Key Neurodegenerative Diseases

Why This Matters

Neurodegenerative diseases are your window into understanding how specific brain structures and cellular mechanisms translate into observable behavior. When you study Alzheimer's, you're really studying how the hippocampus encodes memory; when you examine Parkinson's, you're seeing what happens when the dopaminergic system fails. These diseases aren't just medical conditions—they're natural experiments that reveal the brain's architecture and the consequences when particular systems break down.

You're being tested on the underlying mechanisms of neurodegeneration: protein aggregation, neurotransmitter depletion, demyelination, and genetic mutations. Exams will ask you to connect cellular pathology to behavioral symptoms, compare diseases with overlapping features, and explain why damage to different brain regions produces different deficits. Don't just memorize disease names—know what each condition teaches us about normal brain function and what goes wrong at the cellular level.

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Protein Aggregation Disorders

These diseases share a common mechanism: abnormal proteins accumulate in neurons, disrupting cellular function and eventually causing cell death. The specific protein and its location determine which symptoms emerge.

Alzheimer's Disease

• Amyloid plaques and tau tangles accumulate in the hippocampus and cortex, disrupting synaptic communication and triggering neuronal death
• Progressive memory loss begins with recent memories (hippocampal damage) before affecting older memories and executive function
• Risk factors include age, APOE4 gene variant, and cardiovascular health—demonstrating the interaction between genetics and environment in neurodegeneration

Lewy Body Dementia

• Lewy bodies—abnormal alpha-synuclein protein deposits—form throughout the cortex and brainstem, causing widespread dysfunction
• Fluctuating cognition and visual hallucinations distinguish this from Alzheimer's, reflecting involvement of visual processing and arousal systems
• Parkinsonism symptoms overlap with Parkinson's disease because both involve alpha-synuclein pathology, making differential diagnosis challenging

Prion Diseases

• Misfolded prion proteins cause normal proteins to misfold in a chain reaction, leading to rapid, fatal neurodegeneration
• Creutzfeldt-Jakob disease produces rapidly progressive dementia and ataxia—weeks to months rather than years
• Transmissibility makes prions unique among neurodegenerative causes; they can be inherited, sporadic, or acquired through contaminated tissue

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Dopaminergic and Basal Ganglia Disorders

These conditions result from degeneration of neurons in the basal ganglia circuit, particularly those producing or responding to dopamine. The basal ganglia regulate movement initiation and inhibition.

Parkinson's Disease

• Dopamine-producing neurons in the substantia nigra degenerate, reducing input to the striatum and impairing movement initiation
• Cardinal motor symptoms—tremor, rigidity, bradykinesia, and postural instability—reflect the basal ganglia's role in smooth, voluntary movement
• Non-motor symptoms including depression and cognitive changes reveal dopamine's broader role in mood and executive function

Huntington's Disease

• CAG repeat expansion in the HTT gene causes production of toxic huntingtin protein, destroying neurons in the caudate nucleus and putamen
• Chorea (involuntary, dance-like movements) results from loss of inhibitory control in the basal ganglia—the opposite pattern from Parkinson's rigidity
• Autosomal dominant inheritance means 50% transmission risk, making this a key example of single-gene neurological disorders

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Motor Neuron Diseases

These disorders specifically target motor neurons in the brain, brainstem, or spinal cord, causing progressive weakness and paralysis while often sparing cognition and sensation.

Amyotrophic Lateral Sclerosis (ALS)

• Upper and lower motor neurons degenerate, causing progressive muscle weakness, atrophy, and eventual paralysis including respiratory muscles
• Cognition typically remains intact, demonstrating the selectivity of neurodegeneration—ALS targets motor pathways while sparing cortical association areas
• 3-5 year average survival post-diagnosis reflects the rapid, relentless progression once symptoms appear

Spinal Muscular Atrophy

• SMN1 gene mutations reduce survival motor neuron protein, causing spinal motor neuron death and progressive muscle weakness
• Type severity varies dramatically—Type 1 appears in infancy with severe weakness; Type 4 emerges in adulthood with milder symptoms
• Gene therapy breakthroughs make SMA a landmark example of how understanding genetic mechanisms enables targeted treatment

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Demyelinating and Autoimmune Disorders

Multiple sclerosis demonstrates what happens when the immune system attacks the myelin sheath, disrupting the speed and efficiency of neural transmission throughout the CNS.

Multiple Sclerosis (MS)

• Autoimmune demyelination strips the insulating myelin from axons in the brain and spinal cord, slowing or blocking signal transmission
• Symptoms vary by lesion location—optic neuritis (visual pathways), weakness (motor tracts), numbness (sensory pathways), or coordination problems (cerebellar connections)
• Relapsing-remitting vs. progressive forms illustrate how the same underlying mechanism can produce different disease courses

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Frontotemporal and Cerebellar Degeneration

These conditions target specific brain regions outside the classic memory circuits, producing distinctive behavioral and motor syndromes that differ from typical dementia presentations.

Frontotemporal Dementia

• Frontal and temporal lobe atrophy causes personality changes, disinhibition, and language problems rather than the memory loss typical of Alzheimer's
• Younger onset (ages 40-65) and behavioral symptoms often lead to initial misdiagnosis as psychiatric illness
• Language variants include progressive aphasia, demonstrating how focal degeneration produces specific cognitive deficits

Spinocerebellar Ataxia

• Cerebellar and spinal cord degeneration causes progressive loss of coordination, balance, and fine motor control
• Multiple genetic subtypes exist with different CAG repeat expansions, illustrating how similar mechanisms produce related but distinct disorders
• Ataxia (loss of coordinated movement) reflects the cerebellum's essential role in motor timing and error correction

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Quick Reference Table

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Self-Check Questions

1. Which two diseases both involve abnormal protein aggregation but produce different primary symptoms—one affecting memory and the other causing visual hallucinations and motor problems?

2. Parkinson's and Huntington's both affect the basal ganglia. Explain why one produces too little movement while the other produces too much.

3. A patient presents with progressive weakness but intact sensation and cognition. Which two diseases should you consider, and what distinguishes them mechanistically?

4. Compare and contrast Alzheimer's disease and frontotemporal dementia in terms of brain regions affected, typical age of onset, and presenting symptoms.

5. If an FRQ asks you to explain how understanding the genetic basis of a neurodegenerative disease has led to treatment advances, which condition provides the strongest example and why?