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Introduction to Neuropathology
- 2. Nervous System Overview • Derives from the ectoderm • Neural tube and Neural crest • Consists of two main structural divisions: • Central nervous system • Brain • Spinal cord • Peripheral nervous system • Neurons • Ganglia • Consists of two main functional divisions: • Somatic • Sensory (afferent) • Motor (efferent) • Autonomic • Parasympathetic • Symptathetic Image obtained from: https://s-media-cache-ak0.pinimg.com/originals/e0/4f/cd/e04fcd5f8dc1a0a4bbed2bf0bb371253.jpg
- 3. Neuron Classification Processes • 1. Multipolar • 2. Bipolar • 3. Pseudounipolar Processes • 1. Multipolar • 2. Bipolar • 3. Pseudounipolar Axonal length • Pyramidal cells: • 1. Golgi I • Motor cortex • Extremely long can be more than a meter • 2. Golgi II cells • Interneurons • Very short axons Axonal length • Pyramidal cells: • 1. Golgi I • Motor cortex • Extremely long can be more than a meter • 2. Golgi II cells • Interneurons • Very short axons Function • 1. Motor • 2. Sensory • 3. Interneurons Function • 1. Motor • 2. Sensory • 3. Interneurons NeurotransmitterNeurotransmitter
- 4. Neurotransmitters • NTs will have either a positive or negative effect on the post- synaptic neuron • Act on ionotropic (ligand-gated) and metabotropic (GCPR) receptors • Excitatory synapses • Releases excitatory NTs that cause depolarization in the post- synaptic neuron • usually due to transmitter-gated Na channels • Ex: Acetylcholine, glutamate, serotonin • Inhibitory synapses • Releases inhibitory NTs that hyperpolarize the post- synaptic neuron • Usually due to transmitter-gated Cl channels • Ex: GABA, Glycine • Vesicle transport • Anterograde • Kinesin • Retrograde • Dynein
- 5. Neuron Processes Bipolar neuron •One axon and one dendrite •Uncommon – usually involved in special senses such as equilibrium, hearing, and vision •Also found within the ganglia of the vestibulocochlear (VIII) nerve Pseudounipolar/Unipolar neuron •Technically two processes single process of the nerve divides into two processes, giving the appearance of a unipolar neuron •One branch extends to the periphery, and another to the CNS •Found in: dorsal root ganglia •Afferent Multipolar neuron •Have one axon and multiple dendrites •Found in: multiple places •anterior horn of the spinal cord •Autonomic ganglia •Interneurons •Pyramidal cells and Purkinje cells •Most abundant process Histology: A Text and Atlas. 7th ed
- 6. Neuron histologyNeuron histology • Similarly to muscle tissue, nerve fascicles also have multiple layers. These layers will contain the same prefixes endo-(”within”), peri- (“enclosing”/”surrounding”), and epi- (“on top of”). 1. Epineurium • The epineurium consists of dense connective tissue 1. Perineurium • This layer is thin, flat, and immediately surrounds each fascicle. The perineurium is important when it comes to distinguishing nervous tissue apart from muscle fibers, as this layer, while thin, gives nerve bundles their boundaries 1. Endoneurium • This layer consists of fine connective tissue • Nuclei • Schwann cells-– In the PNS, these crescent=shaped nuclei will be visible tangential to nerve fibers. • Fibroblasts – In the endoneurium, these small and dense nuclei will be present • Endothelium– These usually run parallel to nerve fibers
- 8. Neuron HistologyNeuron Histology Dr. O’Brien OSU-CHS
- 9. SynapsesSynapses 1. Axosomatic • Synapse is between an axon and a cell body 1. Axodendritic • Between axons and cell bodies • Some have dendritic spines projection of actin filaments • Long term memory and/or learning 1. Axoaxonic • Between axons and other axons 1. Axosomatic • Synapse is between an axon and a cell body 1. Axodendritic • Between axons and cell bodies • Some have dendritic spines projection of actin filaments • Long term memory and/or learning 1. Axoaxonic • Between axons and other axons
- 10. Synapse ClassificationSynapse Classification • Chemical Synapses • Release of neurotransmitters from the presynaptic neuron to the post synaptic neuron • Presynaptic element/knob/component/bouton • Synaptic vesicles attach to membrane • Mediated by soluble NSF attachment receptors (SNAREs) • V-snare • T-snare • synaptotagmin 1 – replaces SNARE (NSF/SNAP25) • Active zones Rab-GTPase docking complexes (see page 35), t-SNAREs, and synaptotagmin binding proteins • Synaptic cleft • 20-30nm space • Postsynaptic element/membrane • Formed from a portion of the post-synaptic membrane of the postsynaptic neuron • Electrical synapses • Not common in vertebrates • Mainly just seen in cardiac and smooth msucle
- 11. Nissl Substance Rough ER in a neuronal cell body Photo curtesy of Michigan State University College of Medicine
- 12. Unique features of nervous tissue • Nervous tissue consists of two main cell types: • Neurons • Glia • The CNS and PNS have different glia, which function as supporting cells to neurons • CNS glia 1. Oligodendrocytes 2. Ependymal cells 3. Astrocytes 4. Microglia • PNS glia 1. Schwann cells
- 13. Astrocytes There are no regions of the CNS that are devoid of astrocytes • Astrocytes in the white matter are referred to as fibrous, and astrocytes in grey matter are referred to as protoplasmic • Gold staining (shown in the picture) is a marker for astrocytes. • These star-shaped cells are the largest and most abundant of all glial cells in the CNS • These cells vital for brain functioning are also highly involved in CNS pathologies • They are involved in metabolic functioning such as NT recycling, act as an extracellular K buffer, and are also involved in repair/scarring • Their foot processes make up the blood brain barrier.Photo curtesy of Michigan State University College of Medicine
- 14. Astrocyte function • There are two main types of astrocytes: 1. Fibrous • Found in white matter • Foot processes contact Node of Ranvier • Processes thinner 1. Protoplasmic • Found in gray matter • Less GFAP • Highly branched • Bergmann Glia • Develop from radial glia after the granular layer is developed • Complex and contact Purkinje cells in the cerebellum • “specialized astrocytes” that migrate to the cerebellum • Astrocytes are extremely unique in that they have the ability to also communicate via neurotransmitters Fibrous Astrocytes Protoplasmic Astrocytes Histology: a Text and Atlas. 7 editionFuller GN, Burger PC in Central Nervous System in Sternberg SS, ed Histology for Pathologists. Philadelphia: Lippincott-Raven, 1997
- 15. Astrocyte function Astrocytes are heavily involved in metabolic functioning of the CNS and are also involved in many CNS pathologies. Pathological changes in astrocytes includes hypotrophy (in the case of chronic depression) and hypertrophy (in the case of trauma). Sofroniew & Vinters, 2010
- 16. Glial fibrillary acidic protein (GFAP) – Marker for astrocytes • GFAP- an intermediate filament found in glial cells of the CNS • Provides structure to astrocytes as well as mechanical support • Important for the establishment of the blood brain barrier • Often used clinically as a marker for astrocytic brain tumors • While it is often used as a marker for brain tumors, astrocytes will still stain for this. Just in a smaller amount. In a non pathological brain sample, it should stain positive for GFAP and negative for Vimentin Anon (2017) “Dictionary - Expression: Gfap - The Human Protein Atlas,.
- 17. MicrogliaMicroglia Derive from the neural crest monocytes Appearance: Shape of rod/cigar Glial nodules Vimentin class of intermediate filaments •Microglia are an important part of immunity as well as a major part of inflammation in the CNS.
- 18. GangliaGanglia • Ganglia are nerve cell body bundles located outside of the CNS • They will have nerve fibers leading to them and from them • Ganglia consist of: 1. Sensory ganglia 2. Autonomic ganglia 1. Sympathetic ganglia • Located in sympathetic chain • Some are also located on the aorta (anterior surface) • Send longer processes to viscera 1. Parasympathetic ganglia • Located near target organs 1. Enteric ganglia • Located in submucosal and mesenteric plexus • Receive both parasympathetic (presynaptic) and enteric stimulation • Ganglia are nerve cell body bundles located outside of the CNS • They will have nerve fibers leading to them and from them • Ganglia consist of: 1. Sensory ganglia 2. Autonomic ganglia 1. Sympathetic ganglia • Located in sympathetic chain • Some are also located on the aorta (anterior surface) • Send longer processes to viscera 1. Parasympathetic ganglia • Located near target organs 1. Enteric ganglia • Located in submucosal and mesenteric plexus • Receive both parasympathetic (presynaptic) and enteric stimulation
- 19. Peripheral GangliaPeripheral Ganglia • Contains pseudounipolar neurons • Gives “bullseye” appearance • Can also often see lipofuscin • Contain cell bodies of sensory neurons NOT synaptic stations 1. Dorsal root ganglia – spinal nerves • Posterior region of the spinal cord 1. Sensory ganglia – cranial nerves • Picture shows Gasserian ganglion fifth cranial nerve (trigeminal) • Nerve impulse travels through the ganglion and reaches a synapse on V in the brain stem • Conducts sensory nerve impulses • Contains pseudounipolar neurons • Gives “bullseye” appearance • Can also often see lipofuscin • Contain cell bodies of sensory neurons NOT synaptic stations 1. Dorsal root ganglia – spinal nerves • Posterior region of the spinal cord 1. Sensory ganglia – cranial nerves • Picture shows Gasserian ganglion fifth cranial nerve (trigeminal) • Nerve impulse travels through the ganglion and reaches a synapse on V in the brain stem • Conducts sensory nerve impulses Trigeminal (sensory) ganglion Dorsal root ganglion
- 20. Sensory gangliaSensory ganglia • Trigeminal (V) • Semilunar • Gasserion • Facial (VII) • Geniculate • Vestibulocochlear (VIII) • Spiral ganglion – cochlear division • Vestibular ganglion – vestibular division • Glossopharyngeal (IX) • Superior ganglia • Inferior ganglia • Vagus (X) • Superior ganglia • Inferior ganglia • Trigeminal (V) • Semilunar • Gasserion • Facial (VII) • Geniculate • Vestibulocochlear (VIII) • Spiral ganglion – cochlear division • Vestibular ganglion – vestibular division • Glossopharyngeal (IX) • Superior ganglia • Inferior ganglia • Vagus (X) • Superior ganglia • Inferior ganglia Phot credit: Histology: A Text and Atlas.
- 21. Autonomic Ganglion • Contain postsynaptic neuron cell bodies 1. Sympathetic • Prevertebral • Paravertebral • Adrenal medulla (technically) 1. Parasympathetic • Oculomotor (III) nerve • Ciliary ganglion • Facial (VII) nerve • Pterygopalatine (sphenopalatine) • Submandibular ganglion • Glossopharyngeal (IX) nerve • Otic ganglion Parasympathetic ganglia in the vagina – H&E Histology: A Text and Atlas.
- 22. Sympathetic gangliaSympathetic ganglia • Mesenteric plexus is in between two layers of smooth muscle • Sympathetic trunk/paravertebral ganglia • E.g superior cervical • Prevertebral ganglia next to abdominal aorta • Celiac • Superior mesenteric • Inferior mesenteric • Aorticorenal • Mesenteric plexus is in between two layers of smooth muscle • Sympathetic trunk/paravertebral ganglia • E.g superior cervical • Prevertebral ganglia next to abdominal aorta • Celiac • Superior mesenteric • Inferior mesenteric • Aorticorenal Mesenteric Plexus Tuolodine BluePhoto curtesy of Michigan State University College of Medicine
- 23. Dorsal root vs Autonomic ganglia • Pseudounipolar • Larger than autonomic ganglia • “smooth” and oval • Has more satellite cells due to greater surface volume • Multipolar • Surrounded by satellite cells • More angular than DRG • Parasympathetic are located near the organs • Have lipofuscin Both are located in the peripheral nervous system (so both have Schwann cells), and both consist of large neuronal cell bodies surrounded by nerve fibers.
- 25. Photo curtesy of Michigan State University College of Medicine Ventral root of the Spinal Cord
- 26. Motor (anterior) vs sensory (dorsal) horn Motor (anterior) vs sensory (dorsal) horn • The neurons of the dorsal horn are much smaller compared to the anterior horn • the dorsal horn has less of a metabolic demand to other regions of the CNS; functions as an interneuron • The ventral horn projects onto muscles may have to project a very long distance • The neurons of the dorsal horn are much smaller compared to the anterior horn • the dorsal horn has less of a metabolic demand to other regions of the CNS; functions as an interneuron • The ventral horn projects onto muscles may have to project a very long distance
- 27. Histology of the Brain Categorized histologically into four different regions: 1. Cerebral cortex 2. Cerebellum 3. Hippocampus 4. Lateral Ventricle wall
- 28. Cerebral Cortex Histology • Layer I – Molecular layer • Few neurons/glia • Layer II – Outer granular layer • Small pyramidal neurons • Stellate neurons • Layer III – Outer pyramidal layer • Moderate-sized Pyramidal • Layer IV – Inner granular layer • Dense stellate neurons • Layer V – Inner pyramidal layer • Also called ganglionic layer • Large pyramidal neurons • Layer VI – Multiform cell layer • Mixture of small pyramidal and stellate
- 29. Cerebral cortex Connectome Red at the deepest corical layer shows pyramidal cells intertwined with stellate – the stellate are inhibitory Cell bodies of pyramidal cells seen in layer 5
- 30. Notice how small the glial cells are in relation to the neuron
- 31. Cerebral cortex layers Cerebral cortex layers Notice the difference in size between the pyramidal cells of layer III and layer V (luxol blue stains). Layer V in the motor cortex are able to send projections as far as the spinal cord layer III Layer V
- 32. CerebrumCerebrum Spinal cordSpinal cord Cerebrum vs. Spinal Cord
- 33. Hippocampus Histology • Hippocampal and dentate gyrus are both divided into 3 layers instead of 6 like the cerebral cortex. 1. Polymorphic layer • Both: nerve fibers and mall interneuron cell bodies 1. Middle layer • Dentate gyrus granular cells: cell bodies of dentate gyrus neurons • Hippocampal pyramidal layer-: pyramidal cell bodies of hippocampus 1. Molecular layer • Dentate gyrus: the dendrites of the middle pyramidal layer • Hippocampus: dendrites of pyramidal cells • The dentate gyrus of the hippocampus is one of the few areas of the brain that can regenerate new neurons • Involved in memory • Express nestin (intermediate filament) Photo curtesy of Michigan State University College of MedicineLuxol Blue
- 34. Hippocampus Histology Dictionary - Normal: Hippocampus - The Human Protein Atlas 2017
- 35. Cerebellum Histology White matter Molecular layer Purkinje Cells Photo curtesy of Michigan State University College of Medicine
- 37. Staining- Silver Stain Cajal/Golgi Cajal/ Golgi Stain – University of Oklahoma College of Medicine Silver stain that is used to visualize nervous tissue under light microscopy. Silver stain that is used to visualize nervous tissue under light microscopy.
- 38. Luxol Blue •Stains myelin and myelinated axons in brain/spinal cord blue; Stains phospholipids •H&E •Standard staining method in histology, but difficult to differentiate between axons and dendrites in nervous tissue •Nissl will be basophilic and cytoplasm eosinophilic; astrocytes extremely hard to see- nuclei appear clear •Better for pathology – astrocytes eosinophilic in damaged tissue (fibrous components) Neuro Staining- Common Nissl Stain •Classic Stain •Nissl bodies are stained purple •Good for measuring neuron density Picture curtesy of Duke University Picture curtesy of Duke University Photo credit: Neurodigitch
- 39. Neuro Staining- Pathological PAS •Stains: glucides, glycogen, mucus, fungus, phospholipids, glycolipids •Detects: Metabolic abnormalities Congo red •Stains/detects: Amyloid plaques and amyloid angiopathy Fat Staining – Sudan III, Oil Red O, Sudan Black B •Glycerides, fatty acids, glyco/phospholipids •Glycerides stain red and others blue with SBB •Frozen sections used instead of paraffin-embedded •Detects abnormal deposits – may also detect lipid phagocytes Bielschowsky •Modified silver stain •Neurofibrils black •cytoplasm, nuclei, and blood vessels light brown •RBCs dark brown •Neuropil tannish yellow •In neurology, it’s used for locating neurofibrillary tangles and plaques Photo credits: NewcomerSupply Photo credit: Neuropathology Database Photo credit: Neuropathology DatabasePhoto credit: Neuropathology Database
- 40. Neuropathology – Specific PTAH •NOTE: normally used for muscle tissue •Myelin stains a bluish-purple, nuclei/Nissl stain basophili, cytoplasm stains pinkish brown, collagen stains reddish orange •Pathology: Used to view reactive astrocytosis Masson's Trichrome •Stains bone, nuclei, and collagen blue •Usually used for muscle pathologies, but also stains brain/spinal cord parenchymal tissue (pinkish red) •Pathology: shows fibrosis Toluidine blue •Stains: acid mucopolysaccharides stains red •Also used with cresyl violet and heavy metal impregnation •Detects: Metachromatic leukodystrophy Picture curtesy of Duke UniversityPicture curtesy of Duke University Photo credit: Arai, Nobutaka, MD, DMS
- 41. Vimentin •Stains: mesenchymal tissue •Detects: meningiomas Tau (AT) •Stains: microtubule-associated protein tau •Color: dark brown •Detects: Tauopathies α-Synuclein •Stains: synaptic-associated protein α synuclein •Color: dark brown •Detects: α-synucleinopathies Aβ- amyloid •Stains: Aβ peptide (comes from amyloid precursor protein) •Color: dark brown •Detects: Alzheimer's Immunohistochemical staining Picture credit: PathologyOutlines Picture credit: FrontalCortex Picture credit: Carl HobbsPhoto credit: alzforum
- 42. Good vs bad staining/preservation of the CNS • Bad preservation shrunken cells that look apoptotic (surrounded by an empty space) • This is due to poor fixation • Good preservation large pale-staining nucleus, visible Nissl substance, large cell body
- 43. Neuropathology
- 44. Inclusion BodiesInclusion Bodies • Lipofuscin • Age-related • gold • Neuromelanin • Non-pathological melanocytes derive from the neural crest • Actually pathological when it’s NOT there – neurodegenerative diseases • Missing in the substantia nigra and locus cereleus in Parkinson’s • Lewy bodies • Eosinophilic – seen in Parkinson’s disease • Lipofuscin • Age-related • gold • Neuromelanin • Non-pathological melanocytes derive from the neural crest • Actually pathological when it’s NOT there – neurodegenerative diseases • Missing in the substantia nigra and locus cereleus in Parkinson’s • Lewy bodies • Eosinophilic – seen in Parkinson’s disease
- 45. Neuronal response to injuryNeuronal response to injury Different in CNS and PNS! •Axons in the PNS usually rapidly regenerate, and usually axons in the CNS never regenerate Involves two main processes: 1.Axonal degeneration 2.Neuronal regeneration • Myelin tends to inhibit neuronal regeneration • Schwann cells inhibit/downregulate proteins that are specific for myelin and upregulate glial growth factors (GGFs)
- 46. Neuronal Response to InjuryNeuronal Response to Injury • Both CNS and PNS will induce axonal degeneration and (attempt) neuronal regeneration CNS: the extent of oligodendrocyte damage is dependent on whether or not they’re still receiving signals from the axon. If they detach, the cell will undergo apoptosis • Regeneration is greatly affected by the reduced ability of macrophages to cross the blood-brain barrier, apoptosis, and the formation of a scar by astrocytes PNS: The extent of damage is dependent on the migration and proliferation of macrophages • Schwann cell degeneration and Blood-nerve barrier is disrupted on the entire length of the axon • Both CNS and PNS will induce axonal degeneration and (attempt) neuronal regeneration CNS: the extent of oligodendrocyte damage is dependent on whether or not they’re still receiving signals from the axon. If they detach, the cell will undergo apoptosis • Regeneration is greatly affected by the reduced ability of macrophages to cross the blood-brain barrier, apoptosis, and the formation of a scar by astrocytes PNS: The extent of damage is dependent on the migration and proliferation of macrophages • Schwann cell degeneration and Blood-nerve barrier is disrupted on the entire length of the axon
- 47. Neuronal response to injury in PNS Neuronal response to injury in PNS • Traumatic degeneration degeneration at the site of the axon • Usually only a couple internodal segments • If it extends further or more proximally, it usually results in apoptosis • Regeneration (traumatic) • Schwann cells will arrange themselves in endoneurial tubes Removal of debris from axons and myelin inside of the tubes tubes collapse proliferating Schwann cells form bands of Bungner bands guide the growth of new axons growth cone if the cone sprouts associate with a band, it regenerates between the layers of the Schwann cell external lamina bands guide neurites to rebuild the axon proximally to distally axon regrowth stops Schwann differentiation • Anterograde (Wallerian) degeneration distal to injury site • 8-24 hours after axon damage • Axon swells disintegration axonal cytoskeleton breakdown disassembly of the cytoskeleton (granular disintegration) axon fragmentation f phagocytosis of myelin debris by Schwann cells and (later) macrophages • Secretion of GGFs Schwann cell division Arrangement of Schwann cells on external laminae
- 48. Neuronal response to injuryNeuronal response to injury • Acute damage • Oxygen/Glucose depletion need continuous supply for high metabolic demand • Action potentials – maintain membrane gradients • Cytoplasmic dendritic arborization • May be as long as a meter • Trauma • Chronic damage • Slower • Aberrant protein aggregates • maintaining cellular integrity is extremely important – protein turnover highly regulated • Not doing so leads to misfolding and subsequent proteinopathies Reactive gliosis (astrocytes) •Injury astrocyte activation hypertrophy (increase in cytoplasmic processes) densely packed processes over time with GFAP intermediate filaments permanent scar (plaque) Soma and Axon changes •Changes in the cell body are proportional to the amount of axoplasm destroyed •Axonal injury retrograde signaling c-jun (TF) upregulation cell body swells nucleus moves to the periphery •Chromatolysis: Nissl bodies disappear from the center of the neuron and move to the periphery 1-2 days later (peak ~ 2 weeks)
- 49. Microglia vs Macrophage Pathology
- 50. Neuronal Pathology Acute injury Red Neurons Not one change, but a spectrum Due to hypoxia or ischemia Earliest marker of cell death 12-24 hours after injury Irreversible Histology: 1.Somite shrinkage 2.Pyknosis of nucleus 3.Nucleolus disappears 4.Loss of Nissl substance 5.Cytoplasm stains eosinophilic Introduction to neuropathology UCSF
- 51. Ependymal cell pathology Ependymal granulation oScarring oSeen often in hydrocephalus oNonspecific Subendymal glyosis Little clinical significance Seen in tuberous sclerosis – Shaslan’s gliosis Intranuclear virus inclusion CMV Inclusion bodies Buried ependyma Usually fond in cerebral parenchyma • UCSF School of Medicine
- 52. • Outcome is dependent on severity – can observe via GFAP • Outcome is dependent on severity – can observe via GFAP Astrocyte PathologyAstrocyte Pathology Sofroniew & Vinters, 2010
- 53. Astrocyte Pathology Astrocytes seen at the edge of a malignant brain tumor Hypertrophic astrocytes in progressive multifocal Leukoencephalopathy (PML) NOTE: Astrocytes will often have aberrant morphology according to particular pathology
- 54. Severe Astrogliosis •Scarring after tissue repair •Seen in: degenerative disease •Appearance: Scar will fit in with surrounding tissue called isomorphic gliosis •If it’s sudden, the directions will be random anisomorphic gliosis Alzheimer-type 1 and type 2 glia •NOTE: Not due to Alzheimer’s. •Appearance: Large nuclei with visible nuclear membrane and nucleoli •Type 2 glia (naked glia)- show little cytoplasm •Seen in: Wilson’s disease/hepatic encephalopathy Intranuclear viral inclusion •Inclusion bodies seen in viral infections •Stain: H&E – inclusion bodies are eosinophilic •Can also observe with immunostaining (antibodies) •Seen in: CMV Astrocyte Pathology
- 55. Astrocytosis •Proliferation of astrocytes •Usually due to tissue damage Gemistocytic (“plump”) astrocyte •Appearance: swollen cytoplasm with increased intermediate filaments •Seen in: areas of tissue damage •Acute change reactive •Stain(s): H&E (eosinophilic) shows short, thick processes; GFAP •Swollen nuclei •Seen in: Creutzfeldt-Jakob disease and progressive multifocal leukoencephalopathy Necrobiosis •Death of astrocytes •Seen in: Acute/cytotoxic edema Eosinophilic inclusion • Pink-staining (eosinophilic) cytoplasmic inclusions • Seen in: Polymicrogyria and Aicardi syndrome • Have also been found in some healthy individuals Pathologycenter.jp
- 56. Corpora amylacea (Polyclucosan body) •Masses of hyaline that are located within glia and their processes •Two main types: •Intraneuritic: Not disease-specific •Present before pyramidal loss in hippocampal sclerosis •Amyloid bodies •Accumulates in the processes •Staining: H&E – stains dark eosinophilic; PAS staining – positive (red) Rosenthal fibers •Appearance: Corkscrew-shaped •Stain(s): H&E–eosinophilic in processes; PTAH stains astrocytic fiber bundles blue •Seen in: gliosis and pilocytic astrocytomas •Clinically significant for Alexander’s disease •Appear in end-feet extend throughout the brain, vessels, and pia mater Glial bundles •Stain: GFAP •Formed in the ventral spinal nerve root •Sometimes dorsal root •Seen in: Werdnig-Hoffmann disease clinically significant
- 57. Astrocytes expressing phosphorylated tau Bergmann’s gliosis •Proliferation of Bergmann glia •Appearance: Small cell body with large nuclei Appear in a row in the cerebellar cortex with loss of Purkinje cells • Seen in: Hypoxia/Ischemia; peritumoral compression Thorn-shaped astrocytes •Appearance: aggregations of tau proteins o Appear short and thick • Seen in: tauopathies- not specific Tuft-shaped astrocytes •Appearance: aggregation of phosphorylated tau in the processes o Located close to the cell body •Seen in: PSP confirms diagnosis o Can be aging-related (ARTAG) or pathology- related • Appearance: Morphology can vary according to stains used o BG stain or anti-tau antibodies o Morphologies: thorn-shaped, tuft-shaped, plaques Hard to see with H&E or Bodian silver staining • Seen in: Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD) Neurology.org
- 58. Astrocytic plaques • Aggregates of phosphorylated tau • Distal portions of processes • Appear patchy/wreath-like • Seen in: CBD confirms diagnosis Foamy spheroid bodies • NOTE: May be mistaken for axonal swelling • The bodies are surrounded by bundles of intermediate filament • Punctuate adhesions between them • Indistinct border • Doesn’t stain well with H&E • Some have some eosinophilic granular structrures • Commonly found in substantia nigra zona reticularis Grotesque cells (Bizarre glial cells) • Seen in: dysplastic disorders • Found in lesion sites – focal cortical dysplasia, tuberous scerosis • Appearance: similar to gemistocytic astrocytes in H&E • Eosinophilic cell bodies • Stain with anti-GFAP and anti-vimentin Ig Harvard School of Medicine
- 59. Oligodendrocyte Pathology Acute Swelling •Seen more in oligodendroglia than astrocytes •Usually seen in the case of edema Perineuronal satellitosis •Usually in cerebral grey matter Mucoid degeneration •Polysaccharide accumulation from degeneration •Seen in oligodendrogliomas Intranuclear viral inclusion •extraneural viral inclusions •JC virus •progressive multifocal leukoencephalopathy •Measles virus •subacute sclerosing panencephalitis
- 60. CGIs •argyrophilic inclusions in cytoplasm •ubiquitin and α-synuclein •Seen in multiple system atrophy •Look like tadpoles •olivopontocerebellar atrophy, striatonigral degeneration, or Shy–Drager syndrome CGIs •argyrophilic inclusions in cytoplasm •ubiquitin and α-synuclein •Seen in multiple system atrophy •Look like tadpoles •olivopontocerebellar atrophy, striatonigral degeneration, or Shy–Drager syndrome Abnormal tau proteins •neurodegnerative diseases •Observed with GB/immunostaining Abnormal tau proteins •neurodegnerative diseases •Observed with GB/immunostaining Glial coiled bodies •PSP and CBD, Alzheimer’s disease •GB-stained coiled bodies •Not specifically in tauopathies Glial coiled bodies •PSP and CBD, Alzheimer’s disease •GB-stained coiled bodies •Not specifically in tauopathies Agyrophilic threads •PSP and CBD •Found in processes, not cytoplasm Agyrophilic threads •PSP and CBD •Found in processes, not cytoplasm Oligodendrocyte PathologyOligodendrocyte Pathology CHAO, L. et al Recurrence and histological evolution of dysembryoplastic neuroepithelial tumor: A case report and review of the literature.
- 61. GliomasGliomas
- 62. Glioma vs. normal histology Glioma Normal Dictionary – Normal Cerebral Bortex- The Human Protein Atlas 2017Cancer Dictionary- Glioma- The Human Protein Atlas 2017
- 63. Medulloblastoma Oligodendroglioma Astrocytoma Meningioma Ependymoma Most common Location Neuroaxis- fourth ventricle; ; can send “drop metastases;” to spinal cord Frontal lobe Adults- Frontal lobe Children- Posterior Fossa/cerebellum Parasagittal; olfactory groove and lesser wing of the sphenoid Adults- cauda equina Children- 4th ventricle Cell type- derives from Small cell tumor- primitive neuroectoderm Oligodendrocytes Astrocytes Arachnoid cap cells Ependymal cells Prognosis Variable; responds to radiation Highly malignant- seeding (drop metastasis) Relatively good- 5 year survival ~80% Slow growing Variable- benign or malignant (g. multiforme) Relatively good- not invasive; benign Poor prognosis; technically benign Frequency 20% of primary pediatric intracranial tumors 5% of gliomas 70% of gliomas; Most common tumor Most common benign tumor- 15% 5% of gliomas Other more frequent in children; Homer- Wright rosettes, small blue cells Frequently calcifies Homer-Wright rosettes (neuroblastoma) Associated with NF2; concentric whorls and calcified psammoma bodies Characteristic perivascular rosettes; Rod-shaped blepharoplasts (basal ciliary bodies) found near nucleus
- 64. Astrocytomas • Defined based on morphological features 1. Cellularity 2. nuclear atypia 3. mitotic rate 4. endothelial 5. Proliferation 6. Necrosis • Graded based off of WHO classification system 1. pilocytic astrocytoma (Grade I) 2. astrocytoma (Grade II) • Diffuse 1. anaplastic astrocytoma (Grade III) • Diffuse 1. glioblastoma (Grade IV) • Diffuse Suck et al. 2015Webpathology.com
- 65. Astrocytomas – Classification ContinuedAstrocytomas – Classification Continued Two main types based off of histology: 1.WHO grades II, III, IV – Poor prognosis • Low-grade astrocytoma o Grade II o 10-15% • Anaplastic astrocytoma o Grade III o 25% • Glioblastoma o Grade IV o 50-60% • Giant cell glioblastoma – rare o Grade IV • Gliosarcoma – rare o Grade IV 2. Localized WHO grades I and II – Better prognosis • Pilocytic astrocytoma – most common o Grade I • Pilomyxoid astrocytoma o Grade II • Subependymal giant cell astrocytoma o Grade I • Pleomorphic xanthoastrocytoma o Grade II NOTE: there are no Grade I infiltrating astrocytomas
- 66. Infiltrating AstrocytomasInfiltrating Astrocytomas • ~80% of brain tumors in adults • Usually between 30 and 60 years of age • Symptoms • Seizures • Headaches • Focal neurologic deficits • Usually found in the cerebral cortex Three types of infiltrative astrocytomas depending on WHO classification: 1. Diffuse (grade II) 2. Anaplastic (grade III) 3. Glioglastoma (grade IV) Pathologystudent.com
- 67. Brainstem glioma- usually means pilocytic astrocytoma • Still a grade I and relatively benign, but can lead to more severe symptoms and/or death based off of location • This often involves cranial nerve palsies • May be a cause of “locked-in” syndrome • Symptoms usually related to pressure- headache, loss of balance, nausea/vomiting, AMS The Armed Forces Institute of Pathology Johns Hopkins Pathology
- 68. Glioblastoma multiforme (high grade astrocytoma) • 55% of primary brain tumors Prognosis: Poor – 1 year median survival • Malignant and rapid Histology: • Unique features: pseudopalisades, perivascular pseudorosettes (Homer- Wright) • Tumor cells have an eosinophilic cytoplasm • Contain glial fibrillary acidic protein (GFAP) • Intermediate filament Most common region(s): frontal lobe, temporal lobes, basal nuclei File: Glioblastoma- MR sagittal with contrast.jpg- Wikimedia Commons
- 69. Glioblastoma multiforme • Four molecular subtypes: 1. Classic 2. Proneural 3. Neural 4. Mesenchymal “Butterfly glioma” can pass the corpus callosum Appears similar to anaplastic astrocytoma, except necrosis and proliferation of endothelial cells is also observed. Gross samples will show varying consistency, some firm and some soft/yellow (necrosis); some show hemorrhage as well Robbins & Cotran Pathologic Basis of Disease, 9e
- 71. Angiogenic patterns • Neuroglioblastoma multiforme A. Normal vasculature (cerebral cortex) B. Sprouting angiogenesis at the tumor sight C. Angiogenesis increases; sprouting pattern with increased vessel density D. Proliferation of endothelial cells – looks like a “garland” E. Tufts of capillary along with proliferation of both endothelium and pericytes; look like a glomerulus F. Tumor is invasive; signs of perivascular cuffing Stiver S. Frontiers in Bioscience: A Virtual Library of Medicine, 2004
- 72. MeningiomaMeningioma • Usually affects adults • Common in individuals with NF2 • Derives from precursor cells to the meninges • Usually a good prognosis unless the meningioma develops in a critical area (e.g. grows in the posterior fossa towards the medulla) • Usually well-defined and rounded. Can extend into bone and press on brain, but usually operable Pathologyoutlines.com
- 73. MeningiomasMeningiomas Usually a good prognosis (WHO I/IV) and rarely reoccur •Many different histological patters (do not imply prognosis): 1. Psammomatous 2. Syncytial 3. Fibroblastic 4. Transitional 5. Secretory 6. Microcytic Atypical meningiomas More aggressive and more likely to reoccur; higher rate of mitosis Anaplastic/malignant meningioma Very aggressive and has similar appearance to a sarcoma- bad prognosis Usually a good prognosis (WHO I/IV) and rarely reoccur •Many different histological patters (do not imply prognosis): 1. Psammomatous 2. Syncytial 3. Fibroblastic 4. Transitional 5. Secretory 6. Microcytic Atypical meningiomas More aggressive and more likely to reoccur; higher rate of mitosis Anaplastic/malignant meningioma Very aggressive and has similar appearance to a sarcoma- bad prognosis Robbins & Cotran Pathologic Basis of Disease, 9e
- 74. OligodendrogliomaOligodendroglioma Robbins & Cotran Pathologic Basis of Disease, 9e
- 75. Oligodendroglioma – Macroscopic • Grayish pink masses • Can distinguish from astrocytomas sometimes macroscopically, as oligodendrogliomas are more circumscribed • May show: • Mucoid change • Cystic degeneration • Hemorrhage • Calcification Robbins & Cotran Pathologic Basis of Disease, 9e
- 76. Oligodendroglioma- Microscopic “Chicken-wire” appearance“Chicken-wire” appearance Robbins & Cotran Pathologic Basis of Disease, 9ePathologyoutlines.com
- 78. Ependymoma Robbins & Cotran Pathologic Basis of Disease, 9e
- 79. Four main types of rosettes 1. Homer-Wright 1. Technically a pseudorosette 2. Seen in neuroglioblastoma, medulloblastoma, and primitive neuroectodermal tumors 3. halo of tumor cells surrounding a central region containing neuropil 2. Flexner-Wintersteiner 1. Retinoblastoma 2. Look similar to primitive retinal cells 3. central lumen containing cytoplasmic extensions from the tumor cells Kristine Krafts, MD Pathology Student
- 80. 3. True Ependymal Rosette • Ependymomas • Tumor cells surrounding an empty lumen • Trying to create small ventricles • Not seen in every ependymoma 3. Perivascular Pseudorosette • Ependymomas (most commmon), medullablastoma, PNET, central neurocytoma, glioblastomas • Central structure isn’t part of the tumor Kristine Krafts, MD Pathology Student
- 82. Acoustic neuroma/ SchwannomaAcoustic neuroma/ Schwannoma • Cranial nerves (aside from the optic nerves, which are technically just an extension of the procencephalon) are part of the PNS • This means cancer of peripheral nerves will involve Schwann cells instead of oligodendrocytes • Rare (8%) and benign • It affects women more than men • Usually it is asymptomatic until it grows big enough to affect hearing Photo credit: library.med.utah.edu
- 83. Pituitary adenoma IMPORTANT: Technically NOT a brain tumor! – it’s located in the brain, but isn’t a tumor involving neurons or glia. It involves endocrine cells. Duke Pathology- Nervous System Part 2
- 85. Pediatric CNS tumors • Accounts for ~20% of all childhood cancer • Most occur (~70%) below the tentorium cerebelli in the posterior fossa (compared to adults who are most likely to get it above the tentorium cerebelli) • Most common CNS tumors in children (in decreasing order of prevalence) 1. Cystic cerebellar astrocytoma • Most common overall 1. Medulloblastoma • Most common malignant 1. brainstem glioma • Risk Factors 1. Turcot Syndrome 2. NF1 3. Cigarettes These CNS tumors can affect adults as well, but they are more common in pediatric patients
- 88. Retinoblastoma – Macroscopic White mass, elevated, surface vessels Same patient – shows “glow” in eye Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 9462Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 9461
- 89. Treatment/Prognosis of RetinoblastomaTreatment/Prognosis of Retinoblastoma • Cure rate has risen as high as 90% if discovered early • Surgical treatments involve enucleation and en bloc resection • Other less invasive treatments involve cryotherapy, chemothreapy, laser photocoagulation, thermochemotherapy, and external-beam radiation therapy • Cure rate has risen as high as 90% if discovered early • Surgical treatments involve enucleation and en bloc resection • Other less invasive treatments involve cryotherapy, chemothreapy, laser photocoagulation, thermochemotherapy, and external-beam radiation therapy Source: radiopaedia.org
- 90. Medulloblastoma • Four genetically- defined groups: 1. WNT activated 2. SHH activated (TP53 mutated or TP53 wild type) 3. Medulloblastoma group 3 4. Medulloblastoma group 4 • Four Histologically-defined groups: 1. Classic • More common in childhood 1. Desmoplastic/nodular • More common in infants/adults 1. Medulloblastoma with extensive nodularity • More common in infants 1. Large cell/anaplastic Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 7912
- 91. MedulloblastomaMedulloblastoma • Drop metastasis is a common finding in group 3/4 (shown in picture) • Prognosis strongly influenced by: o surgical resection o presence of metastases o In approximately 40% at time of diagnosis o expression of HER2/Neu • Symptoms typically present associated with raised intracranial pressure due to hydrocephalus • Most arise from the cerebellum- more specifically from the vermis • Posterior vermis syndrome Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 5316
- 92. Medulloblastoma differential diagnosisMedulloblastoma differential diagnosis Children • Ependymoma • It usually arises from the floor of the 4th ventricle same general location • Also found in the foramen of Luschka • Choroid plexus papilloma (CPP) • Pilocytic astrocytoma • Atypical teratoid/rhabdoid tumor • Brainstem glioma (exophytic) Adults • Cerebellar metastasis • Hemangioblastoma • Choroid plexus papilloma (CPP) • Ependymoma Robbins & Cotran Pathologic Basis of Disease, 9e
- 93. Classic Medulloblastoma Classic Medulloblastoma • Usually seenin children • Usuallylocated in themidline • Homer wrightrosettes • Non-SHH orWNT
- 94. Diffuse Brainstem Gliomas • Locations: • Mesencephalon • Pons • Pontine gliomas (DIPG) are the most common location (~70% of cases) • Medulla • Medullary gliomas are the least common location • DIPG • Most common mutation is in the H3F3A gene • “flat floor of the fourth ventricle” sign – the fourth ventricle appears flattened, which may also result in hydrocephaly • Prognosis • Poor – 2 year survival rate is only 20% Case courtesy of Dr Vinay Shah, Radiopaedia.org, rID: 20163 Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 5683 “flat floor” sign
- 95. Sources
- 96. Sources
Editor's Notes
- emerges as anterior rootlets from the anterior lateral sulcus and conveys motor output from visceral and somatic motor neurons. ● joins the posterior roots distal to the spinal ganglion and within the intervertebral foramen to form the spinal nerve.
- Cells in the cortex form columns. In this image the red neurons, called pyramidal cells, are revealed to be entwined by blue fibers from other, inhhibitory neu- rons that slow their firing. The layers of the column are indicated by the numerals to the left: L1, at the surface of the brain, through L6, the deepest cortical layer. Pyramidal cells, which receive messages along their extensively branched fibers, and send long fibers out to other brain areas or down to the spinal cord, are crucial in movement control and in cogni- tion. They have their cell bodies in layer 5 of the cor- tex, and the main receiving fiber, the apical dendrite, rises up to the surface, layer 1. ©BBP/EPFL http://biomedicalcomputationreview.org/content/reverse-engineering-brain
- How does the hippocampus receive input? Information from the thalamus, amygdala, and claustrum is passed through the entorhinal cortex (medial temporal lobe) which projects information to the hippocampus through either the alvear CA1 or the perforant pathway subiculum Most information that is transmitted via the perforant pathway is projected to the granular cells of the dentate gyrus Granular “mossy cells” (which are excitatory/abundant in zinc) CA4/CA3 of dentate hilus polymorphic layer Ammon’s horn of CA1 sibiculum fimbria/fornix mammillary body/anterior thalamic nucleus/cingulate gyrus
- Bielschowsky - This is a gorgeous stain that is used almost exclusively to outline tangles and plaques (which stain black against a gold background). This silver stain colors axis cylinders and neurofibrils black, cytoplasm and nuclei tan to light brown, blood vessels yellow, tan, or brown, and RBCs tan to dark brown. The background or neuropil is a pale tan to yellow (or gold). Glial fibers are usually not stained
- .
- http://neuropathology-web.org/chapter9/images9/9-lb2.jpg
- https://www.researchgate.net/figure/268752619_fig1_Fig-1-Wallerian-degeneration-Following-injury-Schwann-cells-detach-from-the-axons
- The morphologic features consist of shrinkage of the cell body, pyknosis of the nucleus, disappearance of the nucleolus, and loss of Nissl substance, with intense eosinophilia of the cytoplasm. http://missinglink.ucsf.edu/lm/introductionneuropathology/response%20_to_injury/Injury_Images/acute%20ischemia1wc.jpg
- http://missinglink.ucsf.edu/lm/introductionneuropathology/response%20_to_injury/Astrocytes.htm
- Morphological classification varies from histological classification which differs from WHO classification (though WHO tries to bring these two concepts together)