Brain Damage and Neuroplasticity - Neurological Disorders and Neurodegenerative Conditions

Neurological vs. Neurodegenerative Disorders

Technically, all neurodegenerative disorders fall under neurological disorders because they affect the central nervous system (brain and spinal cord). However, not all neurological disorders are degenerative. For example, epilepsy and multiple sclerosis (MS) involve brain dysfunction, but not necessarily the gradual loss of neurons over time. Therefore, their management and treatment differ from neurodegenerative conditions. Further reading on epilepsy and MS is encouraged.

Key Neurodegenerative Conditions

The lecture focuses on three key neurodegenerative conditions: Alzheimer's, Huntington's, and Parkinson's disease.

Alzheimer's Disease

Alzheimer's disease is the most common form of dementia. The World Health Organization (WHO) estimates that over fifty million people worldwide are living with dementia, and this number is increasing with the aging population.

Types of Alzheimer's

• Early-onset Alzheimer's: A genetic form of Alzheimer's, which is rare and tends to run in families, affecting people at a younger age.

• Sporadic Alzheimer's: The most common form, especially in people over 65 years old, occurring by chance without a strong family history or clear genetic link.

Hallmarks of Alzheimer's

Alzheimer's disease is defined by two key features observed in the brain:

1. Beta Amyloid Plaques: Accumulation of beta amyloid protein between neurons, forming clumps that disrupt communication between brain cells and trigger inflammation.

2. Tau Protein Tangles: Tau protein becomes abnormally twisted, forming neurofibrillary tangles inside neurons. These tangles block nutrient transport, leading to cell stress and cell death.

These plaques and tangles accumulate in specific brain areas, particularly those responsible for memory and emotion, such as the hippocampus, amygdala, and entorhinal cortex.

As these brain areas break down, individuals experience memory problems (especially episodic memory) and have trouble thinking clearly. Over time, this pathological process spreads, affecting cognition, planning, communication, language, and the ability to manage daily tasks.

Diagnosis of Alzheimer's

• The only way to confirm Alzheimer's disease with 100% certainty is through a post-mortem brain examination to look for amyloid plaques and tau tangles.

• In clinical practice, diagnosis is based on clear signs of cognitive decline over time (assessed through neuropsychological tests), evidence that this decline affects daily function, patterns of symptoms, age of onset, and medical history to rule out other conditions that may cause similar symptoms.

• Reports often use cautious language like "suspected Alzheimer's disease," "probable Alzheimer's disease," or "consistent with Alzheimer's pathology" to acknowledge the uncertainty while still allowing patients to access support, treatment, and plan for the future.

Beta Amyloid and Tau Tangle Theory

The beta amyloid and tau tangle theory is a major theory behind Alzheimer's disease, but it hasn't yet led to effective treatments. It's important to remember that this is still a theory, not a confirmed cause of the disease.

Recap of the Theory

1. Beta Amyloid: Protein fragments that normally are cleared away by the brain. In Alzheimer's, they accumulate between neurons, forming sticky clumps called plaques. These plaques disrupt communication between brain cells and trigger inflammation.

2. Tau Protein: Normally stabilizes internal cell structures. In Alzheimer's, tau becomes abnormally twisted, forming neurofibrillary tangles inside the neurons. These tangles block nutrient transport, leading to cell stress and eventual cell death.

Amyloid Cascade Hypothesis

The amyloid cascade hypothesis suggests that amyloid builds up first, triggering tau changes and leading to widespread brain degeneration.

Limitations and Challenges

• Not all research supports the amyloid cascade hypothesis.

• Some individuals have high levels of amyloid and tau but no symptoms of Alzheimer's, while others show clear dementia symptoms with low amyloid buildup.

• Many drug trials targeting beta amyloid have failed to improve symptoms, even when plaques were removed.

• These protein changes could be the result of other problems happening earlier in the brain, such as chronic inflammation, immune system issues, or blood vessel damage.

Medical Treatments for Alzheimer's Disease

1. Acetylcholinesterase Inhibitors: Alzheimer's is linked to reduced acetylcholine, a key chemical for brain signaling. These drugs slow the breakdown of acetylcholine, helping to maintain communication between neurons. They may delay cognitive decline but do not change the disease itself.

2. Amyloid Targeting Therapies (Monoclonal Antibodies): Aim to find and clear beta amyloid plaques from the brain. They have shown promise in animal models but have had mixed and sometimes modest effects in human trials.

A key limitation is timing: many treatments are given after the diagnosis, when damage is already advanced. Therefore, prevention and early detection are major research priorities.

Parkinson's Disease

Parkinson's disease is one of the most common neurodegenerative disorders affecting movement.

Characteristics

• A progressive motor disorder, meaning symptoms gradually worsen over time, starting with motor function.

• Affects around 1% of the population over the age of 55 and is slightly more common in males.

• There is no single known cause, but it is likely due to a combination of genetic vulnerability and environmental factors.

Symptoms

• Early signs can be subtle, often starting with a slight tremor or stiffness in the fingers.

• As the condition progresses, patients may develop:

  • Tremor at rest

  • Muscular rigidity (cogwheel movement)

  • Slowness of movement

  • Difficulty initiating movement

  • Mask-like facial expression

  • Cognitive changes later on

Causes and Pathology

• The causes of Parkinson's disease are still unknown, but there is an association with the degeneration of dopamine neurons in the substantia nigra.

• These neurons project to the striatum of the basal ganglia, where motor movement control happens.

• Post-mortem examinations often reveal Lewy bodies (clumps of alpha-synuclein) in the brain. These protein buildups play a role in Parkinson's disease, but their exact role is not fully understood, as Lewy bodies are also seen in Lewy body dementia.

Treatment

• Levodopa (L-DOPA): A dopamine precursor that can cross the blood-brain barrier and help form dopamine in the brain.

• Deep Brain Stimulation (DBS) of the Subthalamic Nucleus: a controversial treatment that involves invasive surgery to implant electrodes in the subthalamic nucleus near the basal ganglia. DBS is not without undesirable effects, including cognitive, speech, and gait problems.

Huntington's Disease

Huntington's disease is a rare and progressive motor disorder with a known genetic cause.

Genetic Basis

Caused by a mutation in a single dominant gene called HTT, which produces the Huntingtin protein. If a person inherits one copy of the mutated gene, they will almost certainly develop the condition.

Symptoms and Progression

• Symptoms usually appear around age 40, but brain changes begin about ten years prior to clinical diagnosis.

• The faulty Huntingtin protein builds up in the striatum (caudate and putamen), leading to neuronal death and loss of connection to the cortex.

• This leads to chorea (involuntary jerky movements) that interfere with voluntary movement.

• Later on, cognitive decline, psychiatric symptoms, disorganized thoughts, and mood disruptions may occur.

Prevalence and Research

• Australia has higher rates of Huntington's in certain regions (Tasmania and parts of Victoria) due to shared ancestry from early settlers.

• Monash University has a leading research lab dedicated to Huntington's disease, working on genetic studies and support programs for individuals and families affected by the disease.

Support Programs

Developing evidence-informed support programs is especially important in Huntington's disease since there is currently no way to stop the degenerative process. Many people with HD have seen or cared for family members going through the progression of the condition, which adds to their emotional burden.

Comparison of Huntington's Disease (HD) and Parkinson's Disease (PD)

Both HD and PD involve degeneration in the motor control part of the brain, but they have completely different biological mechanisms and clinical presentations.