What are the key mechanisms underlying Parkinson's (Parkinson's disease), Huntington's (Huntington's disease), Alzheimer's (Alzheimer's disease), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS) that I need to understand for Step 1?

Key Mechanisms of Neurodegenerative Diseases for Step 1

For Step 1 preparation, focus on the distinct pathophysiological mechanisms of each neurodegenerative disease, as these represent high-yield concepts that differentiate the conditions and explain their clinical presentations. 1

Parkinson's Disease

• Characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to dopamine deficiency in the nigrostriatal pathway 1
• Mitochondrial dysfunction, specifically impaired activity of respiratory chain Complex I, is a key pathophysiological mechanism 1
• Presence of Lewy bodies (intracytoplasmic inclusions containing α-synuclein) is the hallmark pathological finding 1
• Genetic mutations affecting proteins that regulate mitochondrial homeostasis (SNCA, DJ-1, LRRK2, Parkin, PINK-1) contribute to familial forms 1
• Environmental toxins like rotenone and MPTP (which inhibit Complex I) can induce Parkinson-like symptoms in animal models 1

Huntington's Disease

• Autosomal dominant disorder caused by CAG trinucleotide repeat expansion in the huntingtin (HTT) gene on chromosome 4 1
• Impaired activity of mitochondrial respiratory chain Complexes II and III is a key feature 1
• Mutant huntingtin protein forms intranuclear inclusions, leading to transcriptional dysregulation and neuronal dysfunction 1
• Preferential degeneration of GABAergic medium spiny neurons in the striatum 1
• Complex II inhibitors like 3-nitropropionic acid can produce HD-like phenotypes in animal models 1

Alzheimer's Disease

• Characterized by extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein 1
• Mitochondrial dysfunction, particularly impaired activity of respiratory chain Complex IV, is a significant feature 1
• Reduced activity of α-ketoglutarate dehydrogenase contributes to bioenergetic failure 1
• Genetic factors include mutations in amyloid precursor protein (APP), presenilin (PSEN1/2), and apolipoprotein E (APOE) genes 1
• Progressive loss of cholinergic neurons in the basal forebrain contributes to cognitive decline 2

Multiple Sclerosis

• Autoimmune-mediated demyelination of axons in the central nervous system 1
• T-cell mediated inflammatory response against myelin components 1
• Formation of demyelinating lesions (plaques) in the white matter, particularly in the periventricular regions, optic nerves, and spinal cord 1
• Lesions involving the thalamus, lenticular nucleus, globus pallidus, and internal capsule can cause movement disorders 1
• Relapsing-remitting MS is the most common form and can sometimes present with paroxysmal movement disorders 1

Amyotrophic Lateral Sclerosis (ALS)

• Characterized by degeneration of both upper and lower motor neurons in the brain and spinal cord along the corticospinal tracts 3, 4
• Pathophysiology involves increased oxidative stress, glutamate toxicity, mitochondrial dysfunction, inflammation, and apoptosis 4
• Genetic mutations in SOD1, FUS, TARDBP (TDP-43), C9orf72, and CHCHD10 genes are associated with familial forms 1, 4
• Mean survival is typically 3-5 years after symptom onset, with only 5-10% living longer than 10 years 3, 4
• Progressive loss of motor neurons results in atrophy of skeletal muscles including respiratory muscles 4

Common Mechanisms Across Neurodegenerative Diseases

• Mitochondrial dysfunction is implicated in most neurodegenerative diseases 1
• Protein misfolding and aggregation are common features (α-synuclein in PD, huntingtin in HD, Aβ and tau in AD) 1
• Neuroinflammation contributes to disease progression in all conditions 5
• Excitotoxicity due to excessive glutamate signaling is a shared mechanism 6
• Oxidative stress and impaired cellular energy metabolism accelerate neuronal death 1

Clinical Scenarios for Step 1 Questions

Parkinson's Disease Scenario

A 65-year-old man presents with a 6-month history of resting tremor in his right hand, stooped posture, and difficulty initiating movement. Physical examination reveals masked facies, cogwheel rigidity, and bradykinesia.

Key testing points:

• Recognize the classic triad of tremor, rigidity, and bradykinesia 1
• Identify the dopaminergic deficiency as the primary mechanism 1
• Understand the role of Lewy bodies in pathogenesis 1
• Know that Complex I deficiency in mitochondria contributes to pathology 1

Huntington's Disease Scenario

A 42-year-old woman presents with involuntary choreiform movements, irritability, and difficulty concentrating. Her father died of a similar neurological condition at age 50.

Key testing points:

• Recognize the autosomal dominant inheritance pattern 1
• Identify CAG trinucleotide repeat expansion as the genetic mechanism 1
• Understand the preferential degeneration of striatal neurons 1
• Know that mitochondrial Complexes II and III dysfunction contributes to pathology 1

Alzheimer's Disease Scenario

A 75-year-old man is brought to the clinic by his daughter due to progressive memory loss over the past year. He has difficulty remembering recent conversations and gets lost in familiar places.

Key testing points:

• Recognize the amnestic presentation as typical for AD 1
• Identify amyloid plaques and neurofibrillary tangles as hallmark pathological findings 1
• Understand the role of APP, PSEN1/2, and APOE genes in pathogenesis 1
• Know that Complex IV deficiency in mitochondria contributes to pathology 1

Multiple Sclerosis Scenario

A 28-year-old woman presents with blurred vision in her right eye that developed over 2 days. She reports a similar episode affecting her left leg with weakness and numbness 6 months ago that resolved spontaneously.

Key testing points:

• Recognize the relapsing-remitting pattern with lesions disseminated in time and space 1
• Identify autoimmune-mediated demyelination as the primary mechanism 1
• Understand the role of T-cell mediated inflammation 1
• Know that lesions in specific brain regions can cause distinctive neurological deficits 1

ALS Scenario

A 60-year-old man presents with progressive weakness in his right hand over 3 months. Examination reveals muscle atrophy in the hand, fasciculations in the upper limbs, hyperreflexia, and a positive Babinski sign.

Key testing points:

• Recognize the combination of upper and lower motor neuron signs 3, 4
• Identify the degeneration of motor neurons as the primary mechanism 3
• Understand the role of SOD1, FUS, and TDP-43 mutations in familial cases 1, 4
• Know the poor prognosis with respiratory failure as the usual cause of death 3

By mastering these key mechanisms and recognizing their clinical manifestations, you will be well-prepared for Step 1 questions on neurodegenerative diseases.