Neurological Disorders

NEUROLOGICAL DISORDERS ## LEARNING OBJECTIVES

• Explain how malignant and benign tumors can impact brain functioning.
• Describe the different types of strokes, and the process by which they can lead to cell death.
• Describe the symptoms and prevalence of neurodegenerative disorders.
• Explain the assumed causes and treatments for neurodegenerative disorders.

NEURODEGENERATIVE DISORDERS

• Definition: Diseases causing gradual loss of neurons in the Central Nervous System (CNS).
    - Loss can refer to number, structure, or function of neurons.
• Causes:
    - Genetic causes
    - Environmental causes
    - Sporadic: No known genetic or infectious cause.
    - Idiopathic: Unknown cause; spontaneous onset.
• Major disorders discussed:
    - Parkinson’s Disease
    - Alzheimer’s Disease
    - Huntington’s Disease
    - Amyotrophic Lateral Sclerosis (ALS; Lou Gehrig’s disease)

GROUP ACTIVITY

• Outline the major symptoms/clues of conditions discussed and suggest appropriate diagnoses based on these.
    - Left side
    - Right side

OVERVIEW – ALS (Amyotrophic Lateral Sclerosis)

• Prevalence:
    - Very rare, 0.005% of the U.S. population.
    - Approximately 5 cases per 100,000 people.
• Onset:
    - Most commonly in the 50s.
    - Primarily sporadic (90% of cases are sporadic)
    - Genetic factors present in 10% of cases.
• Mortality:
    - Average lifespan post-diagnosis is 5 to 10 years.
• Symptoms:
    - Loss of muscle tone and strength.
    - Head droop.
    - Speech problems (dysarthria).
    - Difficulty breathing and swallowing.
    - Involuntary muscle contractions (fasciculations).

AMYOTROPHIC LATERAL SCLEROSIS

• Amyotrophic means 'no muscle nourishment'.
• Physiological changes include:
    - Degeneration of spinal cord & cranial nerve motor neurons.
    - Resulting muscular atrophy except for eye muscles, which are often spared.
• Causes:
    - Linked to chromosome 21.
    - Associated with issues of protein misfolding and aggregation.
    - 90% of cases are sporadic with no clear identifiable risk factors.
• Treatments discussed:
    - Riluzole (a medication).
    - Stem cell therapy showing promise.

STEM CELLS & MOTOR DISORDERS

ALZHEIMER’S DISEASE (AD)

• Prevalence:
    - Affects 10% of those aged 65 and older.
    - Approximately 50% of individuals aged 85 and older.
• Risk factors: Hormonal changes, brain structure, and longer life expectancy.

AD: PROGRESSION & SYMPTOMS

• Early stages:
    - Anterograde amnesia; confusion; agitation.
• Middle stages:
    - Retrograde amnesia; visual agnosia; prosopagnosia; difficulty completing complex tasks.
• Late stages:
    - Speech problems; loss of mobility; difficulty with basic tasks; can lead to death.

ALZHEIMER’S DISEASE – PHYSIOLOGICAL CHANGES

• Progressive loss of gray matter in the brain.
• Increase in size of brain ventricles correlated with neuron loss.
• Stages of neuronal degeneration:
    - Early stages affect the hippocampus.
    - Ultimately, changes spread across the cerebral cortex.

AD – NEUROLOGICAL CHANGES

• Neuronal degeneration
    - Addition of amyloid plaques and neurofibrillary tangles.
• Development of neurofibrillary tangles:
    - Tau proteins stabilize microtubules.
    - Phosphorylation of tau proteins causes them to detach leading to tangles.

AD – PLAQUES & TANGLES

• Tangles:
    - Found inside the cells.
    - Tau proteins, normally stabilizers of microtubules, become dysfunctional due to abnormal folding, forming tangles.

• Plaques:
    - Formed outside the cells from beta-amyloid, a byproduct of cellular processes.
    - In normal conditions, short and long forms of beta-amyloid are produced, but in AD, the plant’s cleanup system becomes overwhelmed leading to a buildup of sticky plaques.

• The increase of long-form beta-amyloid may rise to 40% in AD patients, whereas it is normally only 5-10%.

• Both plaques and tangles have been implicated in causing cell death.

AD - PRODUCTION OF AB (Amyloid Beta)

• Production Steps:
    - Gene creates Amyloid Precursor Protein (APP).
    - Enzymes beta-secretase and gamma-secretase cut APP into fragments, leading to the production of Ab.
    - Normally, short (40 amino acids) and long (42 amino acids) forms of Ab are produced, with short forms comprising 90-95% and long forms only 5-10%. In AD, the proportion of long form increases significantly.

AD - GENETIC CAUSES

• Genetic elements include:
    - APP gene (located on chromosome 21).
    - Presenilin genes (on chromosomes 1 and 14).
    - ApoE4 variant, which hampers the removal of amyloid beta accumulating significant risk.
• Sporadic factors include traumatic brain injury, diabetes, and obesity.
• Potential protective genetic variants: ApoE2, higher educational attainment, low cholesterol, and controlling hypertension potentially lower risk.

AD - TREATMENTS

• Strategies: Lifelong learning suggested to slow cognitive decline.
• An amyloid beta vaccine tested in mice showed effectiveness in reducing plaques, though human studies suggested some reduction with continuous cognitive improvements.
• Concerns arose as 5% of patients in studies exhibited brain swelling, raising questions about treatment viability.

OVERVIEW – HUNTINGTON’S DISEASE

• Prevalence:
    - Very rare, approximately 0.005% in the U.S.
    - About 5-10 cases per 100,000 individuals.
• Typical Onset:
    - Usually occurs in the 30s or 40s.
    - Primarily genetic origin (97-99% of cases).
    - Sporadic cases comprise only 1-3%.
• Average life expectancy post-onset is 10-15 years.
• Symptoms:
    - Chorea (irregular, uncontrolled movements), rigidity, posture abnormalities, speech, swallowing difficulties, psychiatric symptoms, and decline in executive functioning and learning.

HUNTINGTON’S DISEASE – GENETICS

• Causes include a mutation on chromosome 4 that is linked to the HTT gene, where CAG repeats lead to elongated glutamine chains in the protein.
• Result: The abnormal HTT protein misfolds and accumulates.
• Correlation: The longer the repeated sequence, the earlier the onset of Huntington's disease.
• Currently, no established treatments available.

OVERVIEW – PARKINSON’S DISEASE

• Prevalence:
    - Affects approximately 0.3% of the general population (~1 million people).
    - 1-2% of individuals aged 65 and older; 4-5% for those aged 85+.
• Typical onset:
    - Primarily sporadic cases in early 60s.
    - Genetic forms are typically earlier, affecting individuals 45 years or younger (5-10% of cases).
• Symptoms:
    - Symptoms include tremors, rigidity, bradykinesia (difficulty initiating/completing movements), posture/gait changes, impaired speech, dementia risk, sleep difficulties. Diagnosis can be complex due to symptom overlap with Huntington's disease.

PARKINSON’S DISEASE – PHYSIOLOGICAL CHANGES

• Key changes:
    - Loss of dopaminergic neurons in the nigrostriatal pathway connecting the substantia nigra to the striatum, with approximately 70% neuron loss detectable by the time symptoms manifest and over 90% at death.
• Development of Lewy bodies, which are implicated in Lewy Body Dementia, the second most common form of dementia.
• Research suggests that 83% of Parkinson’s disease patients may develop dementia (Galvin et al., 2006).

PARKINSON’S DISEASE - CAUSES

• Genetic components:
    - Mutations of alpha-synuclein link directly to the formation of Lewy bodies.
    - Commonly found in dopaminergic neurons.
• Other genetic factors:
    - Mutation affects the Parkin protein that should clean up misfolded proteins (located on chromosome 6).
• Environmental contributions: Rural living (pesticides), poor metabolism, untreated infections, traumatic brain injury have been associated with sporadic cases.

PARKINSON’S DISEASE – TREATMENTS

• L-DOPA administration increases dopamine availability in remaining neurons but eventually becomes ineffective, eliciting side effects similar to those seen in schizophrenia.
• Deep brain stimulation involves surgically placing electrodes in the subthalamic nucleus to inhibit motor activity, effectively reducing tremor symptoms.

NEUROLOGICAL DISORDERS PART 2 ## TUMORS

• Definition: Tumors comprise rogue cells.
• Tumor classification:
    - Benign tumors: Defined by an encapsulated border.
    - Malignant tumors: Lack an encapsulated border and have potential for metastasis (spreading to new sites).

TUMORS IN THE BRAIN

• Causes & origins of brain tumors primarily arise from:
    - Glial cells (Gliomas)
    - Astrocytes (Astrocytoma)
    - Ependymal cells (Ependymoma)
    - Oligodendrocytes (Oligodendrocytoma)
    - Cells of meninges (Meningioma)
    - Schwann cells or connective tissue of cranial nerves (Neurinoma)
    - Cells of blood vessels (Angioma)
    - Cells of pineal gland (Pinealoma)

BRAIN TUMORS AND DAMAGE

• Effects of tumors on brain functioning can arise from:
    - Compression: Involves pressure exerted on tissue, which can block blood and cerebrospinal fluid (CSF) flow, affecting both benign and malignant tumors.
    - Infiltration: Malignant tumors may invade surrounding areas, harming healthy neural tissue, disrupting processing, and impairing growth and health of surrounding cells.

CEREBROVASCULAR ACCIDENTS (STROKES)

• Overview: Blood-related incidents impacting brain function.
• Key blood vessels involved include:
    - Circle of Willis
    - Anterior communicating artery
    - Internal carotid artery
    - Basilar artery
    - Vertebral arteries

TYPES OF CEREBROVASCULAR ACCIDENTS

Hemorrhagic Stroke

• Definition: Occurs when blood vessels rupture, causing bleeding either
  inside the brain or around the brain within the meninges.
    - Aneurysms often lead to hemorrhage by causing the artery to widen and weaken.
    - Hematomas can form:
      - Subdural hematoma (between the dura mater and the brain)
      - Epidural hematoma (above the dura mater)

Ischemic Stroke

• Definition:
    - Thrombosis: A clot forms within an artery and impedes blood flow (hypoxia), often leading to tissue infarcts.
    - Embolism: A clot (embolus) travels from another part of the body and blocks a small artery.

STROKE AND CELL DEATH

• Mechanism of neuron death:
    - Loss of blood supply results in deprivation of glucose and oxygen.
    - Cells cannot fire normally, and excessive firing may occur in absence of glucose and oxygen, leading to dysfunction.
    - Sodium and potassium transporters stop functioning, causing alterations in ionic balances.
    - Cell depolarization results in the release of excessive glutamate, activating NMDA receptors in the post-synaptic neuron, which leads to intracellular calcium influx, causing cell death through mechanisms including swelling and eventual phagocytosis.

TREATMENTS FOR STROKE

• Treatment options include:
    - Reducing blood pressure to lower the risk of rupture.
    - Anticoagulants to reduce blood clot formation and diminish thrombi presence.
    - Surgical interventions like introducing stents to open arteries, allowing for improved blood flow to the brain.
    - Effectiveness of treatments can vary greatly and requires careful assessment.

TISSUE PLASMINOGEN ACTIVATOR (TPA)

• Definition: A protein involved in the breakdown of blood clots.
• Clinical involvement in treatment of ischemic strokes caused by thrombus or embolus.
    - Administered within three hours of symptom onset for greatest efficacy.
    - Cautions against administration when the blood-brain barrier is compromised, due to risks of cerebral hemorrhage.