CNS: Stroke

What are cerebrovascular diseases and stroke?

• Cerebrovascular diseases:

  • Brain disorders caused by pathological processes involving blood vessels

    • These processes disrupt normal blood circulation in the brain

  • Broad category of disorders involving the brain's blood vessels

• Stroke: A clinical phenomenon that occurs when there is acute and sudden loss of blood flow and oxygen to the brain

  • Stroke is a type of cerebrovascular disease

Why does the brain require a continuous supply of blood and oxygen?

• The brain is highly dependent on oxygen and requires a continuous supply

• Lacks significant energy stores → cannot store enough energy to sustain itself without a continuous supply of glucose and O₂ (which provides the main source of ATP → can’t keep that much energy for itself)

• Requires continuous supply of glucose and O₂ from the blood

  • These are needed for ATP production, which supports action potentials (needs ATP for ion pumps for depolarization/hyperpolarization) + axonal transport (ATP powers motor proteins that transport materials along axons)

• Mechanisms to maintain consistent blood flow over a wide range of blood pressure and intracranial pressure

Stroke: What is hypoxia?

Low levels of oxygen in tissue

Stroke: What is ischemia?

Inadequate blood supply to tissues

Stroke: What is infarction?

Tissue death (necrosis) due to inadequate blood supply

Stroke: What is embolism?

Blocked artery caused by a foreign body, like a blood clot or air bubble, that traveled through the bloodstream

Stroke: What is thrombosis?

Blood clot forms locally and blocks or slows flow of blood

Stroke: What is hemorrhage?

Acute loss of blood from a damaged blood vessel

What are the two ways strokes can be classified?

• Ischemic stroke: Blood flow to the brain is blocked (~90% strokes)

  • Thrombotic occlusion: A blood clot forms locally in the blood vessel, usually where blood flow is slowed or disrupted

  • Embolic occlusion: Blocks a blood vessel like an artery via a blood clot or air bubble that travels through the bloodstream

• Hemorrhagic stroke: Sudden bleeding in the brain (~10% of stroke)

  • Vascular rupture: Blood vessel that broke or burst

What is the epidemiology of stroke?

• 5th leading cause of death in the U.S.

• In 2021, 1 in 6 deaths from cardiovascular disease was due to strokeq

• Every year, more than 795,000 people in the US have a stroke

• About 610,000 of these are first or new strokes

• A leading cause of disability: reduces mobility in >50% of stroke survivors over 65y

• Health disparities:

  • Risk of having a first stroke is nearly twice as high for non-Hispanic Black adults as for white adults

    • Environmental factors + status cause these stats (inadequate access to healthcare)

  • Non-Hispanic Black adults and Pacific Islander adults have the highest rates of death due to stroke

  • Native American populations have a higher risk than non-Hispanic whites

• Age-related increase in risk:

  • Stroke risk increases with age

  • In 2014, 38% of people hospitalized for stroke were less than 65 years old

What are the risk factors of stroke?

• Age: The incidence of stroke increases with age, double for each decade after 55 years of age

• Sex:

  • Young ages: Women have a high or higher risk of stroke as men

  • Older ages: Risk is slightly higher for men

• Race/ethnicity

What are the genetic factors of stroke?

• Mendelian Stroke (single-gene inheritance)

  • Sickle cell disease: Most common cause of stroke

    • Autosomal recessive disorder

  • Familial Amyloid Angiopathy: Autosomal dominant mutation of APP

• Sporadic stroke: Shared risk variants with high cholesterol, high blood pressure, other cardiovascular disease

What are the (6) risk factors of stroke?

• Hypertension (high blood pressure)

• Dyslipidemia (high cholesterol)

• Smoking → 15% of stroke deaths per year

• Diabetes mellitus

• Obesity/metabolic syndrome/diet/sedentary behavior

• Inflammation and infection

What is Global Cerebral Ischemia?

A generalized reduction in blood flow throughout the brain, resulting in inadequate oxygen delivery

Global cerebral ischemia → Reduced blood flow or oxygen delivery throughout the brain → Decreased ATP production → Widespread neuronal dysfunction/damage

Global Cerebral Ischemia: How can oxygen delivery to the brain fail?

• Reduced cerebral perfusion (blood flow)

  • Cardiac arrest: Heart stops effectively pumping blood → brain receives insufficient blood and oxygen

  • Shock or severe hypotension: Very low blood pressure → reduced blood flow to the brain

• Reduced oxygen-carrying capacity of blood

  • Carbon monoxide poisoning (CO): CO binds to hemoglobin → reduces oxygen transport → inadequate oxygen delivery of blood

Global Cerebral Ischemia: What determines the clinical outcome?

• Depends on the duration and severity of reduced oxygen delivery:

  • Shorter/less severe reduction: May cause temporary neurological dysfunction with potential recovery

  • Longer/more severe reduction: Can cause extensive neuronal damage, permanent disability, or death

Global Cerebral Ischemia: What are the severe outcomes?

• Persistent vegetative state: Loss of conscious awareness, although some basic brain functions remain

• Brain death: Irreversible loss of all brain function, including brainstem function

Which neurons are most sensitive to hypoxia in global cerebral ischemia? What are the three most sensitive neuronal populations? What are two consequences of severe ischemia?

1. Neurons vs. Glial Cells

• Neurons are more sensitive to hypoxia than glial cells

• Neurons have high ATP requirements and depend heavily on continuous oxygen delivery

2. Three most sensitive neuronal populations:

• Pyramidal neurons in the hippocampus

• Pyramidal neurons in the neocortex

• Purkinje cells in the cerebellum

3. Consequences of Severe Ischemia

• Severe ischemia → decreased oxygen and glucose delivery → ATP depletion

• Leads to widespread necrotic neuronal death (irreversible cell injury)

What happens during a brief episode of Global Cerebral Ischemia?

1. Temporary reduction in blood flow

• Reduced blood flow → decrease O₂ and glucose delivery to the brain

• Causes energy failure (↓ ATP) → Neurons cannot maintain normal electrical activity

• Neuronal electrical activity temporarily ceases (b/c action potentials stop ig) → loss of consciousness (fainting)

2. Restoration of Blood Flow:

• If circulation is restored before neurons and glial cells undergo irreversible damage:

  • ATP production and neuronal electrical activity recover

  • Neurons and glial cells remain viable

  • No permanent pathological damage → patient returns to normal

How does brief global cerebral ischemia cause fainting?

What happens during prolonged global cerebral ischemia?

• Prolonged ischemia: Blood flow and oxygen delivery to the brain are reduced for too long, resulting in irreversible neuronal damage

• Cellular Damage

  • ↓ O₂ and glucose → ↓ ATP production

  • Cellular metabolism slows and eventually stops

  • ATP depletion → ion pump failure → loss of cell membrane integrity

  • Neurons undergo necrosis (irreversible cell death)

Why does the duration matter for prolonged global cerebral ischemia?

• 4-5 minutes: Severe complete ischemia can permanently damage the most sensitive neurons

• Longer periods: Damage extends to additional neurons, including those in the thalamus and brain stem

What is Hypoxic-Ischemic Encephalopathy?

• Widespread brain injury caused by inadequate oxygen and blood supply

• Can cause cerebral edema (brain swelling)

• Swelling results in:

  • Widened gyri: Brain folds become swollen

  • Narrowed sulci: Grooves between folds become compressed

Why is gray matter more vulnerable than white matter?

• Gray Matter: Contains many neuronal cell bodies and synapses → high metabolic activity and ATP demand

• White Matter: Primarily contains myelinated axons → generally lower metabolic demand than gray matter

• Therefore, gray matter is often more vulnerable to hypoxic-ischemic injury

  • However, both gray and white matter can still be damaged by severe ischemia.

What are the pathological hallmarks of prolonged global cerebral ischemia? 🟠

1. Anoxic Neurons (Oxygen-deprived neurons)

• Injured neurons shrink

• Mitochondria becomes damaged

• Nuclei condense (pyknosis)

• These changes indicate severe, irreversible neuronal injury

2. Selective Loss of Sensitive Neurons

• The most vulnurable neurons are:

  • Pyramidal neurons of the hippocampus, neurons of the neocortex, purkinje cells of the cerebellum

3. Astrocyte Swelling

• Astrocytes surrounding injured (anoxic) neurons swell

• This occurs partly b/c ATP depletion disrupts ion balance (like the pumps), causing water to enter the cells

4. Macrophage removal:

• Severely damaged neurons eventually undergo cell death

• Macrophages (including activated microglia) break down and remove dead neurons and cellular debris

5. Cortical Atrophy and Gliosis

• Cortical Atrophy: Shrinkage of the cerebral cortex due to neuronal loss

• Gliosis: Reactive glial cells, especially astrocytes, respond to injury and form glial scars

• Prolonged ischemic injury can cause pseudolaminar necrosis

  • Neurons die preferentially in certain cortical layers

  • This produces bands-like pattern of necrosis

  • Over time, neuronal loss and gliosis contribute to cortical atrophy

What are the clinical consequences of Global Cerebral Ischemia? 🟠

1. Bilateral Hippocampal Damage → Korsakoff’s (severe) Amnesia

• Damage to both hippocampi causes significant memory impairment

• Anterograde amnesia is more affected than Retrograde amnesia

  • Anterograde: Difficulty forming new memories

  • Retrograde: Difficulty recalling previously formed memories

• Episodic memory is more affected than Semantic memory impairment

  • Episodic: Memory of personal experiences/events

  • Semantic: Memory of general facts and knowledge

2. Cortical and/or Thalamic Damage (Brainstem Intact)

• Can cause dementia-like cognitive impairment or persistent vegetative state

  • Loss of conscious awareness and emotion

  • Preserved: Sleep-wake cycles, autonomic functions, and spontaneous breathing

  • Severe impairment of cerebral function, but brainstem functions remain intact

3. Damage Extends to Brainstem → Brain Death

• Irreversible loss of cerebral and brainstem function

• Characterized by:

  • Complete unresponsiveness

  • Absence of brainstem reflexes

  • Apnea: Inability to breathe spontaneously

  • Electrical silence (flat EEG)

  • Absence of cerebral perfusion (blood flow)

What is the difference between a persistent vegetative state and brain death?

What are the treatments of Global Cerebral Ischemia?

• Neonatal HIE: therapeutic hypothermia

• FAST heroes

  • Face, arm, speech, and time

• Tissue plasminogen activator (tPA): Breaks up blood clots blocking blood flow, given within 4.5 hrs of system onset

What is vascular dementia?

Cognitive decline caused by reduced blood supply to the brain, learding to neuronal damage

What is the epidemiology of vascular dementia?

Epidemiology:

• 2nd most common cause of dementia after Alzheimer’s

• Approx 5-10% of people with dementia have vascular dementia

What is the pathogenesis of vascular dementia?

• Multiple mini-strokes over several years can cause repeated brain damage

• These produce multiple infarcts in the white and gray matter

  • Infarcts: Area of tissue death due to insufficient blood supply

• Accumulation of damage → neuronal loss → cognitive decline

What is the etiology of vascular dementia? [do we really need to know this? it sounds too clinical]

• Cerebral atherosclerosis

• Vessel thrombosis

• Embolization from carotid vessels of the heart

• Cerebral arteriolosclerosis from chronic hypertension

• Cerebral amyloid angiopathy

What are the pathological changes of vascular dementia?

• Cortical atrophy

• Hippocampal sclerosis: Scarring and neuronal loss in the hippocampus

• These changes may occur after chronic vascular injury

What are the clinical symptoms of vascular dementia? [do i rlly need to know this?]

• Dementia

• Gait abnormalities

• Pseudobulbar signs

• Additional symptoms related to specific affected sites

How are action potentials fired?

How are neurotransmitters released?

Explain the process of synaptic plasticity or long term potentiation.

1. Glutamate binds to AMPA and NMDA channels

2. Net Na⁺ entry through AMPA channels depolarizes the postsynaptic cell

3. Depolarization ejects Mg²⁺ from NMDA receptor-channel and opens the channel

4. Ca²⁺ enters cytoplasm through NMDA channel

5. Ca²⁺ activates second messenger pathways → cell becomes more sensitive to glutamate

6. Paracrine from postsynaptic cell enhances glutamate release