Pathobiology of Neurologic Diseases¶

Chapter 435 | Harrison's 22e · Part 13 – Neurologic Disorders · Chapter 435

Key Clinical Points¶

The CNS is an exceptionally complex organ containing approximately 100 billion neurons, several million miles of axons, and >10^15 synapses.
Neuroimmunology focuses on immune-mediated diseases (e.g., multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome) and disorders involving immune-mediated damage during infection or neoplasia.
Microglia are the primary cells for innate immunity and antigen presentation in the CNS; they are derived from a primitive macrophage population in the yolk sac and migrate to the CNS before the blood-brain barrier (BBB) is formed.
Microglia exist in 'resting' (ramified), 'activated' (amoeboid), and 'primed' states; primed microglia (e.g., via type 1 interferons) are hyperresponsive to secondary immune challenges.
Microglial homeostasis includes the secretion of BDNF, synaptic pruning, and phagocytosis of debris and protein aggregates.
Pathological microglial activation leads to the release of cytokines (IL-1α, TNF, C1q) and the induction of neurotoxic A1 astrocytes.
Experimental allergic encephalomyelitis (EAE) serves as a model for multiple sclerosis (MS), illustrating the progression from T cell activation to immune-mediated myelin destruction.
The prion hypothesis posits that neurodegeneration results from the post-translational modification of precursor proteins into high β-sheet content forms; these are most toxic as oligomers.
Prion-based classification categorizes diseases by causative proteins: PrPSc (e.g., CJD, Kuru), α-Synuclein (e.g., PD, MSA), and others (e.g., SOD1, TDP43 in ALS).
Advanced neurovascular interventions include detachable coils for aneurysms, stent retrieval for large-vessel occlusions, and various embolization techniques.

DEFINITION & CLASSIFICATION¶

• Neuroimmunology: The study of immune-mediated diseases of the nervous system. ◦ Includes autoimmune diseases: multiple sclerosis (MS), myasthenia gravis, and Guillain-Barré syndrome. ◦ Includes disorders where immune-mediated neurologic damage occurs in the context of infection or neoplasia. • Prion Hypothesis: Concept that neurodegeneration results from the post-translational modification of a precursor protein into a prion form. ◦ Characterized by high β-sheet content. ◦ Toxicity: Most toxic as oligomers; less toxic after polymerization into amyloid fibrils. ◦ Drug targets for therapy: (1) lowering the precursor protein, (2) inhibiting prion formation, and (3) enhancing prion clearance. ◦ Differentiation based on causative proteins: ◦ PrPSc: Creutzfeldt-Jakob disease (CJD), Kuru, Gerstmann-Sträussler-Scheinker disease (GSS), Fatal insomnia, Bovine spongiform encephalopathy (BSE), Scrapie, Chronic wasting disease (CWD), Feline spongiform encephalopathy, and Transmissible mink encephalopathy. ◦ α-Synuclein: Parkinson’s disease (PD), Dementia with Lewy bodies, and Multiple-system atrophy. ◦ ALS: SOD1, TDP43, FUS (C9orf72).

ETIOLOGY & PATHOPHYSIOLOGY¶

Microglia and Macrophages¶

• Role: Most abundant cell types in the nervous system responsible for antigen presentation and innate immunity. ◦ Different isoforms are expressed, increasing specificities and potential functionality. • Origin: Derived from a primitive macrophage population in the yolk sac; migrate to the CNS before the blood-brain barrier (BBB) is formed. • Maintenance: Primarily through self-renewal; not repopulation from circulation. ◦ Peripherally derived macrophages can become "microqu-like" and replace damaged or defective microglia throughout the life span. • Signaling: Survival via colony-stimulating factor 1 receptor (Csf1r). ◦ Ligands: Csf1 (produced by astrocytes and oligodendrocytes) and interleukin (IL) 34 (produced by neurons). • States: ◦ Resting: Extensively ramified appearance. ◦ Activated: Globular amoeboid phenotype. ◦ Primed: Transitioned by factors like type 1 interferons; these are hyperresponsive to secondary immune challenges including infection.

Neuroinflammation and EAE¶

• EAE Model: Experimental allergic encephalomyelitis (EAE) serves as a model for multiple sclerosis (MS). ◦ Illustrates the progression of neuroinflammation. • Pathogenesis Sequence (Fig. 435-2): 1. Peripheral activation of preexisting autoreactive T cells → 2. Homing to the CNS and extravasation across the blood-brain barrier (BBB) (involving enzymes like Gelatinases and molecules such as CD31, ICAM-1, LFA-1, VCAM-1) → 3. Reactivation of T cells by exposed autoantigens → 4. Secretion of cytokines (TNF, IFN, IL-1, IL-2, IL-12, TNFα, LT, GM-CSF) and chemokines → 5. Activation of microglia and astrocytes and recruitment of a secondary inflammatory wave → 6. Immune-mediated myelin destruction.

MANAGEMENT & TREATMENT¶

• General Note: The highest complication rates are found with the therapies designed to treat the highest risk diseases. • Neurovascular Interventions: 1. Detachable coil therapy: Used for cerebral aneurysms; reduced morbidity and mortality at 1 year compared to neurosurgical clipping. 2. Stent retrieval systems: Used for large-vessel occlusions with signs of acute stroke. 3. Particulate or computational liquid adhesive embolization: Used for arteriovenous malformations. 4. Retrieval systems: Used for embolectomy in acute stroke. 5. Balloon angioplasty and stenting: Used for arterial stenosis or vasospasm. 6. Transarterial or transvenous embolization: Used for dural arteriovenous fistulas of the spine. 7. Balloon occlusion: Used for carotid-cavernous and vertebral fistulas. 8. Endovascular treatment: Used for vein-of-Galen malformations. 9. Preoperative embolization: Used for tumors. 10. Thrombolysis: Used for acute arterial or venous thrombosis.

KEY PEARLS & HIGH-YIELD POINTS¶

• CNS Complexity: 100 billion neurons, several million miles of axons, and >10^15 synapses. • Microglia Role: Primary cells for innate immunity; distinct from other cells by their yolk sac origin and lack of repopulation from circulation. • Prion Toxicity: Highest as oligomers; less toxic after polymerization into amyloid fibrils. • Neurovascular Success: Detachable coils have become standard therapy for many proximal circle of Willis aneurysms.

Reference Tables¶

TABLE 435-1 Prion-Based Classification of Neurodegenerative Diseases¶

Harrison's 22e, p.3401

NEURODEGENERATIVE DISEASE	CAUSATIVE PRION PROTEINS
Creutzfeldt-Jakob disease (CJD) Kuru Gerstmann-Sträussler-Scheinker disease (GSS) Fatal insomnia Bovine spongiform encephalopathy (BSE) Scrapie Chronic wasting disease (CWD) Feline spongiform encephalopathy Transmissible mink encephalopathy	PrPSc PrPSc PrPSc PrPSc PrPSc PrPSc PrPSc PrPSc PrPSc
Parkinson’s disease (PD) Dementia with Lewy bodies Multiple-system atrophy	α-Synuclein α-Synuclein α-Synuclein
Amyotrophic lateral sclerosis (ALS)	SOD1, TDP43, FUS (C9orf72)