CNS Pathology: Neuron & Astrocyte Injury, Reactions & Neu...

NEUROPATHOLOGY — Complete Study Notes Unit: CNS Cellular Pathology, Malformations & Cerebral Edema --- PART 1: CELLULAR PATHOLOGY OF THE CNS --- The Neuron — The Functional Unit The neuron is the principal functional unit of the CNS. Key characteristics: Postmitotic — cannot divide or replace themselves once destroyed Highly metabolically active — require continuous oxygen and glucose Selectively vulnerable — different neuron populations are vulnerable to different insults based on shared properties (neurotransmitters, metabolic needs, connectivity) Long-lived — their lengthy lifespan makes them unusually prone to accumulation of misfolded proteins , triggering the unfolded protein response , central to many neurodegenerative diseases 💡 Key Concept: Because neurons cannot regenerate, even small focal losses can produce permanent neurological deficits. Clinical signs depend on both the pathological process AND the anatomical region affected. --- Reactions of Neurons to Injury 1. Acute Neuronal Injury — "Red Neurons" Seen after acute hypoxia/ischemia, hypoglycemia, or trauma Earliest morphological marker of neuronal cell death Changes visible by 6–12 hours after irreversible injury Morphological Features: Feature Change --- --- Cell body Shrinkage Nucleus Pyknosis (dark, shrunken) Nucleolus Disappears Nissl substance Lost Cytoplasm Intensely eosinophilic (hence "red") --- 2. Subacute/Chronic Neuronal Injury — "Degeneration" Occurs over months to years in progressive diseases e.g. ALS, Alzheimer disease Sequence of events: 1. Loss of synapses — aberrant synaptic pruning 2. Neuronal cell death — selective for functionally related groups 3. Reactive gliosis At early stages, glial changes are the best indicator of neuronal injury Predominant cell death mechanism: Apoptosis --- 3. Axonal Reaction — Chromatolysis Occurs during axonal regeneration after axon cutting or damage. Best seen in anterior horn cells of the spinal cord Morphological Features: Cell body enlarges and rounds up Nucleus displaced to periphery Nucleolus enlarges Nissl substance disperses to periphery → central chromatolysis 💡 Reflects increased protein synthesis for axonal repair --- 4. Neuronal Inclusions Inclusion Disease/Context --- --- Lipofuscin Normal aging Neurofibrillary tangles Alzheimer disease Lewy bodies Parkinson disease Cowdry A/B bodies Herpes virus infection Negri bodies Rabies CMV inclusions Cytomegalovirus infection Vacuolization Creutzfeldt-Jakob disease (prion) 💡 Wallerian Degeneration = degeneration of axon distal to the site of nerve fiber disruption --- Reactions of Astrocytes to Injury Structure and Function Star-shaped cells with multipolar branching processes Express GFAP (Glial Fibrillary Acidic Protein) — specific astrocyte marker Functions: Metabolic buffering and detoxification Blood-brain barrier maintenance via foot processes around capillaries Extend to subpial and subependymal zones --- Gliosis Most important histopathologic marker of CNS injury, regardless of cause Characterized by hypertrophy and hyperplasia of astrocytes Reactive astrocytes = gemistocytic astrocytes Bright pink cytoplasm (↑ GFAP) Large vesicular nuclei Stout ramifying processes Two subtypes exist (morphologically identical but functionally distinct): Type A → promotes CNS injury Type B → contributes to CNS repair --- Special Astrocytic Pathological Forms Alzheimer Type II Astrocyte (not related to Alzheimer disease) Large nucleus (2–3× normal), pale chromatin, intranuclear glycogen droplet, prominent nucleolus Seen in hyperammonemia : chronic liver disease, Wilson disease, urea cycle disorders --- Rosenthal Fibers Thick, elongated, eosinophilic structures in astrocytic processes Contain: αB-crystallin, hsp27, ubiquitin Found in: long-standing gliosis, pilocytic astrocytoma Abundant in Alexander disease (GFAP gene mutation — leukodystrophy) Located periventricularly, perivascularly, subpially --- Corpora Amylacea (Polyglucosan Bodies) Round, faintly basophilic, PAS-positive , concentrically lamellated (5–50 μm) Located at astrocytic end processes — subpial and perivascular zones Contain: glycosaminoglycan polymers, heat-shock proteins, ubiquitin Increase with advancing age — represent degenerative astrocyte change Similar structure to Lafora bodies (neurons, hepatocytes, myocytes in myoclonic epilepsy) --- Reactions of Microglia to Injury Normal Function Phagocytic cells — resident macrophages of the CNS Derived from yolk sac or fetal liver early in embryonic development Share surface markers with bone marrow–derived monocytes/macrophages At rest: tiled arrangement (non-overlapping territories) During development: prune unused synaptic connections via complement system ⚠️ Aberrant reactivation of microglial synaptic pruning implicated in schizophrenia, Alzheimer disease, frontotemporal dementia, and encephalitis Responses to Injury Microglia respond by: 1. Proliferating 2. Developing elongated nuclei 3. Forming microglial nodules around sma