Lecture 8 (1): Causes of brain dysfunction (tumors, strokes, contusion & hematoma, mTRI, CTE

Encapsulated tumors

20% of tumors

Tumors, aka neoplasms

Meningioma–better type,grow between the menings

Encapsulated: Has a membrane, so you can see the line between healthy region and tumor region. Remove → rare recurrence, great recovery

Benign: Does not invade nearby tissues, and does not metastasize (spread) to other parts of the body

Infiltrating tumors

80% of tumors

Grow diffusely through surrounding brain tissue (no clear lines to seperate healthy and unhealthy brain tissue)

Referred to as Malignant, because (a) Even removing it, (almost guaranteed that) it’s gonna grow back., and (b) Aggressive growth

Encapsulated tumors

20% of tumors

Tumors, aka neoplasms

Meningioma–better type,grow between the menings

Encapsulated: Has a membrane, so you can see the line between healthy region and tumor region. Remove → rare recurrence, great recovery

Benign: Does not invade nearby tissues, and does not metastasize (spread) to other parts of the body

Infiltrating tumors

80% of tumors

Grow diffusely through surrounding brain tissue (no clear lines to seperate healthy and unhealthy brain tissue)

Referred to as Malignant, because (a) Even removing it, (almost guaranteed that) it’s gonna grow back., and (b) Aggressive growth

Metastatic tumors

Some infiltrating brain tumors grow from a body part (tumor fragments) and carried them to the brain via the bloodstream

Quite malignant, usually infiltrating

Commonly originate from breast cancer or lung cancer

Where do most tumors come from?

Glia! Not neurons! In adulthood, we’re not really creating new neurons, that can clump into tumors, instead, from astrocytes or oligodendrocytes, most commonly.

Glioblastoma

Most common type of malignant brain tumor in adults (40%) astrocytes grow out of control.

Most malignant (guaranteed that it grows back even after removing it)

Very very small survival rate

From diagnosis to the end of your life: 14 months (thats including removing the largest part to slow it down

What exactly are strokes?

Sudden-onset cerebrovascular (blood flow in the brain) disorders that cause brain damage

During the stroke, you are disrupting the blood flow in the brain → no oxygen and glucose coming in → lose ATP production → inactive sodium-potassium pump → lose the ability to maintain resting potential, can’t fire action potential → cell death within 5 mins

Infarct

The direct area of dead/dying tissue. By the time you get to the hospital, this part is already dead, so the doctor won’t try to save this part

Penumbra

Dysfunctional area surrounding the infarct — getting some glucose and blood flow, but not enough that it’s dysfunctional.

Tissue in this area may either recover or die (maximize the chance of surviving). Doctors will try to save this region.

Ischemic stroke

The area that has a Clot blocking blood flow in the artery, and any branches after that doesn’t get blood

i.e. resulting from cerebral ischemia

Hemorrhagic stroke

You still have an infarct, but you also have the bleeding in the brain as a secondary concern, cuz (a) blood has a toxic effect (high level of iron), (b) blood is a highway of pathogens (risk of infection)

i.e. resulting from cerebral hemorrhage

Better recovery than ischemic strokes

Cerebral hemorrhage: Aneurysm

Most commonly in arteries than veins

Ballooning of a blood vessel due to a weakened vessel wall → pop

Can be congenital (born with this) or develop later

Risk factors: Diabetes, hypertension, smoking cigarettes, alcoholism, but the biggest predictor is aging (40-60 —2%, 60-80—7%)

Treatment option 1 for Aneurysm: Clipping

Requires craniotomy (open brain surgery), but slightly lower rate of recurrence than treatment option 2, and permanent solution

Titanium clip (cuz not magnetic, so MRI-safe), clip the neck of aneurysm (where the blood is entering), and the blood in the aneurysm dome (balloon part) will dry and harden, and you just leave it like that! It’s too risky to take it out!

Advantages of clipping (older treatment of aneurysm)

Lower rate of recurrence than option 2, and permanent solution

Risk of clipping (older treatment of aneurysm)

Brain swelling or stroke (due to blood vessel manipulation), Seizures (in some cases), Infection when you put the piece of skull back on, or over-bleeding at the surgical site

Undergo really hard anesthesia (risk of low tolerance of anesthesia as you get older → dangerous)

Treatment option 2 for Aneurysm: Endovascular coiling

Coil is made of platinum (interact w blood → preventing blood from filling it more)

While using the real-time X-ray machine to navigate, cut open the femoral artery (the largest artery, and it’s in your thigh), insert a tube in the thigh, up to the heart, up to the brain, and insert a coil in the aneurysm dome

Advantages of endovascular coiling (Newer treatment for aneurism)

FARRRRRR less invasive than clipping, much less risk of infection

Risks of endovascular coiling (Newer treatment for aneurism)

Higher rate of recurrence

Cerebral ischemia

Blockage inside the artery itself

Three main causes of cerebral ischemia

1. Thrombosis: Plug the artery when it becomes narrow, so anything after is clogged by blood

2. Embolism: A moving thrombosis (can be anything that’s not blood, piece of fat, tumor tissue, air bubble, etc.)

3. Arteriosclerosis: Narrowing of the artery + relatively small thrombosis(due to cholesterol), plugging much further in the branch

Thrombosis

Plug the artery when it becomes narrow, so anything after is clogged by blood

Embolism

A moving thrombus (can be anything that’s not blood: piece of fat, tumor tissue, air bubble, etc.)

Arteriorsclerosis

Narrowing of the artery + relatively small thrombus (due to cholesterol), plugging much further in the branch

Ischemia-produced brain damage has three important properties

1. It takes a while to develop (can be days)

2. Some parts of the brain are more at risk (e.g. hippocampus—probably cuz it’s more metabolically active → hard to detect through fMRI cuz BOLD level is high in general)

3. The mechanisms of ischemia-induced damage vary between brain structures

   • One example of why you get ischemia stroke wayyy later after the blockage: excitotoxicity

Excitotoxicity

1. Blood clog in penumbra

2. Less O2 → less energy (ATP)

3. Na K pumps are not working (that normally maintain resting potential)

4. Glutamate keeps releasing until too much (glutamate excitory level)

5. Lots of binding on NMDA receptors → NMDA allow Ca+ to enter the cell

6. Too much Calcium coming in (Ca usually triggers apoptosis)

7. ACCIDENTAL apoptosis → Some of the penumbra will die

Apoptosis

Programmed cell death, and it’s normal

Normally, apoptosis is valuable in day-to-day life. On a daily basis, we need millions of cell removal, cuz it’s a major part of development

So what can we do to avoid the apoptosis?

The idea is: Targeting NMDA receptor with the hope of saving penumbra → control the amount of Ca coming in → reduce the likelihood of apoptosis

BUT!!! It hasn’t been effective so far, cuz the Ca is still coming in

On the axon terminal, there’s voltage-gated Ca terminal. If the cell is unable to maintain the resting potential, maybe it accidentally open these gate channels and let the Ca come in anyway

Open-head injuries

Gets through the skull (ex. bullets, 73% of gunshot to head dies on the spot)

Perforating means smth comes in through one side of the skull, to the other side of the skull

Penetrating means coming in just one side

Typically very severe

High risk of infection, complications

High velocity (high speed) worse than low

• That’s why gunshot in your head is 90% death rate (So go in ur head slowly is safer)

Closed-head injuries: Contusion

A bruise caused by capillary damage, leading to bleeding under the skin or brain tissue. So you got a crack in the head, but it doesn’t penetrate through the skull.

Involve damage to the cerebral circulatory system, producing internal hemorrhaging and a resultant hematoma–The bleeding that harden and clot, that forms within or outside an organ

Occurs where the brain slams against the skull

Epidural hematoma

Bleeding and harden in between the skull and the menings

The least risky one out of all types of hematoma

Subdural hematoma

Bleeding and harden between dura mater and arachnoid mater

Intracranial hematoma

Bleeding and harden in the brain itself

The worst hematoma

Coup contrecoup injury

When you hit ur head.

Coup Injury (Primary Impact) (called coo injury)

• The brain hits the inside of the skull at the site of impact.

• This is common in direct head trauma (e.g., falling and hitting your forehead

Contrecoup Injury (Rebound Impact)

• The force then causes the brain to slam against the opposite side of the skull.

• This often happens in high-impact injuries like car accidents, where the head forcefully jerks forward and backward

Mild traumatic brain injury (mTBI)

• Mild trauma to the brain without skull fracture or severe bleeding

• When there is a blow to the head but no evidence of contusion (bruising) or other structural damage. It’s not mild tho, there’ll still be disruptions in your life

• Typically synonymous with concussion, which is a syndrome, but you can injure your brain without getting a concussion (subconcussive mTBIs)

• Temporary damage ex.: Super sensitive to light, sleep disorder, mood, attention span, dizziness

• The damage last 8-19 months, and can’t take the blow in the head again during this healing duration

Subconcussive mTBIs

A brain impact that does not cause immediate concussion symptoms but may still lead to cumulative brain damage over time.

Unlike a full concussion, a subconcussive impact does not cause noticeable loss of consciousness or cognitive impairment at the moment of injury.

"Subconcussive" = below the concussion threshold, but still a brain injury.

Chronic traumatic encephalopathy (CTE)

A form of dementia, same as how Alzheimer’s is also a form of Dementia

Triggered by repeated blows (hitting ur head to a hard object) to the head, even though you’ve never had a concussion

A progressive, irreversible neurodegenerative disease. Will still progress, even when you stop taking blows to the head

Not just professional athletes, not concussion. You don’t necessarily need to have concussions to get this disorder

99% Guaranteed that if you play in the NFL, you’ll have this disorder

4 stages of CTE

1. Confusion, disorientation, headaches

2. Lapses in memory, social norms, impulsivity, judgement

3. And 4: Progressive dementia, movement disorders (Parkinsonism), speech disorders, depression, suicidality

Pathological aggression, jealousy, and paranoia are common

Tau

Tau is a protein, binding to the cytoskeleton → stabilizes cytoskeleton → change and break down cytoskeleton to rebuild it

Is Tau a cause of CTE?

Tau is NOT necessarily a cause of CTE, because tau can also be seen in Alzheimer’s (AD), Parkinson’s (PD)

A clear marker of CTE, but relies on postmortem staining (after death)

Neurofibrillary tangles

Tau tangles.

When tau is hyperphosphorylated, it aggregates, and the cytoskeleton becomes unstable

(COULD be a cause of CTE)

Tau progression in CTE vs. AD

In CTE: The medial temporal lobe (memory) is the first place to spread out! The little spots seen around the cortex first

In AD: Spread from the deeper region first

Where does Tau spread first? (Sulci/gyri)

Sulci first (the inner fold). The most common theory of why this is, is cuz you are having a series of micro-hemorrhages from taking blows to the head, so you have small bleeds in your brain. Blood has toxic effects (ex. iron), and the vessels run in the folds (sulci) than on gyri.

Taupathies

PET (detects protein) uses radioactive marker that binds to hyperphosphorylated tau

It works, detects in brainstem (deeper part), but doesn’t detect in the cortex (which is where tau grows first in CTE)