NEUR 1002 final

What is huntington’s disease

a rare, progressive genetic disorder caused by a defect in a dominant gene on chromosome 4, with its function still unknown.

What is the epidemiology of huntington’s disease

In Canada, 1 in 7000 people have HD, and 1 in 5500 are at risk. 1

What are some clinical features of HD

Characterized by a mix of symptoms that include movement disorder, cognitive disorder, and psychiatric disturbances. symptoms are very gradual and don’t appear until late adulthood (insidious disease)

What are some Motor Symptoms of HD

• hyperkinesia (excessive movement),

• involuntary movements (chorea)

• Slow/unusual movements

• Dystonia (muscle contracture)

• impaired gait, posture, balance,

• speech/swallowing problems.

What are some Cognitive Symptoms of HD

• difficulty organizing/prioritizing tasks

• lack of mental flexibility

• poor impulse control

• slower cognitive processing

• difficulty learning

• dementia.

What are some Psychiatric Disturbances of HD

1. depression

2. irritability

3. apathy

4. social withdrawal

5. fatigue/loss of energy.

What is the Most common psychiatric disturbance in HD

depression

What part of the brain does HD affect

basal ganglia

What are medium spiny neurons (MSN)

specialized GABAergic cells that make up 95% of the striatum. 2 types:

1. D1 MSN - contain dopamine receptor 1 and excite the direct motor pathway;

2. D2 MSN - contain dopamine receptor 2 and excite the indirect motor pathway

What leads to motor symptoms in HD

damaged Basal ganglia, Loss of D2 MSN = loss of inhibitory tone of the BG motor circuit

What is the pathology of HD

• The basal ganglia is damaged, leading to motor symptoms. Loss of D2 MSN = loss of inhibitory toneof the BG motor circuit

• Loss of cortical neurons leads to dementia and severe cognitive disability in later stages

• Damage is caused by aggregates of misfolded proteins

What are some causes of HD

HD is an inherited disorder passed on through genes. It is a dominant allele, so only one copy needs to be present to cause the disorder.

What is HTT

HTT is a protein found throughout the brain. When there's a mutation in the HTT gene (like in Huntington’s disease), the protein misfolds and starts to clump together. These clumps build up in brain cells, causing them to stop working properly and eventually die.

What are the 4 bases of DNA

cytosine, adenine, thymine and guanine

What does a mutation in HD cause

expansion of CAG (codon) repeats in the disease. CAG repeats are common in genes and help repair systems. In HD, too many repeats occur and cause the formation of polyglutamine (increased aggregation)

How is HD diagnosed

Since symptoms usually show up later in life, doctors use a few methods:

• Physical exam – checks for movement problems like chorea or coordination issues.

• MRI or other brain scans – can show shrinkage in the basal ganglia and cortex, and larger ventricles.

• Genetic testing – confirms the diagnosis by checking for too many CAG repeats in the HTT gene.

Is there a cure to HD

there is currently no cure for HD - terminal illness

What are some treatments of HD

• Tetrabenazine – Helps reduce chorea (involuntary movements) by lowering certain brain chemicals. May cause side effects.

• Antipsychotics – Help with movement problems and psychiatric symptoms like mood swings or aggression.

• Therapies – Physical, occupational, and speech therapy can support movement, daily tasks, and communication.

• Exercise – Improves balance, mood, and brain function.

What are some novel treatment of HD

gene/RNA therapies because of monogenic nature; RNA and DNA targeting therapies, Stem cell therapies, Antibody therapies

What is CRISPR therapy in HD

• Edits DNA to remove CAG repeats.

• inactivate mHTT alleles or reduce total HTT.

What is Alzhelmer’s disease

a chronic degenerative disease associated with aging, starting with minor forgetfulness and leading to severe memory problems, general dementia, and widespread physiological dysfunction.

How is AD associated with dementia

causes 60-70% of all dementia

What is the epidemiology of AD

650-700 cases per 100,000 people.

What are the early stage clinical symptoms of AD

• Short-term memory loss

• Mild executive dysfunction

• Apathy (most consistent symptom across progression)

• Typically just seen as “Old Timer’s” disease

What are the late stage clinical symptoms of AD

Language difficulty, Disorientation, Mood swing

What are the advanced stage clinical symptoms of AD

Loss of motivation, Loss of bodily function, Patients become fully dependent on caregivers

What is the main feature of AD

the loss of neurons/synapses in specific brain regions (i.e. basal forebrain, cortex,etc.)

What is seen in the cerebral cortex as AD progresses

mass shrinking

What are some causes of AD

1. Genetics (70% is genetic).

2. Environmental exposure.

3. Immune system inflammation.

4. Slow viruses and prions.

5. Modifiable lifestyle factors.

What worsens the symptoms of AD

the deterioration of neurons - degeneration of dendritic arbours and general atrophy

What are some genetic factors of AD

genetics mainly increase the risk of AD- typical AD is not inherited. Early-onset AD is typically inherited

What is the most common gene that increases risk of AD

APOE, which has 3 different alleles. e2, e3 and e4

• e2 decreases risk, e3 has no effect and e4 increases risk

What are some environmental factors of AD

Long-term exposure conveys some risk. Includes things like Pollution, nitrogen oxide, Aluminum, arsenic, Certain solvents

What are the 2 main changes in the brain seen throughout AD, regardless of how the disorder developed

Loss of cholinergic cells in the basal forebrain & Development of neuritic plaques and tangles in the cerebral cortex

What is the Cholinergic system

in the forebrain - essential for cognitive function, especially learning and memory

What cells in AD are the first to die

cells in the basal forebrain. Neurodegeneration will then spread out from there into the cortex

What is 𝜷-amyloid

a small piece of the Amyloid Precursor Protein (APP) plays a role in kinase activation, oxidative stress protection, cholesterol transport regulation,etc

How is 𝜷-amyloid formed

• APP is cleaved at 2 sites by beta-secretase and gamma-secretase enzymes.

• 𝛽-Amyloid is released into the extracellular space.

• Abnormal cleavage of 𝛽-Amyloid causes aggregation and plaque formation

What are Neuritic Plaques

• Made of 𝛽-amyloid protein.

• Surround synapses, blocking neuronal transmission.

• Leads to swollen axons and cell death.

• present in AD

Where are Neuritic Plaques mainly found

in the temporal areas that are involved in memory (hippocampus, amygdala, etc.)

What are the 2 purposes of cytoskeleton

• Structural support: Maintains cell 3D shape .

• Transport: Moves materials within the cell.

What are the 3 main components to the cytoskeleton

Neurofilaments – control and transport of membrane proteins

Microtubules – regulates the transportation of substances throughout cytoplasm

Microfilaments – structural support to axons and dendrites

What are tau proteins and what happens to them in AD

Tau proteins help stabilize the structure of neurons by supporting microtubules and microfilaments.
In AD, tau becomes hyperphosphorylated (too many phosphate groups are added), which makes it break away from microtubules and clump together. These clumps form neurofibrillary tangles inside neurons, leading to cytoskeleton no longer being functional and cell death.

What happens to tangles and plaques during AD

• Tangles = interrupt cellular transport; intracellular.

• Plaques = decrease neuronal communication; extracellular

How is AD diagnosed

true diagnoses can only occur postmortem with the observation of plaques and Neurofibrillary tangle performed by a neurologist

What are the 5 main characteristics that doctors look for for a AD diagnoses

1. impaired memory and/or cognition

2. Changes in personality/behaviour

3. Degree of memory/cognitive impairment

4. How are you affected in daily living

5. The cause (i.e rule out brain injury, etc.)

What are some treatments of AD

Currently no cure for AD but many drugs have been approved to help with the progression like:

• Cholinesterase inhibitors: Keep acetylcholine (ACh) levels up by stopping its breakdown, mild symptoms

• NMDA Inhibitor: Block too much glutamate to protect brain cells, moderate to severe symptoms

• other drugs that target formation of 𝜷-amyloid

How can you prevent AD

1. Exercise

2. Healthy diet

3. Education

4. Low/none alcohol/drug consumption.

What is ALS

progressive degenerative disease that affects neurons controlling voluntary muscles - leads to respiratory failure in 2-4 years

What does ALS stand for

1. Amyotrophic (no muscle nourishment)

2. Lateral (location on spinal cord where lesions occur)

3. Sclerosis (scarring/hardening)

What is the epidemiology of ALS

Age-related disease, 5-7 cases per 100,000 in US. Affects slightly more men than women (1.6x)

What are some clinical symptoms of ALS

Loss of motor neurons =

• Stiff muscles

• Muscle spasms

• Weakness

• Difficulties with speaking, swallowing and eventually breathing

Eventually, loss off all voluntary
motor function

Some cases present with cognitive
dysfunction (<50%)

Stiff muscles, Muscle spasms, Weakness, Difficulties with speaking,swallowing and eventually breathing

What are some causes of ALS

• Degeneration of both upper motor neurons (motor cortex) and lower motor neurons (spinal cord and brainstem).

• Some cases (10%) – caused by genes, especially SOD1.

  • SOD1 normally breakdown of reactive

    oxygen species (ROS)

  • Lower motor neurons are extra sensitive to oxidative stress

  Other possible causes: genetic disorders, viruses (like Polio or West Nile), or spinal muscular atrophy.

What type of disease is ALS

sporadic or random because In over 90% of ALS cases, the cause of the motor neuron degeneration is unknown

What are the 2 types of motor neurons

1. Upper Motor Neurons (UMN): Found in the motor cortex; send signals to interneurons in the spinal cord.

2. Lower Motor Neurons (LMN): Connect the spinal cord to the muscles. found in spinal cord and forbrain

What is the main pathological feature of ALS

The presence of inclusion bodies inside of motor neurons. Found in both familial and sporadic cases thought to influence neurodegeneration

What is Superoxide Dismutase (SOD)

Superoxide Dismutase is an enzyme that protects cells by breaking down superoxide (O₂⁻)

• Superoxide is a reactive oxygen species (ROS) that can damage DNA, mitochondria, and other cell parts.

• SOD converts it into safer molecules, like oxygen (O₂) or hydrogen peroxide (H₂O₂).

• This process is vital for cell survival.

• If SOD doesn’t work well like ALS, the buildup of toxic molecules can lead to cell death

How is ASL diagnosed

• MRI typically used to rule out other injuries

• muscle biopsy to rule out other muscular diseases

• electromyography (EMG) to assess motor neuron/muscle function

What are the 2 types of EMG

• Needle EMG: Uses a small needle to record electrical activity in muscles.

• Surface EMG: Uses electrodes placed on the skin to measure muscle activity.

How is ALS treated

No known treatment that can reverse neuronal damage in ALS, but Some drugs have been approved by FDA that seem to slow the progression

What is pain

An unpleasant sensory and emotional experience associated with, or resembling actual or potential tissue damage - Subjective in nature

Is pain always bad

no, Acute/nociceptive pain is good; its the body’s warning system that allows a response to a damaging stimulus

What is chronic pain

pain that persists after initial tissue damage has resolved (3+ months) - impairs function and daily life

What is the Epidemiology of Chronic Pain

1 in 5 people >15 years old live with chronic pain - females are 5% more affected than males

What are some clinical symptoms of chronic pain

aching, burning, shooting, squeezing, stiffness, stinging, or throbbing pain

What are some comorbidities of chronic pain

anxiety, depression, fatigue, insomnia, and mood swings

What are some causes of chronic pain

• Arthritis

• Cancer

• Previous injuries

• Migraines

• Psychogenic (anxiety, depression, stress)

• Neurogenic (fibromyalgia, nerve damage)

What is nociception

Nociception is the process of encoding noxious (tissue-damaging) stimuli, leads to a functional consequence: behavioural (motor withdrawal) or autonomic (increased blood pressure, heart rate, etc.)

What is the Nociceptive Pathway

• A special pathway that carries pain signals to the brain

• Starts at nerve endings with pain receptors (in the dorsal root ganglion)

• Signal travels to the dorsal spinal cord (sensory side)

• Then goes to the thalamus (for processing) and amygdala (for emotional response)

What i​​s Congenital Insensitivity to Pain

a disease where people can be born without any thermal and mechanical pain response, caused by a mutation in a pain specific sodium channel. Results in high rates of injury

What is the nociceptive (pain) pathway

1. Pain detection: Starts at nerve endings with special receptors that sense harmful things like heat, pressure, or injury.

2. Neuron cell bodies: These nerves have their cell bodies in the dorsal root ganglion, just outside the spinal cord.

3. Entering the spinal cord: The pain signal travels into the dorsal spinal cord, following the Bell-Magendie Law (which says sensory info goes in the back of the spinal cord).

4. Signal to the brain: From the spinal cord, the signal goes to the thalamus (which sorts and processes sensory info) and the amygdala (which handles the emotional side of pain).

What is the Bell-Magendie Law

states that dorsal pathways are sensory (incoming signals), while ventral pathways are motor (outgoing signals).

What is a Nociceptor

A peripheral somatosensory receptor that can detect and respond to painful (noxious) stimuli. It has a higher activation threshold, meaning it needs stronger or more intense input to get triggered.

Can nociception always be directly correlated with the perceived level of pain?

No, nociception does not always correlate directly with perceived level of pain

What is the most basic type of sensory receptor for pain? What is its structure?

nociceptors are the most basic type of sensory receptors for pain and they have free nerves endings

What is a receptor field? How does its size and number relate to sensitivity in different limbs?

• The somatosensory system creates receptor fields on the surface of the skin.

• More sensitive limbs have smaller and more receptor fields, allowing for more discrimination

How is receptor field density and size related to tactile acuity and the homunculus?

Higher receptor field density and smaller receptor field size are directly related to higher tactile acuity, which corresponds to a larger processing power in the homunculus

What type of cells in the epidermis are nociceptors associated with? What might be their role?

Schwann cells in the epidermis. Stimulating these Schwann cells increase the firing rate of nociceptors

Where are nociceptors located

embedded in the epidermis, surrounded by skin cells and tissues

What types of stimuli can nociceptors respond to?

• Extreme mechanical or temperature changes.

• Oxygen deprivation (H+ build-up).

• substances released by damaged cells (e.g., proteases, lipids, K+, ATP, cytokines).

What are the 3 types of nociceptors

1. Type I A𝛅: Mechanical and chemical stimulation.

2. Type II A𝛅: Thermal stimulation

3. C-fibers: polymodal; respond to almost all types of noxious stimuli

   respond to almost all types of noxious stimuli

What is the difference between A𝛅 and C fibers

• A𝛅 Fibers: Myelinated, intermediate size, responsible for first pain (sharp, immediate pain).

• C Fibers: Unmyelinated, narrow diameter, responsible for secondary pain (dull, lingering pain).

What role does diameter play in nociceptors

larger the diameter the faster the conduction

What are the 7 main parts of an action potential

Stimulus, Threshold (-50mV), Depolarization (influx Na+), Peak (+30mV), Repolarization (K+ efflux), Refractory period (relative refractory), Return to resting state

How many subtypes of voltage-gated sodium channels (Nav) are there? Which ones are specifically expressed in nociceptors? Which one is associated with certain chronic pain conditions?

There are 9 subtypes (Nav 1.1 to 1.9) of voltage-gated sodium channels. Nav 1.7, 1.8, and 1.9 are expressed only in nociceptors, and Nav 1.3 is expressed in certain chronic pain conditions

What is the consequence of Nav channel activation in the nociceptive pathway?

Nav channels sense the depolarisation and cause an action potential, leading to glutamate release from Dorsal root ganglion neurons to the spinal cord

What is the overall path of the nociceptive pathway from the periphery to the brain?

from the peripheral nociceptor → dorsal horn spinal cord → brainstem → thalamus → cortex.

How is the spinal cord organized? Where are nociceptors mainly found? What is lamina 2 also known as?

The spinal cord is arranged into laminae (layers) characterized by morphology and cell density. Nociceptors are mainly found in laminae 1 & 2, with lamina 2 also known as the substantia gelatinosa

Where are spinal cord projection neurons located? Where do they send signals?

Spinal cord projection neurons are located in Laminae I and V and send signals to the brain (thalamus and brainstem)

What type of nociceptive inputs does Lamina I receive? What about Lamina V?

Lamina I receives direct nociceptive inputs from A𝛅 and C- fibers. Lamina V receives both nociceptive (A𝛅) and non-nociceptive (A𝜷) inputs

Where do Lamina I projection neurons send their axons? What regions do they target?

through the lateral spinothalamic tract. Targets many regions including amygdala, midline thalamic nuclei, and the periaqueductal grey

What is characteristic of chronic (pathological) pain? What are allodynia and hyperalgesia?

Chronic (pathological) pain is characterised by hypersensitivity.

• Allodynia: a nociceptive response produced by a non-noxious stimulus - Pain from something that shouldn’t hurt

• hyperalgesia: an increased sensitivity to noxious stimuli

What are the two main mechanisms thought to underlie chronic pain?

peripheral or central sensitization

What is peripheral sensitization? What can trigger it and what does it lead to?

changes in the sensitivity of peripheral nociceptors to a noxious stimulus. Triggered by release of inflammatory molecules or persistent activation. Leads to persistent changes in neuronal excitability

What is central sensitization? What can cause it and what does it result in?

when CNS neurons (like in the spinal cord) become extra sensitive to pain.

• Can be caused by ongoing pain signals from the body

• Or by reduced pain-blocking signals from the brain

• Leads to too much excitation and not enough inhibition in the spinal cord → increased pain response

How is chronic pain diagnosed

The first step is a physical exam. Depending on the hypothesized cause of the pain, further tests may be ordered. Can range from MRI to look for tissue damage to blood test and nerve conduction tests

Why is diagnosing chronic pain complex?

there is no way to directly measure pain, so patient reports need to be taken at face value.

How is chronic pain treated

• Anticonvulsants – often used for nerve pain.

• Corticosteroids – help reduce inflammation, especially in arthritis or joint pain.

• Opioids – strong painkillers, but now used only when other options don’t work due to the risk of addiction.

• Medical marijuana – can help with cancer-related and nerve pain in some cases.

What are some other treatments that might be considered if first-line treatments for chronic pain fail?

Other treatments include TENS, nerve blocks, and epidural steroid injections