Reactions of Reactions of Neural Neural

Tissues to Tissues to DiseasesDiseasesRAMON S. JAVIER, MDRAMON S. JAVIER, MD

Department of Neurology & Department of Neurology & PsychiatryPsychiatry

University of Santo TomasUniversity of Santo Tomas

Santiago Ramón y Cajal teaching anatomy to some of his pupils at the University Central of Madrid, circa 1915. From left to right, back row Torres Alonso, Castillo, Achúcarro; front row, Rodríguez Díaz, Sapena, Santiago Ramón y Cajal, Sáinz de Aja, Tello, and Bengoa.

Meninges

Cortex

Subcortical white matter

Pyramidal Neurons

Neurons H&E

Cresyl violet

Silver

Cortical pyramidal neuron

Myelin StainMyelin Stain

White matter

Cortex

A.A. Pyramidal cell – Pyramidal cell – cortexcortex

B.B. Pyramidal cell- Pyramidal cell- hippocampushippocampus

C.C. Betz cellBetz cell

D.D. Dentate gyrus Dentate gyrus neuronsneurons

E.E. Purkinje and Purkinje and granule cell of granule cell of cerebellumcerebellum

F.F. Anterior horn cellAnterior horn cell

Special NeuronsSpecial Neurons

Cell Types in the CNSCell Types in the CNSNeuronsNeurons

Special types:Special types:Bioaminergic neurotransmitterBioaminergic neurotransmitterproducing neurons (usually producing neurons (usually

pigmented grossly)pigmented grossly)

a. a. Substantia Substantia nigranigra neuromelanin neuromelanin (oxidized (oxidized dopaminedopamine and and polymerized polymerized dopamine)dopamine)

b. b. Locus ceruleusLocus ceruleus - - lateral lateral to 4 to 4thth ventricle, contains ventricle, contains norepinephrine norepinephrine

c. c. Raphe nucleusRaphe nucleus - - center of brain stem, center of brain stem, contains contains serotoninserotonin

d. d. N. basalis of N. basalis of MeynertMeynert - collection of - collection of cholinergic cholinergic neurons in the neurons in the basal forebrainbasal forebrain

Pathology of NeuronsPathology of NeuronsAcute changes - swelling, vacuolation, chromatolysis, shrinkage Acute changes - swelling, vacuolation, chromatolysis, shrinkage

of nucleusof nucleus (acute infectious, toxic, vascular, metabolic diseases) (acute infectious, toxic, vascular, metabolic diseases) Chronic changes – atrophy – shrunken cell bodies, corskscrew-Chronic changes – atrophy – shrunken cell bodies, corskscrew-

like dendrites, shrunken, intensely basophilic nuclei like dendrites, shrunken, intensely basophilic nuclei (degenerative diseases)(degenerative diseases)

lipofuscin accumulation – small golden brown pigments in lipofuscin accumulation – small golden brown pigments in perikaryon seen in normal agingperikaryon seen in normal aging

Specific Neuronal ChangesSpecific Neuronal Changes Axonal/retrograde reactionAxonal/retrograde reaction Hypoxic-ischemic changesHypoxic-ischemic changes FerruginationFerrugination Distension in storage diseasesDistension in storage diseases Ballooned achromasiaBallooned achromasia Granulovacuolar degenerationGranulovacuolar degeneration Inclusion bodiesInclusion bodies

DegenerativeDegenerative ViralViral

Neoplastic transformationNeoplastic transformation

Vacuolated swollen motor neuron in medulla.

Chronic atrophy of pyramidal neuron: The perikaryon is shrunken, the dendrites are corkscrew-like, and the nucleus is densely basophilic.

Axonal or retrograde changes in hypoglossal neuron caused by tumorous infiltration of the nerve roots. The swollen perikaryon is rounded, the dendrites are retracted, the Nissl bodies are partially dissolved, and remaining ones are clustered around the peripherally displaced nucleus ( [HE] stain).

Ischemic Purkinje cells in the cerebellar cortex showing eosinophilic shrunken perikaryons and homogenous basophilic nuclei (HE).

Axonal or Retrograde Neuronal Changes-in response to axonal transection. The cytoplasm swells and becomes rounded with retracted dendrites. The Nissl bodies partially dissolve and some of the remaining Nissl bodies surround the eccentrically displaced nucleus.

Hypoxic-Ischemic Changes (Red Neurons)The shrunken perikaryon, partially or totally devoid of Nissl bodies, stains brightly red with eosin, and the pyknotic triangular- shaped nucleus stains uniformly blue with hematoxylin.

Spinal motor storage neuron in Tay-Sachs disease; the cytoplasm is markedly distended and the nucleus displaced to the periphery (LFB-CV).

Distended Storage NeuronsDistended storage neurons in neurometabolic diseases are markedly swollen and pear-shaped, with the nucleus and the Nissl bodies displaced toward the apical dendrite. Histochemical stains reveal the composition of the substances stored within the perikaryon.

Ferrugination of the NeuronsFerrugination of the NeuronsFerrugination in chronic ischemic-hypoxic lesions Ferrugination in chronic ischemic-hypoxic lesions

results from the deposition (incrustation) of results from the deposition (incrustation) of basophilic calcium and iron granules on the basophilic calcium and iron granules on the dendrites and cytoplasm of dead neuronsdendrites and cytoplasm of dead neurons

Ballooned Achromatic NeuronsBallooned Achromatic NeuronsBallooned neurons seen in corticobasal Ballooned neurons seen in corticobasal dementia display enlarged palely stained dementia display enlarged palely stained perikaryon, a lack of Nissl bodies, andperikaryon, a lack of Nissl bodies, and argyrophilic fibrillary structures.argyrophilic fibrillary structures.

Granulo-Vacuolar DegenerationGranulo-Vacuolar DegenerationThis degenerative change manifests small basophilic This degenerative change manifests small basophilic

granules within vacuoles in the pyramidal neurons granules within vacuoles in the pyramidal neurons of the hippocampus. It is found both in Alzheimer’s of the hippocampus. It is found both in Alzheimer’s disease and normal aging.disease and normal aging.

Lipofuscin Lipofuscin -PAS

Granulovacuolar degeneration

Neuronal Cytoplasmic Inclusions in Neuronal Cytoplasmic Inclusions in Degenerative Degenerative DiseasesDiseases

Inclusions Inclusions ProteinsProteins

Neurofibrillary tangle Neurofibrillary tangle Tau protein Tau protein (microtubule (microtubule associated protein)associated protein)

Pick bodyPick body Tau protein Tau protein

Lewy body Lewy body αα-Synuclein (synaptic -Synuclein (synaptic protein)protein)

Hirano body Hirano body ActinActin

Bunina body Bunina body Cystatin CCystatin C

Skein-like inclusions Skein-like inclusions Ubiquitin (stress Ubiquitin (stress protein)protein)

Neuronal Inclusion Bodies in Neuronal Inclusion Bodies in Degenerative DiseasesDegenerative Diseases

Neurofibrillary tanglesNeurofibrillary tangles, a histologic hallmark of Alzheimer’s , a histologic hallmark of Alzheimer’s disease, are disease, are argyrophilicargyrophilic torch-torch- and and basketshapedbasketshaped or or globoseglobose filamentous cytoplasmic structures that filamentous cytoplasmic structures that immunoreact for tau protein. They also are found in immunoreact for tau protein. They also are found in normal agingnormal aging and in a variety of diseases. and in a variety of diseases.

Pick bodiesPick bodies, histologic hallmarks of Pick’s disease, are , histologic hallmarks of Pick’s disease, are argyrophilicargyrophilic, round, homogenous structures in the swollen , round, homogenous structures in the swollen perikaryons of cortical and subcortical neurons.perikaryons of cortical and subcortical neurons.

Lewy bodies Lewy bodies are are eosinophiliceosinophilic, round inclusions in the , round inclusions in the melanin-containing neurons of the substantia nigra and melanin-containing neurons of the substantia nigra and locus ceruleus in idiopathic Parkinson’s disease and in the locus ceruleus in idiopathic Parkinson’s disease and in the cortical neurons of the diffuse Lewy body dementia. They cortical neurons of the diffuse Lewy body dementia. They immunoreact for á-synuclein and ubiquitin.immunoreact for á-synuclein and ubiquitin.

Hirano bodies Hirano bodies are are rod-shaped rod-shaped oror ovoid ovoid eosinophilic eosinophilic structures structures within or adjacent to the pyramidal neurons of the within or adjacent to the pyramidal neurons of the hippocampus in Alzheimer’s disease, and they are also hippocampus in Alzheimer’s disease, and they are also found in normal aging. They immunoreact for actin.found in normal aging. They immunoreact for actin.

Bunina bodies Bunina bodies are small, are small, eosinophiliceosinophilic granules in the granules in the cytoplasm of motor neurons in amyotrophic lateral cytoplasm of motor neurons in amyotrophic lateral sclerosis (ALS). They immunoreact for cystatin C.sclerosis (ALS). They immunoreact for cystatin C.

Skein-like inclusions Skein-like inclusions in ALS immunoreact for ubiquitinin ALS immunoreact for ubiquitin..

Neuronal inclusions

NFT in AD (Gallyas silver stain)

(+) Tau protein

Pick bodies (Bodian silver stain)

Lewy bodies in SN in PD (HE)

Hirano bodies in hippocampus (HE)

Pick bodiesPick bodies Rounded, homogenous, intracytoplasmic neuronal inclusionsRounded, homogenous, intracytoplasmic neuronal inclusions Characteristic of Pick diseaseCharacteristic of Pick disease Intensely argyrophilic Intensely argyrophilic Immunoreactive to neurofilament, ubiquitin, tau and tubulinImmunoreactive to neurofilament, ubiquitin, tau and tubulin

Lewy bodiesLewy bodies Intracytoplasmic, found in the perikaryon or processesIntracytoplasmic, found in the perikaryon or processes Classic: round, eosinophilic with haloClassic: round, eosinophilic with halo Present in Lewy body diseases, especially Parkinson and Diffuse lewy body dementiaPresent in Lewy body diseases, especially Parkinson and Diffuse lewy body dementia Immunoreactive to ubiquitin, aBcrystallin, and a-synucleinImmunoreactive to ubiquitin, aBcrystallin, and a-synuclein

Alpha-synuclein

Diseases with Neurofibrillary Diseases with Neurofibrillary TanglesTangles

Alzheimer’s diseaseAlzheimer’s diseaseDown’s syndromeDown’s syndromeParkinson-Dementia-ALS complex of GuamParkinson-Dementia-ALS complex of GuamProgressive supranuclear palsyProgressive supranuclear palsyPostencephalitic parkinsonismPostencephalitic parkinsonismDementia pugilisticaDementia pugilisticaSubacute sclerosing panencephalitisSubacute sclerosing panencephalitisTuberous sclerosisTuberous sclerosisNiemann-Pick disease, type CNiemann-Pick disease, type CGerstmann-Sträussler-Scheinker diseaseGerstmann-Sträussler-Scheinker disease

Neuronal Inclusions in Viral InfectionsNeuronal Inclusions in Viral Infections

In viral diseases, the inclusions are commonly intranuclear, In viral diseases, the inclusions are commonly intranuclear, except that in rabies they occur in the cytoplasm of the except that in rabies they occur in the cytoplasm of the Purkinje cells and the pyramidal neurons of the Ammon’s Purkinje cells and the pyramidal neurons of the Ammon’s horn.horn.

Neoplastic TransformationNeoplastic Transformation

Transformation of the neurons into neurocytomas, Transformation of the neurons into neurocytomas, neuroblastomas, and gangliogliomas are relatively rare but neuroblastomas, and gangliogliomas are relatively rare but may occur from infancy to old age.may occur from infancy to old age.

cmv sspe

Pathology of the DendritesPathology of the Dendrites

The The reduction and loss of dendritic processes reduction and loss of dendritic processes in cortical neurons occur in cortical neurons occur in neurodegenerative diseases, chiefly in Alzheimer’s disease, prion in neurodegenerative diseases, chiefly in Alzheimer’s disease, prion diseases, and HIV encephalitis.diseases, and HIV encephalitis.

Cactus formation Cactus formation refers to a focal enlargement of the dendrites of the refers to a focal enlargement of the dendrites of the Purkinje cells in Menkes kinky hair disease, storage diseases, and Purkinje cells in Menkes kinky hair disease, storage diseases, and granular cell aplasia of the cerebellum. and ischemic. The injured axons granular cell aplasia of the cerebellum. and ischemic. The injured axons swell,swell, become become fusiform fusiform, and , and disintegratedisintegrate into small argyrophilic into small argyrophilic fragments that are gradually removed by macrophages. Early fragments that are gradually removed by macrophages. Early degeneration of axons is readily detected with immunohistologic stain degeneration of axons is readily detected with immunohistologic stain using antibodies against â-amyloid precursor protein (â-APP)).The â-using antibodies against â-amyloid precursor protein (â-APP)).The â-APP- immunoreactivity of damaged axons precedes changes observed APP- immunoreactivity of damaged axons precedes changes observed in conventional histologic stain.in conventional histologic stain.

Axonal spheroids Axonal spheroids are round, homogenous, or slightly granular are round, homogenous, or slightly granular eosinophiliceosinophilic and and argyrophilic argyrophilic structurescommonly found in traumatic shearing structurescommonly found in traumatic shearing injuries and at the edge of infarcts. They consist of axoplasm extruded injuries and at the edge of infarcts. They consist of axoplasm extruded from the disrupted ends of the axons.from the disrupted ends of the axons.

Axonal torpedoAxonal torpedo, a , a fusiformfusiform enlargement of the proximal portion of the enlargement of the proximal portion of the Purkinje cell axon, frequentlyoccurs in cerebellar cortical Purkinje cell axon, frequentlyoccurs in cerebellar cortical degenerations.degenerations.

Dystrophic axonal spheroids Dystrophic axonal spheroids are distinctive histologic features of infantile are distinctive histologic features of infantile neuroaxonal dystrophy. They also may occur in congenital biliary neuroaxonal dystrophy. They also may occur in congenital biliary atresia, mucoviscidosis of children, and in nucleus gracilis of elderly atresia, mucoviscidosis of children, and in nucleus gracilis of elderly subjects.subjects.

Axonal degeneration

Fusiform swelling

Disintegration of axon into small argyrophilic fragments ( Holmes stain)

Beta-amyloid precursor protein (B-APP) (+) immunostain in injured axons

Axonal spheroids in traumatic injury (Holmes stain)

Fusiform enlargement of the axon (torpedo) of a degenerated Purkinje cell (Bodian stain)

Axonal degeneration

Death of the NeuronsDeath of the Neurons

ApoptosisApoptosis, or programmed cell death, is genetically , or programmed cell death, is genetically regulated and commonly occurs in degenerative regulated and commonly occurs in degenerative diseases. During brain development, the apoptosis diseases. During brain development, the apoptosis of excess neurons is physiologic. In apoptotic cell of excess neurons is physiologic. In apoptotic cell death, the nuclear chromatin condenses into masses death, the nuclear chromatin condenses into masses of various sizes and shapes, the nuclear membrane of various sizes and shapes, the nuclear membrane buds and fragments. These nuclear buds, along with buds and fragments. These nuclear buds, along with cytoplasmic buds, form the apoptotic bodies, which cytoplasmic buds, form the apoptotic bodies, which then are phagocytosed by macrophages or then are phagocytosed by macrophages or neighboring cells. An apoptotic cell in HE-stained neighboring cells. An apoptotic cell in HE-stained section appears as a round, dense, strongly section appears as a round, dense, strongly eosinophilic mass. eosinophilic mass.

Apoptosis occurs Apoptosis occurs rapidlyrapidly, usually affects , usually affects individual individual neuronsneurons, and elicits , and elicits no inflammatory response.no inflammatory response.

Death of the NeuronsDeath of the Neurons

Necrosis Necrosis is initiated by a variety of is initiated by a variety of exogenous factors: toxins, infectious exogenous factors: toxins, infectious pathogens, metabolic disorders and, pathogens, metabolic disorders and, chiefly, by hypoxia and ischemia. The chiefly, by hypoxia and ischemia. The nucleus undergoes pyknosis, nucleus undergoes pyknosis, fragmentation, and lysis. The cytoplasm fragmentation, and lysis. The cytoplasm loses its organelles, becomes strongly loses its organelles, becomes strongly eosinophilic and, ultimately, by enzymatic eosinophilic and, ultimately, by enzymatic digestion, dissolves. digestion, dissolves.

Necrosis usually affects a Necrosis usually affects a group of neuronsgroup of neurons and is and is accompanied byaccompanied by an an inflammatory inflammatory responseresponse..

Glial CellsGlial Cells

Astrocytes, oligodendrocytes, and ependymal cells Astrocytes, oligodendrocytes, and ependymal cells originate, as do neurons, from the primitive originate, as do neurons, from the primitive neuroepithelium of the neural tube, whereas neuroepithelium of the neural tube, whereas microglial cells originate from bone marrow–derived microglial cells originate from bone marrow–derived monocytes. Glial cells play important roles in both monocytes. Glial cells play important roles in both physiologic and pathologic conditions:physiologic and pathologic conditions:

• • They maintain an environment appropriate for the They maintain an environment appropriate for the efficient functioning of the neurons.efficient functioning of the neurons.

• • They respond to diseases by removing tissue debris, They respond to diseases by removing tissue debris, repairing damaged tissue, and taking the place of lost repairing damaged tissue, and taking the place of lost tissue.tissue.

• • They are specifically implicated in a number of They are specifically implicated in a number of degenerative, infectious, and metabolic diseases. By degenerative, infectious, and metabolic diseases. By displaying cytoplasmic inclusions, glial cells are displaying cytoplasmic inclusions, glial cells are important in defining several neurodegenerative important in defining several neurodegenerative diseases. Infected glial cells are pathologic markers diseases. Infected glial cells are pathologic markers for certain viral diseases. Furthermore, glial changes for certain viral diseases. Furthermore, glial changes are the diagnostic features of several metabolic are the diagnostic features of several metabolic diseases.diseases.

• • Glial cells are capable of proliferating into a variety of Glial cells are capable of proliferating into a variety of gliomasgliomas, which constitute the largest group of , which constitute the largest group of primary intracranial tumors.primary intracranial tumors.

AstrocytesAstrocytes

Multi-polar / “star-like” cellsMulti-polar / “star-like” cells Types: Types:

Protoplasmic Protoplasmic - reside in the cortex - reside in the cortex FibrillaryFibrillary - populate white matter - populate white matter

All astrocytes contain GFAPAll astrocytes contain GFAP Resting state: angulated nuclei, thin cytoplasm, Resting state: angulated nuclei, thin cytoplasm,

inconspicuous process (blends with neuropil)inconspicuous process (blends with neuropil) Contribute to the BBB and brain CSF barrier (via Contribute to the BBB and brain CSF barrier (via

processes extending to the blood vessels and pial processes extending to the blood vessels and pial surface respectively)surface respectively)

Variety of pathologic responses (“reactive Variety of pathologic responses (“reactive astrocytes”)astrocytes”)

Usually indicate a more chronic process when Usually indicate a more chronic process when present, where they take the form of gemistocytes present, where they take the form of gemistocytes (abundant eosinophilic materials)(abundant eosinophilic materials)

Pathology of AstrocytesPathology of AstrocytesHypertrophy and hyperplasia. Hypertrophy and hyperplasia. In acute and chronic diseases, astrocytes In acute and chronic diseases, astrocytes

commonly increase in size and number. A commonly increase in size and number. A gemistocytic gemistocytic or hypertrophied or hypertrophied astrocyte displays a large, round cytoplasm with short fibrillated processes and astrocyte displays a large, round cytoplasm with short fibrillated processes and a vesicular, eccentrically displaced nucleus. The cytoplasm stains intensely with a vesicular, eccentrically displaced nucleus. The cytoplasm stains intensely with eosin and immunoreacts strongly with GFAP .eosin and immunoreacts strongly with GFAP .

Fibrillary gliosis. Fibrillary gliosis. Astrocytes are capable of replacing destroyed tissue by Astrocytes are capable of replacing destroyed tissue by producing more and more fibrils and ultimately forming a dense fibrillary gliosis producing more and more fibrils and ultimately forming a dense fibrillary gliosis or or glial scarglial scar. A glial scar is isomorphic when the astrocytic fibers conform to the . A glial scar is isomorphic when the astrocytic fibers conform to the pattern of the original structures, or is anisomorphic when the pattern is pattern of the original structures, or is anisomorphic when the pattern is haphazard .haphazard .

Alzheimer’s type 1 and type 2 astrocytes. Alzheimer’s type 1 and type 2 astrocytes. Alzheimer’s type 2 astrocytes have Alzheimer’s type 2 astrocytes have large, round or lobulated vesicular nuclei with scanty chromatin condensed at large, round or lobulated vesicular nuclei with scanty chromatin condensed at the margin of well-defined nuclear membranes . They are characteristic findings the margin of well-defined nuclear membranes . They are characteristic findings in hepatic and other metabolic encephalopathies and Wilson disease, and are in hepatic and other metabolic encephalopathies and Wilson disease, and are commonly found in the cerebral cortex, pallidum, and dentate nucleus. commonly found in the cerebral cortex, pallidum, and dentate nucleus. Alzheimer’s type 1 astrocytes, also found in metabolic encephalopathies, have Alzheimer’s type 1 astrocytes, also found in metabolic encephalopathies, have large lobulated nuclei and large slightly granular cytoplasms.large lobulated nuclei and large slightly granular cytoplasms.

Rosenthal fibers. Rosenthal fibers. These alterations in astrocytic processes appear as homogenous These alterations in astrocytic processes appear as homogenous oval, round, elongated, or carrot-shaped eosinophilic structures. They are found oval, round, elongated, or carrot-shaped eosinophilic structures. They are found in the walls of cystic cavities, fibrillary gliosis, and astrocytic tumors, and are the in the walls of cystic cavities, fibrillary gliosis, and astrocytic tumors, and are the diagnostic hallmark of Alexander’s leukodystrophy (see Fig. 2.6).diagnostic hallmark of Alexander’s leukodystrophy (see Fig. 2.6).

Corpora amylacea. Corpora amylacea. Corpora amylacea are the degenerative products of astrocytic Corpora amylacea are the degenerative products of astrocytic processes. They are round, basophilic and argyrophilic structures, 20 to 50 processes. They are round, basophilic and argyrophilic structures, 20 to 50 microns in diameter. They commonly occur beneath the pia mater and around microns in diameter. They commonly occur beneath the pia mater and around the ventricles and blood vessels. They contain polyglucosans, are PAS positive, the ventricles and blood vessels. They contain polyglucosans, are PAS positive, and immunoreact for ubiquitin. Corpora amylacea are found in variable amounts and immunoreact for ubiquitin. Corpora amylacea are found in variable amounts in brains after the age of 40 to 45 years, and are particularly abundant in in brains after the age of 40 to 45 years, and are particularly abundant in chronic degenerative diseases .chronic degenerative diseases .

Pathology of AstrocytesPathology of AstrocytesCytoplasmic argyrophilic and tau positive inclusions.Cytoplasmic argyrophilic and tau positive inclusions.These features are characteristic of several These features are characteristic of several

neurodegenerative diseases collectively referred to as neurodegenerative diseases collectively referred to as tauopathies .tauopathies .

Viral nuclear inclusions. Viral nuclear inclusions. These inclusions are found in These inclusions are found in herpes simplex encephalitis, subacute sclerosing herpes simplex encephalitis, subacute sclerosing panencephalitis, and in progressive multifocal panencephalitis, and in progressive multifocal leukoencephalopathy, in which the astrocytes are leukoencephalopathy, in which the astrocytes are transformed into large atypical cells.transformed into large atypical cells.

Neoplastic transformation. Neoplastic transformation. Astrocytes have the capacity Astrocytes have the capacity to proliferate into a variety of relatively benign or to proliferate into a variety of relatively benign or malignant astrocytomas constituting the malignant astrocytomas constituting the most commonmost common glial tumorsglial tumors..

Protoplasmic astrocytes. Cerebral cortex shows oval and round astrocytic nuclei with moderate amount ofchromatin and prominent nucleoli (Cresyl violet).

Fibrillary astrocytes display numerous short, fine processes and one long process attached to the capillary wall with a foot plate (Cajal gold stain).

Positive immunostaining for glial fibrillary acidicprotein (GFAP).

astrocytes

Gemistocytic (reactive) astrocytes display a large eosinophilic glassy cytoplasm with short processesand a peripherally displaced nucleus (HE).

Fibrillary astrogliosis beneath the pia mater. Fibrous astrocytes showing numerousfine fibrillated processes (Holzer stain).

Alzheimer’s type 2 astrocytes display a large vesicular nucleus with scanty chromatinand a prominent nucleolus (HE).

pathology of Astrocytes

Rosenthal fibers in an astrocytoma appear as eosinophilic rod-shaped, homogenous structures (HE).

Corpora amylacea around blood vessels (HE).

Argyrophilic astrocytic plaque in cortical basal degeneration(Gallyas).

Bergmann astrocytes replace degenerated Purkinje cells in cerebellar cortex (HE).

pathology of Astrocytes

OligodendrocytesOligodendrocytes Myelinating cells of the CNSMyelinating cells of the CNS Myelinate multiple axonsMyelinate multiple axons Processes are not visible in standard H&EProcesses are not visible in standard H&E Round basophilic nucleiRound basophilic nuclei In the gray matter, oligodendrocytes serve as In the gray matter, oligodendrocytes serve as

satellite cells around the neurons and satellite cells around the neurons and regulate the perineuronal environment. In regulate the perineuronal environment. In the white matter, oligodendrocytes are the white matter, oligodendrocytes are aligned along the myelin sheaths as aligned along the myelin sheaths as interfascicular glia . The major function of interfascicular glia . The major function of interfascicular oligodendrocytes is the interfascicular oligodendrocytes is the formation of myelin during brain formation of myelin during brain development and its maintenance thereafter. development and its maintenance thereafter.

Pathology of Pathology of OligodendrocytesOligodendrocytes

SatellitosisSatellitosis, an increase in number of satellite cells, , an increase in number of satellite cells, indicates neuronal injury.indicates neuronal injury.

Cytoplasmic argyrophilic inclusions Cytoplasmic argyrophilic inclusions are markers of are markers of several neurodegenerative diseases. Cap-, flame- or several neurodegenerative diseases. Cap-, flame- or sickle-shaped inclusions are the histologic hallmarks of sickle-shaped inclusions are the histologic hallmarks of multiple system atrophy . These inclusions are multiple system atrophy . These inclusions are distinguished by positive immunostaining for ubiquitin, distinguished by positive immunostaining for ubiquitin, á-synuclein and á-â crystalline. Argyrophilic coiled á-synuclein and á-â crystalline. Argyrophilic coiled bodies occur in progressive supranuclear palsy, bodies occur in progressive supranuclear palsy, corticobasal dementia, and argyrophilic grain dementia.corticobasal dementia, and argyrophilic grain dementia.

Viral nuclear inclusions Viral nuclear inclusions in large, monster-like in large, monster-like oligodendrocytes are characteristic of progressive oligodendrocytes are characteristic of progressive multifocal leukoencephalopathy. They contain virions of multifocal leukoencephalopathy. They contain virions of JC virus of the papova virus group.JC virus of the papova virus group.

Neoplastic transformationNeoplastic transformation. . Oligodendrocytes commonly Oligodendrocytes commonly proliferate into slowly growing neoplasms.proliferate into slowly growing neoplasms.

Satellite oligodendrocytes around cortical neurons (HE).

Interfascicular oligodendrocytes along myelin sheaths (LFB-CV).

Oligodendrocytes showing argyrophilic cytoplasmic inclusions in multiple system atrophy (Gallyas stain).

Oligodendrocytes

EpendymaEpendymaCuboidal to columnar glial cells that form the covering of Cuboidal to columnar glial cells that form the covering of

the ventricular the ventricular system; oval nuclei with system; oval nuclei with moderate amount of eosinophilic cytoplasmmoderate amount of eosinophilic cytoplasm

Ciliated with microvilli on electron microscopyCiliated with microvilli on electron microscopyLateral surfaced tethered with desmosomes to form a Lateral surfaced tethered with desmosomes to form a

functional CSF-brain functional CSF-brain barrierbarrierFairly regular within the other areas of ventriclesFairly regular within the other areas of ventriclesIt is usually collapsed or vestigial in the central canal of It is usually collapsed or vestigial in the central canal of

spinal cordspinal cord

Choroid plexusChoroid plexusFunctionally differentiated regions of the ependymaFunctionally differentiated regions of the ependymaForm tufts and fronds into the ventriclesForm tufts and fronds into the ventriclesSecrete ultrafiltrate CSF (400-500ml/day)Secrete ultrafiltrate CSF (400-500ml/day)More cobble stoned cell bodies than ependymaMore cobble stoned cell bodies than ependymaAlso contain desmosomes, cilia and microvilliAlso contain desmosomes, cilia and microvilli

Pathology of Ependymal Pathology of Ependymal gliaglia

Atrophy, tearingAtrophy, tearing, and , and discontinuity discontinuity commonly occur in chronic commonly occur in chronic hydrocephalus. hydrocephalus. EpendymitisEpendymitis, causedby a variety of pathogens, , causedby a variety of pathogens, consists of necrosis, breaking up of the ependymal lining, and consists of necrosis, breaking up of the ependymal lining, and subependymal inflammatory infiltrations.subependymal inflammatory infiltrations.

Subependymal gliosisSubependymal gliosis, or , or granular ependymitisgranular ependymitis, develops in , develops in syphilitic and various other infectious, toxic, metabolic, and syphilitic and various other infectious, toxic, metabolic, and vascular diseases. Grossly, tiny nodules from the ventricular vascular diseases. Grossly, tiny nodules from the ventricular surface project into the lumen. Histologically, these nodules are surface project into the lumen. Histologically, these nodules are proliferated subependymal fibrillary astrocytes. Some are proliferated subependymal fibrillary astrocytes. Some are covered with continuous or disrupted ependymal layer and covered with continuous or disrupted ependymal layer and others are denuded. Occasionally, these nodules may enlarge others are denuded. Occasionally, these nodules may enlarge enough to obstruct the aqueduct of Sylvius and cause enough to obstruct the aqueduct of Sylvius and cause hydrocephalus (see Fig. 2.8).hydrocephalus (see Fig. 2.8).

Nuclear and cytoplasmic viral inclusions Nuclear and cytoplasmic viral inclusions in enlarged ependymal in enlarged ependymal cells are characteristic of cytomegalovirus infection.cells are characteristic of cytomegalovirus infection.

Neoplastic Transformation. Neoplastic Transformation. Ependymal cells are capable of Ependymal cells are capable of proliferating into neoplasms that may grow into the parenchyma proliferating into neoplasms that may grow into the parenchyma or project into the ventricle.or project into the ventricle.

Choroid and ependymaChoroid and ependyma

A – choroid forming villi and papillaeB- higher magnification differentiating ependyma (arrow head) from choroid (arrow)

Ependymal glia. Cuboidal epithelial cells cover the ventricularsurface and small nodules of proliferated astrocytes projectinto the ventricular lumen (granular ependymitis) (HE).

normal ependyma atrophic ependyma

Subventricular glial nodules (a) These result from focal loss of ependyma, and subsequent proliferation of subventricular astrocytes. Multiple foci can often be seen along a length of ependyma (arrows in a). Sometimes sheaf-like bundles of glial fibers are prominent within these nodules (arrow in c). Glial nodules are also referred to as ‘granular ependymitis’.

AB

C

MicrogliaMicroglia

Non-neuroepithelial cell derived, small, Non-neuroepithelial cell derived, small, elongated cells located throughout CNSelongated cells located throughout CNS

Derived from monocytes/macrophage lineage Derived from monocytes/macrophage lineage during developmentduring development

~20% of glial population~20% of glial population Resting state: bland appearance, elongated Resting state: bland appearance, elongated

neurons with “rod-like” nucleineurons with “rod-like” nuclei Small delicate processes with special stainsSmall delicate processes with special stains Antigen presenting, inflammatory responseAntigen presenting, inflammatory response Activated microglia migrate to site of damageActivated microglia migrate to site of damage A major function of microglia is the A major function of microglia is the

surveillance of and participation in surveillance of and participation in immunologic processes.immunologic processes.

Pathology of MicrogliaPathology of Microglia Activated microglia. Activated microglia. Rod cellsRod cells, prominent in viral diseases and , prominent in viral diseases and

parenchymal neurosyphilis, are distinguished by conspicuously parenchymal neurosyphilis, are distinguished by conspicuously hypertrophied rod-shaped nuclei. They are diffusely distributed in hypertrophied rod-shaped nuclei. They are diffusely distributed in gray and white matter and are almost perpendicularly oriented to gray and white matter and are almost perpendicularly oriented to the cortical surface . Rod-, crescent-, and kidney–shaped the cortical surface . Rod-, crescent-, and kidney–shaped microglial cells occur around neuritic plaques in Alzheimer’s microglial cells occur around neuritic plaques in Alzheimer’s disease.disease.

Microglial nodules. Microglial nodules. Nodules commonly are found in viral Nodules commonly are found in viral diseases, in which they cluster around infected neurons, invade diseases, in which they cluster around infected neurons, invade and digest them (neuronophagia), and eventually replace them and digest them (neuronophagia), and eventually replace them with residual nodules. Loose collections of microglial cells with residual nodules. Loose collections of microglial cells (shrubs) are occasionally found in the molecular layer of the (shrubs) are occasionally found in the molecular layer of the cerebellar cortex.cerebellar cortex.

Multinucleated giant cells. Multinucleated giant cells. These giant cells, derived from These giant cells, derived from microglia and macrophages, are distinctive features of HIV microglia and macrophages, are distinctive features of HIV encephalitis.encephalitis.

Macrophages. Macrophages. Macrophages with phagocytic activity are Macrophages with phagocytic activity are scavengers of the neural tissue. They are prominent in vascular scavengers of the neural tissue. They are prominent in vascular infarcts, acute demyelinating diseases, leukodystrophies, infarcts, acute demyelinating diseases, leukodystrophies, hemorrhages, and traumatic lesions.Distinguished by large, hemorrhages, and traumatic lesions.Distinguished by large, rounded, foamy cytoplasms and small eccentric nuclei, the rounded, foamy cytoplasms and small eccentric nuclei, the macrophages engulf and remove degraded myelin, necrotic tissue macrophages engulf and remove degraded myelin, necrotic tissue debris, and hemosiderin pigments .debris, and hemosiderin pigments .

Resting microglia showing small elongated nucleus, scanty cytoplasm, and bipolar processes (Hortega silver stain).

Activated rod-shaped microglia in encephalitis.

Macrophages showing large, round, foamy cytoplasms and small eccentric nuclei (HE).

Microglia

MyelinMyelin

Myelin ensheathes the nerve fibers in a spiral lamellar Myelin ensheathes the nerve fibers in a spiral lamellar fashion, promoting a faster and more effective fashion, promoting a faster and more effective conduction of nervous impulses along the nerve fibers. conduction of nervous impulses along the nerve fibers. It is produced by the oligodendrocytes during It is produced by the oligodendrocytes during development of the brain and spinal cord and development of the brain and spinal cord and maintained by them after completion of myelination . maintained by them after completion of myelination .

The major chemical components of myelin are lipids, The major chemical components of myelin are lipids, which constitute about 70% to 85%. The sphingolipids which constitute about 70% to 85%. The sphingolipids and cholesterol are the most important of these. The and cholesterol are the most important of these. The remaining 15% to 30% of myelin consists of proteins; remaining 15% to 30% of myelin consists of proteins; among them, myelin basic protein, proteolipid protein, among them, myelin basic protein, proteolipid protein, and myelin oligodendrocyte-glycoprotein are and myelin oligodendrocyte-glycoprotein are particularly important because of their antigenic role particularly important because of their antigenic role in autoimmune diseases .in autoimmune diseases .

Schematic drawing of axons,myelin sheaths, and oligodendrocytes.

Light microscopic picture showinglongitudinally oriented myelin sheaths(stained blue) along nerve fibers (stainedblack) ( Holmes stain).

Myelin

DegenerationDegenerationMyelin is primarily involved in immune- and virus Myelin is primarily involved in immune- and virus

mediated diseases, hereditary and acquired mediated diseases, hereditary and acquired metabolic diseases, and various toxic disorders. It is metabolic diseases, and various toxic disorders. It is also affected in vascular, infectious, and traumatic also affected in vascular, infectious, and traumatic disorders, and in wallerian degeneration of the disorders, and in wallerian degeneration of the axons. The pattern of myelin degeneration is the axons. The pattern of myelin degeneration is the same regardless of the cause. The myelin sheath same regardless of the cause. The myelin sheath swells, becomes irregular, and breaksswells, becomes irregular, and breaks

down first into larger, and then smaller and smaller down first into larger, and then smaller and smaller globules, which contain cholesterol ester and globules, which contain cholesterol ester and triglycerides. These globules are phagocytosed and triglycerides. These globules are phagocytosed and gradually removed by macrophages to the gradually removed by macrophages to the perivascular and subarachnoid spaces perivascular and subarachnoid spaces

Swelling and breaking up of myelin sheaths (LFB-eosin).

Disintegration of myelin into small oil-red O-positive lipid globules.

Myelin

Swelling and breaking up of myelin sheaths (LFB-eosin).

Disintegration of myelin into small oil-red O-positive lipid globules.

Chemical Composition of Central Myelin

Lipids 70%–85% Sphingolipids: Sphingomyelin: phospholipid Cerebroside: glycolipid (galactose) Sulfatide: cerebroside sulfate ester Cholesterol

Proteins 15%–30% Myelin basic protein Myelin proteolipid protein Myelin-associated glycoprotein Myelin oligodendrocyte-glycoprotein

Balo’s Concentric SclerosisBalo’s Concentric Sclerosis

Chronic MSChronic MS

MeningesMeninges

The brain and spinal cord are covered with three membranes:The brain and spinal cord are covered with three membranes:

(a)(a) the dura materthe dura mater, a thick outer fibrous membrane, containing large , a thick outer fibrous membrane, containing large venous sinuses and separating the cranial cavity into a venous sinuses and separating the cranial cavity into a supratentorial and an infratentorial compartment;supratentorial and an infratentorial compartment;

(b)(b) the arachnoidthe arachnoid, beneath the dura, a thin avascular membrane , beneath the dura, a thin avascular membrane covered with mesothelial cells; the arachnoid villi (granulations) covered with mesothelial cells; the arachnoid villi (granulations) are tufts of arachnoidal (meningothelial) cells that project into are tufts of arachnoidal (meningothelial) cells that project into the venous sinuses and veins; and the venous sinuses and veins; and

(c)(c) the pia materthe pia mater, a thin, inner fibrous membrane attached to the , a thin, inner fibrous membrane attached to the surface of the brain and spinal cord and connected to the surface of the brain and spinal cord and connected to the arachnoid by delicate fibrous trabeculae. The arachnoid and the arachnoid by delicate fibrous trabeculae. The arachnoid and the pia together form the pia together form the leptomeningesleptomeninges. Between them is the . Between them is the subarachnoid space, filled with cerebrospinal fluid (CSF). The subarachnoid space, filled with cerebrospinal fluid (CSF). The CSF is absorbed into the venous sinuses at the arachnoid villi. CSF is absorbed into the venous sinuses at the arachnoid villi. The pia mater contains blood vessels, accompanying them into The pia mater contains blood vessels, accompanying them into the neural parenchyma and forming the perivascular or Virchow-the neural parenchyma and forming the perivascular or Virchow-Robin spaces filled with CSF. The Virchow-Robin spaces usually Robin spaces filled with CSF. The Virchow-Robin spaces usually end at the level of transition of arterioles to capillaries. They end at the level of transition of arterioles to capillaries. They provide a route for the extension of inflammation or neoplasm provide a route for the extension of inflammation or neoplasm from the subarachnoid space into the parenchyma .from the subarachnoid space into the parenchyma .

skullduraarachnoid

pia matercortex

Schematic drawing of the anatomic relationship between the dura, arachnoid, and pia.

Leptomeningeal carcinomatosis extends into the cerebral cortex along the Virchow- Robin spaces (HE).

Meninges

Pathology of the MeningesPathology of the Meninges

The meninges are involved in traumatic, infectious, The meninges are involved in traumatic, infectious, hemorrhagic, and neoplastic diseases. hemorrhagic, and neoplastic diseases.

The epidural and the subdural spaces are common The epidural and the subdural spaces are common sites of traumatic hemorrhages. sites of traumatic hemorrhages.

The subarachnoid space is the site of exudates from The subarachnoid space is the site of exudates from leptomeningeal inflammation, of hemorrhage from leptomeningeal inflammation, of hemorrhage from rupture of a berry aneurysm, and of neoplastic rupture of a berry aneurysm, and of neoplastic infiltration from primary or metastatic neoplasms. infiltration from primary or metastatic neoplasms. Postinflammatory and posthemorrhagic fibrosis of Postinflammatory and posthemorrhagic fibrosis of the leptomeninges and arachnoid villi interferes the leptomeninges and arachnoid villi interferes with the circulation and absorption of CSF, with the circulation and absorption of CSF, ultimately leading to hydrocephalus.ultimately leading to hydrocephalus.

Epidural hematoma. Hyperlucent area.

a.

chronic epidural abscesschronic epidural abscess

Subdural (left) Epidural (right) hematomasSubdural (left) Epidural (right) hematomas

Subarachnoid hemorrhage.

Ruptured saccular aneurysm at the

bifurcation of the internal carotid

artery to form the anterior and

middle cerebral arteries. The non-enhanced CT

reveals bloodin the subarachnoid space,particularly along the

course of the middle cerebral artery.

Blood VesselsBlood Vessels

Cerebral arteries Cerebral arteries differ from systemic arteries by differ from systemic arteries by having only one elastic layer.having only one elastic layer.

Capillaries Capillaries are distinguished by the presence of are distinguished by the presence of (a) tight junctions between endothelial cells, (a) tight junctions between endothelial cells, (b) basement membrane, and (b) basement membrane, and (c) astrocytic foot-plates attached to the (c) astrocytic foot-plates attached to the

adventitia. adventitia. These three features provide a barrier between the These three features provide a barrier between the

blood and the brain. This blood–brain barrier (BBB) blood and the brain. This blood–brain barrier (BBB) can prevent harmful substances from reaching the can prevent harmful substances from reaching the nervous parenchyma, but it can also prevent nervous parenchyma, but it can also prevent therapeutic agents from crossing to the parenchyma.therapeutic agents from crossing to the parenchyma.

Arteriovenous malformation (unruptured).a Coronal, T2-weighted spin-echo image. The feeding and draining vessels, and part of the nidus,

appear as zones of decreased signal (flow voids).b Parasagittal, proton-density image of the same lesion.

Right carotid arteriography. The malformation is fed by the right middle cerebral and pericallosal arteries.

Left carotid angiography. The left pericallosal artery also contributes to the arterial supply of the lesion, which lies in the right hemisphere.

Types of degenerations in Types of degenerations in the CNSthe CNS

Anterograde DegenerationAnterograde DegenerationAnterograde (wallerian) degeneration results Anterograde (wallerian) degeneration results

from transection of the axons commonly by from transection of the axons commonly by infarcts, hemorrhages, tumors, and trauma. infarcts, hemorrhages, tumors, and trauma. Distal to the injury, first the axons break Distal to the injury, first the axons break down into small argyrophilic fragments, then down into small argyrophilic fragments, then their myelin sheaths break down into neutral their myelin sheaths break down into neutral lipid globules. The neurons of the injured lipid globules. The neurons of the injured axons undergo retrograde degeneration: The axons undergo retrograde degeneration: The cytoplasm swells, the dendrites retract, the cytoplasm swells, the dendrites retract, the Nissl bodies dissolve, Nissl bodies dissolve,

and the nucleus is peripherally displaced .and the nucleus is peripherally displaced .

Wallerian degeneration

Transynaptic atrophy

Retrograde Transynaptic atrophy

types of degenerations in the central nervous system

(left) Lacunar infarct in the internal capsule. (right) Degeneration of the ipsilateral pyramidal tract in the medulla (myelin stain).

Anterograde or Wallerian degeneration.

Anterograde or Wallerian degeneration.

MRI of a 68-year-old man showing an old infarct in distribution of middle cerebralartery. Note the atrophy of the ipsilateral pedunculus due to wallerian degeneration of the descending corticopontine and pyramidal tracts.

Wallerian degeneration. Degeneration of the fasciculus gracilis from compression of the sensory nerve roots by a metastatic carcinoma in the lumbar spine (myelin stain).

Trans-Synaptic DegenerationTrans-Synaptic Degeneration

In trans-synaptic degeneration or transneuronal In trans-synaptic degeneration or transneuronal atrophy, those neurons that lose their chief or only atrophy, those neurons that lose their chief or only afferent connection (that is, their synaptic input) afferent connection (that is, their synaptic input) atrophy. atrophy. Particular sites of trans-synaptic neuronal atrophy Particular sites of trans-synaptic neuronal atrophy are are (a) the (a) the lateral geniculate bodieslateral geniculate bodies following following degeneration of the ganglion cells of the retina, degeneration of the ganglion cells of the retina, optic nerve, or optic tract; optic nerve, or optic tract; (b) the (b) the mammillary bodymammillary body following following degeneration of the fornix; and degeneration of the fornix; and (c) the neurons of the (c) the neurons of the gracile and cuneate gracile and cuneate nucleinuclei of the medulla following degeneration of of the medulla following degeneration of the posterior columns in the spinal cord.the posterior columns in the spinal cord.

Transsynaptic degeneration

Retrograde Trans-Synaptic DegenerationRetrograde Trans-Synaptic DegenerationRetrograde trans-synaptic degeneration develops in those Retrograde trans-synaptic degeneration develops in those

neurons that project to neurons that have already degenerated. neurons that project to neurons that have already degenerated. For example, the neurons of the inferior olivary nuclei atrophy For example, the neurons of the inferior olivary nuclei atrophy when the Purkinje cells in the contralateral cerebellar cortex when the Purkinje cells in the contralateral cerebellar cortex have degenerated.have degenerated.

Dying-Back DegenerationDying-Back DegenerationDegeneration of the axons begins in their distal ends and Degeneration of the axons begins in their distal ends and

progresses toward the neurons of their origin. It occurs in progresses toward the neurons of their origin. It occurs in systemic degenerative diseases.systemic degenerative diseases.

Pseudohypertrophic Degeneration of the Inferior OlivesPseudohypertrophic Degeneration of the Inferior OlivesPseudohypertrophic degeneration of the inferior olivary nucleus is Pseudohypertrophic degeneration of the inferior olivary nucleus is

a particular type of trans-synaptic degeneration . It is a particular type of trans-synaptic degeneration . It is associated with lesions either in the ipsilateral central associated with lesions either in the ipsilateral central tegmental tract or the contralateral dentate nucleus of the tegmental tract or the contralateral dentate nucleus of the cerebellum. The olivary neurons enlarge and display cerebellum. The olivary neurons enlarge and display cytoplasmic vacuoles, peripherally displaced nucleus, and cytoplasmic vacuoles, peripherally displaced nucleus, and thick, rich, dendritic arborization.thick, rich, dendritic arborization.

Pseudohypertrophic degeneration of the inferior olivary nuclei in a 45-year-old man with bilateral palatal myoclonus and a large malignant glioma infiltrating the dentate nuclei and the upper midbrain. (left) Medulla showing hypertrophy of both inferior olivary nuclei (myelin stain). (right) The neurons are enlarged, their cytoplasms vacuolated, and the processes thickened and fragmented (Bodian stain).

a particular type of trans-synaptic degeneration

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CT scan showing massive edema and mass effect around a malignant neoplasm with ring-like enhancement. The ipsilateral ventricle is obliterated.

Focal swelling of the white matter around a large temporal lobe glioblastoma: The ipsilateral ventricle is compressed and the third ventricle is shifted to the opposite side.

Generalized edema associated with a large temporal lobe glioma. Dorsal view shows diffuse enlargement, broadened convolutions, and obliterated sulci.

Cerebral edema.

Pathologic Consequences of Intracranial Expanding Mass Lesions

Herniations Vascular Lesions

Transtentorial uncal/ Infarcts hippocampal MesiotemporalCentral OccipitalCerebellar tonsillar FrontalCerebellar transtentorial Superior

cerebellarSubfalcial cingular Brainstem hemorrhage

Pituitary necrosis

Bony erosion

Dorsum sellaePost clinoid process

Normal Aging AD

Neurofibrillary tangle formation. Histologic appearances of NFTs. (a) Band-shaped perikaryal NFT: a single well-defined band runs from the base of the neuron into the apical dendrite. This type of NFT is seen in both large and small pyramidal cells, and is perhaps an early stage of NFT formation. (b) Flame-shaped perikaryal NFT: a triangular mass of filaments, usually surrounding the nucleus and extending into the apical dendrite, and seen mainly in large pyramidal cells. (c) Small globose perikaryal NFT: a rounded mass of filaments displacing the nucleus to one side of the neuron. This type of NFT is seen in small cortical neurons, especially in layers 5 and 6, and also in the periamygdaloid cortex. (d) Large globose NFTs: seen in the nucleus basalis of Meynert, periaqueductal gray matter, substantia nigra, locus ceruleus, and raphe nuclei. (e) Ghost NFTs: faintly eosinophilic extracellular structures that persist after the death of the neuron. (f) Ghost NFTs: the extracellular ghost NFTs are moderately well seen on silver impregnation. (g) Ghost NFTs may become immunoreactive for Aβ peptide as a result of its deposition around them. (h) Ghost NFTs may seem to be immunoreactive for glial fibrillary acidic protein (GFAP), due to ingrowth of glial cell processes.

Neurofibrillary tangle formation. Histologic appearances of NFTs.

(a)Band-shaped perikaryal NFT: a single well-defined band runs from the base of the neuron into the apical dendrite. This type of NFT is seen in both large and small pyramidal cells, and is perhaps an early stage of NFT formation.

(b) Flame-shaped perikaryal NFT: a triangular mass of filaments, usually surrounding the nucleus and extending into the apical dendrite, and seen mainly in large pyramidal cells.

(c) Small globose perikaryal NFT: a rounded mass of filaments displacing the nucleus to one side of the neuron. This type of NFT is seen in small cortical neurons, especially in layers 5 and 6, and also in the periamygdaloid cortex.

Neurofibrillary tangle formation. Histologic appearances of NFTs.

(d) Large globose NFTs: seen in the nucleus basalis of Meynert, periaqueductal gray matter, substantia nigra, locus ceruleus, and raphe nuclei. (e) Ghost NFTs: faintly eosinophilic extracellular structures that persist after the death of the neuron. (f) Ghost NFTs: the extracellular ghost NFTs are moderately well seen on silver impregnation. (g) Ghost NFTs may become immunoreactive for Aβ peptide as a result of its deposition around them.(h) Ghost NFTs may seem to be immunoreactive for glial fibrillary acidic protein (GFAP), due to ingrowth of glial cell processes.