

Brain DamageBrain Damage

1.1. Traumatic brain injuryTraumatic brain injury2.2. StrokesStrokes3.3. Alzheimer’s DiseaseAlzheimer’s Disease4.4. Parkinson’s DiseaseParkinson’s Disease

Other neurological disorders discussed in the book willNOT be subject to test questions

Traumatic Brain InjuryTraumatic Brain InjuryFACTS: FACTS:

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

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

What causes TBI?What causes TBI?

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

Who is at highest risk for TBI?Who is at highest risk for TBI?

Males Males are about 1.5 times as likely as females to sustain a TBI.are about 1.5 times as likely as females to sustain a TBI.11 The two age groups at highest risk for TBI are The two age groups at highest risk for TBI are 0 to 4 year olds 0 to 4 year olds and and 15 15 to 19 year olds to 19 year olds Certain military duties (e.g., paratrooper) increase the risk of Certain military duties (e.g., paratrooper) increase the risk of sustaining a TBIsustaining a TBI

Langlois JA (2006)Langlois JA (2006)

Types of Traumatic Brain InjuryTypes of Traumatic Brain Injury

““Closed Head Injury”Closed Head Injury”

ConcussionConcussion. . Concussions are the Concussions are the most common most common type of TBI. A type of TBI. A concussion is concussion is damage to nerves or blood vessels in the brain often caused by damage to nerves or blood vessels in the brain often caused by an impactan impact to the head. to the head.

ContusionsContusions. . A contusion is a A contusion is a bruise or bleeding on the brain bruise or bleeding on the brain that that can be caused by an impact. can be caused by an impact.

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

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

acute: acute: confusion, visual disturbance, unconsciousness if severe confusion, visual disturbance, unconsciousness if severe long-term: long-term: memory problems, sensory problems .memory problems, sensory problems .

- “dementia pugalistica”- “dementia pugalistica”

How does traumatic brain injury develop ?How does traumatic brain injury develop ?-direct, mechanical injury to neurons (axons, dendrites or soma)direct, mechanical injury to neurons (axons, dendrites or soma)

- damage to blood supply deprives neurons and glia of nutrientsdamage to blood supply deprives neurons and glia of nutrients

-Overactivity of glutamate receptorsOveractivity of glutamate receptors

A little bit of A little bit of CaCa2+2+ inflow is good at the right time, too much is toxic inflow is good at the right time, too much is toxic

Strokesdisruption of blood flow in brain 3rd leading cause of death in adults

1.1. HemorrhageHemorrhage: : bleeding in brain, blood vessel bleeding in brain, blood vessel rupturesruptures

- can be from traumatic injury to blood vessel- can be from traumatic injury to blood vessel- can be from “aneurysm”- can be from “aneurysm”

weakening of blood vessel wall, weakening of blood vessel wall, balloonlikeballoonlike

dialation forms and can burstdialation forms and can burst

caused by some caused by some infectionsinfections, , toxinstoxins like like cigarettecigarette

Smoke. Can also be Smoke. Can also be develomental abnormalitydevelomental abnormality..

2.2. Ischemia Ischemia: : blood flow to a brain region is blockedblood flow to a brain region is blocked

- a blockage that comes from another part- a blockage that comes from another partof the body is an “embolism” (vs. thrombosis)of the body is an “embolism” (vs. thrombosis)

for example, a blood clot in leg, can travel to brainfor example, a blood clot in leg, can travel to brainand cause ischemia is gets stuck in a smaller artery.and cause ischemia is gets stuck in a smaller artery.

““arteriosclerosisarteriosclerosis”: fat deposits in brain blood vessels grow”: fat deposits in brain blood vessels growover time and block blood flow. (can become embolism)over time and block blood flow. (can become embolism)

How does a loss of blood supply kill neurons ?How does a loss of blood supply kill neurons ?-deprived neurons become overexcited, release glutamate-deprived neurons become overexcited, release glutamate

-glutamate activates NMDA receptors-glutamate activates NMDA receptors

- and because no blood supply=no energy, no reuptake of glutamate- and because no blood supply=no energy, no reuptake of glutamate

Dementiasdeterioration of intellectual abilities due to disease*memory, judgment, concentration *usually w/ personality changes, emotional

instability

What causes dementia ??What causes dementia ??12-15% 12-15% strokestroke12-15% 12-15% HuntingtonsHuntingtons, , Parkinson’s Diseases (motor diseases)Parkinson’s Diseases (motor diseases)

* other similar disease that are rare* other similar disease that are rare

>5% >5% Korsakoff’s syndromeKorsakoff’s syndrome

severe anterograde amnesiasevere anterograde amnesia

Alzheimer’s Disease Alzheimer’s Disease (leading cause of severe dementia in U.S.)(leading cause of severe dementia in U.S.)- +1% of population, most over 65 yrs old- +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 Alzheimer’s Disease !

But, we know that…:

1. Risk of developing it is heritablethere is a “genetic” factor involved

2. Some AD patients have a specific genetic problemThat can cause early-onset and severe form (~45 yrs old)

Alzheimer’s Disease is probably just 1 term used to describethe symptoms of lots of different diseases that cause

brain damage and similar symptoms.

3. But, many other AD patients don’t have family members with AD and don’t have an identified genetic problem

I. Plaques: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

in late AD: lots of areas

(all areas that produce or receive acetylcholine)

1.1. Plaques are made of a protein called beta-amyloidPlaques are made of a protein called beta-amyloid

2. Beta amyloid come from a normal protein that neurons need to function 2. Beta amyloid come from a normal protein that neurons need to function normally,normally,

called Amyloid Precursor Protein (APP)called Amyloid Precursor Protein (APP)

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

--neurons can get rid of a small amount of beta amyloid, butneurons can get rid of a small amount of beta amyloid, butif there is too much, beta amyloid clumps together to form plaques inside of if there is too much, beta amyloid clumps together to form plaques inside of

neurons.neurons.Neurons don’t function normally and die-offNeurons don’t function normally and die-off

Key to understanding plaques:Key to understanding plaques:

II. Tangles:II. Tangles: Many AD patients also have “tangles” in neurons

Microtubules are long string-like structures that transportthings from the cell body to the end of the axon and dendrites

In AD, these microtubules break apart and In AD, these microtubules break apart and collapse into a tangles mess and neurons don’t function normally,collapse into a tangles mess and neurons don’t function normally,so they die-off.so they die-off.

Tau proteins (like rungs of a ladder)

Normal Human

Human with Alzheimer’s Disease

Gross Pathology:Gross Pathology:

Ventricles largerVentricles larger

gray matter lossgray matter loss

white matter losswhite matter loss

Drug Treatment of DementiasDrug Treatment of DementiasDrugs approved by the U.S. Food and Drug Administration

Cognex®

Aricept®

Reminyl®

Exelon®

Namenda®

All are inhibitors of acetylcholinesterase, except Namenda

1.1. AcetylcholineAcetylcholine is release from “presynaptic” neuron, and then re-absorbed is release from “presynaptic” neuron, and then re-absorbed

lots of it in hippocampus and cortexlots of it in hippocampus and cortex

2. 2. AcetylcholinesteraseAcetylcholinesterase is an enzyme that breaks down acetylcholine is an enzyme that breaks down acetylcholine

3. That means that 3. That means that more acetylcholine is present in synaptic cleft to stimulatemore acetylcholine is present in synaptic cleft to stimulate receptors receptors on neurons in learning/memory areason neurons in learning/memory areas

YOU DON’T NEED TO KNOW THESE

Key facts about acetylcholinesterase inhibitors:

some improvement in daily living skillssome 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®Namenda® FDA approved to treat late-stage Alzheimer’s FDA approved to treat late-stage Alzheimer’s

the newest approved drug (2004)the newest approved drug (2004)

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

-Based on theory that over activity of NMDA receptors contributeBased on theory that over activity of NMDA receptors contribute to neuron death in Alzheimer’s diseaseto neuron death in Alzheimer’s disease

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

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

Parkinson’sParkinson’s DiseaseDisease

""An Essay on the Shaking PalsyAn Essay on the Shaking Palsy," ," published in 1817 by a London published in 1817 by a London physician named James Parkinson, physician named James Parkinson,

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

SymptomsDifficulty initiating movementDifficulty initiating movementShuffling gaitShuffling gait““Cogwheel” rigidityCogwheel” rigidityTremor at restTremor at restAdvanced stages may include psychiatric Advanced stages may include psychiatric

complicationscomplicationsdepressiondepressionhallucinationshallucinationsParanoiaParanoiaCognitive declineCognitive decline

http://www.youtube.com/watch?v=13ftfmYwfaw

IncidenceOnset usually appears after age of 40 years Onset usually appears after age of 40 years

but can begin at any time including childhood but can begin at any time including childhood when it is termed when it is termed juvenile parkinsonismjuvenile parkinsonism

affects 1% aged 50 years and overaffects 1% aged 50 years and over

10% aged 60 years and over may have 10% aged 60 years and over may have undiagnosed, early stages of the diseaseundiagnosed, early stages of the disease

about 1½ times more common in men than about 1½ times more common in men than in womenin women

Subtypes

PrimaryPrimary (idiopathic- most common) (idiopathic- most common) unknown origin but unknown origin but notnot induced by obvious induced by obvious

stimulusstimulus

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

FamilialFamilialgenetically linkedgenetically linkedaccounts for < 20% of the diagnosed casesaccounts for < 20% of the diagnosed cases

Progression: identified too late ?

Considerable dopamine loss must occur Considerable dopamine loss must occur before the disease is apparentbefore the disease is apparent

clinical diagnosis is usually made after clinical diagnosis is usually made after 80% 80% loss loss in in basal gangliabasal ganglia dopamine content dopamine content

symptoms may emerge after a symptoms may emerge after a 60% reduction 60% reduction in basal ganglia dopamine contentin basal ganglia dopamine content

The disease is probably present > 20 years The disease is probably present > 20 years before diagnosisbefore 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 Parkinson’s DiseaseSubstantia Nigra neurons die = reduced excitatory input into basal ganglia

The two parts of the basal ganglia (Caudate and Putamen) also die

brain photographs courtesy of the brain photographs courtesy of the University of Utah Medical SchoolUniversity of Utah Medical School

Roberta J. SeidmanRoberta J. Seidman, , M.D.,M.D., SUNYSUNY

Shrunken Substantia NigraShrunken Substantia Nigra

Loss of cellular activity in the Basal Loss of cellular activity in the Basal GangliaGanglia

PET Scan PET Scan

Pathology in Parkinson’s DiseasePathology in Parkinson’s Disease

Lewy body pathology: Lewy body pathology: these bodies are circular structuresthese bodies are circular structures found in cytoplasm.found in cytoplasm.

-Dense core of protein called Dense core of protein called αα-synuclein-synuclein

- normally aids in synaptic vesicle function- normally aids in synaptic vesicle function

Abnormality in gene that makes this protein is aAbnormality in gene that makes this protein is asignificant risk for Parkinson’s diseasesignificant risk for Parkinson’s disease

Many environmental toxins lead to clumping ofMany environmental toxins lead to clumping ofαα-synuclein too (pesticides, drugs of abuse ?)-synuclein too (pesticides, drugs of abuse ?)

Parkin abnormalities ? (familial PD)Parkin abnormalities ? (familial PD) gene mutation that is a risk factor for Parkinson’s Diseasegene mutation that is a risk factor for Parkinson’s Disease

ParkinParkin: a protein found in neurons that transport abnormal proteins: a protein found in neurons that transport abnormal proteins to a “to a “proteosomeproteosome” and tag these proteins with a “death flag”” and tag these proteins with a “death flag” called “called “ubiquitinubiquitin”.”.

““Ubiquitination” of a protein signals the proteosome to degrade the Ubiquitination” of a protein signals the proteosome to degrade the protein into its amino acid subparts.protein into its amino acid subparts.

Overactivity of Parkin in brain regions controlling motor function canOveractivity of Parkin in brain regions controlling motor function cancause over-activation of the proteosomecause over-activation of the proteosome

neuronal deathneuronal 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 surgerylesions 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)

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.

PET images courtesy of the UCLA School of Medicine, Division of Brain Mapping

Substantia nigra cells were surgically implanted into the right putamen. Note the continued degeneration seen on the contralateral (left) side revealed by the PET.