CELLULAR PATHOLOGY OF THE CENTRAL NERVOUS SYSTEM Neuropathology MKU Pathology — Dr. Lilian Bosire --- OVERVIEW The neuron is the principal functional unit of th
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 , PAS-positive, concentrically lamellated structures - Size: 5–50 μm - Located at astrocytic end processes — especially subpial and perivascular zones - Composition: glycosaminoglycan polymers + heat-shock proteins + ubiquitin - Increase with advancing age → represent degenerative astrocytic change - Similar structure to Lafora bodies (seen in neurons, hepatocytes, myocytes in myoclonic epilepsy) --- III. REACTIONS OF MICROGLIA TO INJURY Normal Microglial Properties - Derived from yolk sac or fetal liver early in embryonic development (not bone marrow like other macrophages) - Serve as resident macrophages of the CNS - Share surface markers with peripheral monocytes/macrophages - At rest: tiled arrangement (non-overlapping territories) with highly branched processes - During development: prune unused synaptic connections via phagocytosis (possibly complement-mediated) Aberrant reactivation of synaptic pruning has been implicated in schizophrenia, encephalitis, Alzheimer disease, and frontotemporal dementia Microglial Responses to Injury 1. Proliferation 2. Developing elongated nuclei (rod cells) 3. Microglial nodules — aggregates around small foci of tissue necrosis 4. Neuronophagia — congregating around and engulfing dying neurons Blood-derived macrophages may also be present at inflammatory foci alongside resident microglia. --- IV. REACTIONS OF OTHER GLIAL CELLS A. Oligodendrocytes - Wrap cytoplasmic processes around axons to form myelin - Each oligodendrocyte myelinates multiple internodes on multiple axons (contrast with Schwann cells, which myelinate only one internode of a single axon) - Injury/apoptosis → feature of acquired demyelinating disorders (e.g., MS) and leukodystrophies - Oligodendroglial nuclear viral inclusions → seen in Progressive Multifocal Leukoencephalopathy (PML) - Glial cytoplasmic inclusions (α-synuclein) in oligodendrocytes → Multiple System Atrophy (MSA) --- B. Ependymal Cells - Ciliated columnar epithelial cells lining the ventricles - Do not show specific reaction patterns - With inflammation or marked ventricular dilation: - Ependymal lining disrupts - Subependymal astrocytes proliferate → form ependymal granulations (small surface irregularities) - CMV can cause extensive ependymal injury with viral inclusions in ependymal cells Neither oligodendrocytes nor ependymal cells mediate significant responses to most forms of CNS injury. --- SUMMARY TABLE Cell Type Key Marker Response to Injury Pathological Associations --- --- --- --- Neuron Nissl substance, neuronal morphology Red neurons, chromatolysis, degeneration Ischemia, neurodegeneration, trauma Astrocyte GFAP Gliosis (hypertrophy + hyperplasia) Any CNS injury; Alexander disease, liver failure Microglia CD68, Iba1 (monocyte markers) Nodules, neuronophagia, proliferation Infection, ischemia, neurodegeneration Oligodendrocyte Myelin proteins Demyelination, apoptosis MS, leuko