Dr. Lilian Bosire — OVERVIEW The neuron is the principal functional unit of
CELLULAR PATHOLOGY OF THE CENTRAL NERVOUS SYSTEM Neuropathology MKU Pathology — Dr. Lilian Bosire --- OVERVIEW The neuron is the principal functional unit of the CNS. Key properties: Neurons have diverse roles, neurotransmitters, synaptic patterns, and metabolic requirements Selective vulnerability — groups of neurons sharing properties may be selectively damaged by specific insults Mature neurons are postmitotic — incapable of division; even small losses can cause permanent deficits Clinical deficits depend on both the pathological process and the anatomical region affected Other CNS cells include astrocytes, oligodendrocytes, microglia, and ependymal cells (collectively, the glia) --- I. REACTIONS OF NEURONS TO INJURY Neurons are highly vulnerable due to: High metabolic demand — continuous oxygen and glucose supply required Postmitotic nature — must be maintained throughout life; cannot regenerate Susceptibility to misfolded proteins — triggers unfolded protein response; central to neurodegeneration --- A. Acute Neuronal Injury — "Red Neurons" Causes: Hypoxia/ischemia, severe hypoglycemia, other acute insults Timing: Morphological changes evident 6–12 hours after irreversible insult Morphological features: Shrinkage of cell body Pyknosis of nucleus (dark, condensed) Disappearance of nucleolus Loss of Nissl substance (rough ER) Intense cytoplasmic eosinophilia (hence "red neurons") These are the earliest morphologic markers of neuronal cell death. --- B. Subacute & Chronic Neuronal Injury — "Degeneration" Causes: Progressive neurodegenerative diseases (Alzheimer disease, ALS) — months to years Sequence of events: 1. Loss of synapses (may stem from aberrant synaptic pruning) 2. Selective death of functionally related neuron groups 3. Reactive gliosis Key points: Early cell loss is difficult to appreciate — reactive glial changes are often the best indicator Predominant mechanism of death: apoptosis --- C. Axonal Reaction (Chromatolysis) Context: Occurs in the cell body during axon regeneration, after axon is cut or severely damaged. Best seen in anterior horn cells when motor axons are damaged. Represents: Upregulation of protein synthesis for axon repair Morphological features: Enlargement and rounding of cell body Peripheral displacement of nucleus (eccentric nucleus) Enlargement of nucleolus Central chromatolysis — Nissl substance disperses from center to periphery --- D. Neuronal Inclusions Intracellular accumulations that reflect aging, metabolic disease, infection, or neurodegeneration: Inclusion Association --- --- Lipofuscin Normal aging — complex lipid accumulation Neurofibrillary tangles Alzheimer disease Lewy bodies Parkinson disease Negri bodies Rabies Cowdry A/B bodies Herpes simplex virus CMV inclusions Cytomegalovirus infection Abnormal vacuolization Creutzfeldt-Jakob disease (prion disease) Storage material Inborn errors of metabolism (enzyme deficiency → lipid/glycogen accumulation) --- E. Wallerian Degeneration Degeneration of the axon and its myelin sheath distal to the site of nerve fiber disruption The proximal stump may regenerate; the distal portion undergoes phagocytosis --- II. REACTIONS OF ASTROCYTES TO INJURY Normal Astrocyte Functions Star-shaped cells with multipolar branching processes Express GFAP (Glial Fibrillary Acidic Protein) — a cell-type specific intermediate filament, used as a marker Act as metabolic buffers and detoxifiers Foot processes surround capillaries and extend to subpial/subependymal zones → contribute to the blood-brain barrier Control flow of macromolecules between blood, CSF, and brain --- A. Gliosis The single most important histopathologic marker of CNS injury , regardless of etiology. Definition: Hypertrophy + hyperplasia of astrocytes in response to injury Morphology of reactive (gemistocytic) astrocytes: Nuclei enlarge, become vesicular, may develop prominent nucleoli Cytoplasm becomes bright pink (increased GFAP expression) Cells develop numerous stout, ramifying processes Two subtypes of reactive astrocytes (morphologically indistinguishable): One subtype promotes CNS injury One subtype promotes CNS repair --- B. Alzheimer Type II Astrocyte Not related to Alzheimer disease — named after the same neuroscientist Morphology: Large nucleus (2–3× normal) Pale-staining central chromatin Intranuclear glycogen droplet Prominent nuclear membrane and nucleolus Associations: Hyperammonemia from: Chronic liver disease (hepatic encephalopathy) Wilson disease Hereditary urea cycle disorders --- C. Rosenthal Fibers Thick, elongated, brightly eosinophilic , irregular structures within astrocytic processes Contain: αB-crystallin, hsp27 (heat-shock proteins) + ubiquitin Found in areas of long-standing gliosis Characteristic of pilocytic astrocytoma (glial tumor) Abundantly found in Alexander disease (leukodystrophy due to GFAP gene mutation) — periventricular, perivascular, and subpial locations --- D. Corpora Amylacea (Polyglucosan Bodies) Round, faintly basophilic