Difference between revisions of "Neurodegenerative diseases"
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TDP-43 proteinopathies: | TDP-43 proteinopathies: | ||
*[[Amyotrophic lateral sclerosis]]. | *[[Amyotrophic lateral sclerosis]]. | ||
*Frontotemporal lobar degeneration | *Frontotemporal lobar degeneration. | ||
FUS proteinopathies: | FUS proteinopathies: | ||
*[[Amyotrophic lateral sclerosis]]. | *[[Amyotrophic lateral sclerosis]]. | ||
*Frontotemporal lobar degeneration | *Frontotemporal lobar degeneration. | ||
Prionopathies: | Prionopathies: | ||
Revision as of 21:52, 16 February 2015
Neurodegenerative diseases is a big part of neuropathology. It includes some discussion of dementia.
Overview
- Neurodegenerative disease = essentially progressive and selective neuron loss.
- Clinically, they are not unique, e.g. dementia can be caused by several diseases (with different molecular etiologies).
- Each syndrome (e.g. dementia, parkinsonism, ataxia) has a most common etiology and a DDx.
- They are defined by molecular pathology.[1]
- The diseases are due to the accumulation of abnormal protein.
- The amino acid sequence of the protein may be completely normal. The problem may just be folding/protein conformation.
- The diseases are due to the accumulation of abnormal protein.
Molecular schema of neurodegenerative disorders:[1]
| Neurodegenerative disorders | |||||||||||||||||||||||||||||||||
| Amyloidoses | Tauopathies | α-synucleinopathies | TDP-43 | ||||||||||||||||||||||||||||||
Common diseases
- Alzheimer disease (Abeta).
'Pure' tauopathies:
- Progressive supranuclear palsy.
- Pick's disease.
- Corticobasal degeneration.
- FTDP-17.
- Dementia pugilistica.
Synucleinopathies:[2]
- Parkinson disease.
- Dementia with Lewy bodies.
- Multiple system atrophy.
TDP-43 proteinopathies:
- Amyotrophic lateral sclerosis.
- Frontotemporal lobar degeneration.
FUS proteinopathies:
- Amyotrophic lateral sclerosis.
- Frontotemporal lobar degeneration.
Prionopathies:
- Creutzfeldt-Jakob disease (PrP).
Table
Disease/pathology/clinical correlation based on Dickson:[1]
| Disease | Mutated protein | Distribution | Clinical | Histology | Image |
|---|---|---|---|---|---|
| Alzheimer disease | Abeta (mutated APP) | corticolimbic, usu. spares occipital |
dementia | plaques, neurofibrillary tangles | [1] |
| Creutzfeldt-Jakob disease | PrPres (mutated PrP) | cortical & basal ganglia | dementia (rapid progression), movement disorder |
cytoplasmic vacuolization | [2] |
| Progressive supranuclear palsy | tau 4R | basal ganglia, brainstem | atypical parkinsonism with early gait instability, falls, and supranuclear gaze palsy | tau-positive globose neurofibrillary tangles in neurons, tufted astrocytes, coiled bodies in oligodendrocytes |
Image? |
| Pick disease | tau 3R | corticolimbic | dementia + focal cortical syndrome |
Pick body ??? | Image? |
| Parkinson disease | alpha-synuclein | brainstem | parkinsonism | Lewy bodies | [3] |
| Dementia with Lewy bodies |
alpha-synuclein | corticolimbic, brainstem | dementia + parkinsonism | Lewy bodies | [4] |
| Multiple system atrophy | alpha-synuclein | basal ganglia, brainstem, cerebellum | parkinsonism, ataxia | cytoplasmic inclusion in oligodendrocytes[3] | Image |
| Amyotrophic lateral sclerosis (ALS) |
TDP-43 | motor neurons | spasticity, weakness | histology? | Image |
| Frontotemporal lobar degeneration (FTLD) |
TDP-43 | cortex, basal ganglia | dementia, focal cortical syndromes | histology? | Image? |
![[1]](http://en.wikipedia.org/wiki/File:Cerebral_amyloid_angiopathy_-2a-_amyloid_beta_-_high_mag.jpg){kind=link}
![[2]](http://en.wikipedia.org/wiki/File:SpongiformChangeCJD.jpg){kind=link}
![[3]](http://firstaidteam.com/usmlerximages/v/USMLERxLewy+bodies.gif.html){kind=link}
Immunohistochemistry
Alpha-synuclein
Look for:
- Lewy bodies (seen in Parkinson's d., Dementia with Lewy bodies) = round cytoplasmic eosinophilic body +/- pale halo.
Tau
TDP-43
- May accumulate due to a progranulin mutation.
Microscopic
- TDP-43 - normally in the nucleus.
- Pathologic: Micrograph (label B) - neurites, skein-like formations (ama-assn.org)[6]
- Fibrillar or skein-like formations = cytoplasmic staining.
- "Skein" = yarn or thread wound on a reel or flock of birds in flight.[7]
- Neurites = "squiggly appearance"; "worm-like appearance".
- Fibrillar or skein-like formations = cytoplasmic staining.
- Pathologic: Micrograph (label B) - neurites, skein-like formations (ama-assn.org)[6]
Ubiquitin
- Marks proteins for recycling.
Microscopic
- p62; poli-ubiquitin-binding protein p62.[4]
Look for:
- Lewy bodies. (???)
Clinical perspective
Dementia general (mostly useless) DDx
- Alzheimer's dementia - most common.
- Vascular.
- Multi-infarct dementia.
- Parkinson's associated dementia.
- Lewy body dementia.
- Alcohol-related dementia.
- Fronto-temporal dementia (Pick disease).
- Multisystem atrophy.
Mnemonic
Dementia mnemonic VITAMIN D VEST:[8]
- Vitamin deficiency (B12, folate, thiamine).
- Infection (HIV).
- Trauma.
- Anoxia.
- Metabolic (Diabetes).
- Intracranial tumour.
- Normal pressure hydrocephalus.
- Degenerative (Alzheimer's, Huntington's, CJD).
- Vascular.
- Endocrine.
- Space occupying lesion (chronic subdural hematoma).
- Toxins (alcohol).
Functional anatomy of dementia
- Hippocampus (essential for forming new memories).
- Frontal lobe (essential for retrieval of memories).
Parkinsonism causes
- Parkinson's disease [9]
- Dementia with Lewy bodies.
- Multiple system atrophy (MSA).[10]
- Progressive supranuclear palsy (PSP).[11]
- Drug induced (valproic acid).[12]
Amyloidoses
Alzheimer disease
General
- Onset: episodic memory loss.
- Diagnosis is clinical & pathologic.
- Pathologic finding alone are not diagnostic.
- Seen in conjunction with vascular amyloid deposition; see cerebral amyloid angiopathy.
Genetics
Genes associated with Alzheimer disease:[13]
- Amyloid precursor protein (APP).
- On chromosome 21 - may explain why Trisomy 21 (Down syndrome) increases the risk of Alzheimer disease.[14]
- Presenilin 1 (PSEN1).[15]
- Presenilin 2 (PSEN2).[16]
- Apolipoprotein E (APOE)[17] - specifically the epsilon-4 allele.
Gross
Features:
- Temporal atrophy, esp. hippocampus.
- Dilation of:
- Lateral ventricles.
- Third ventricle.
Gross/microscopic - disease spread by NF tangles (staging):[18]
- Alzheimer "spreads" in a reproducible pattern:
- Stage I-II: entorhinal cortex.
- Stage III-IV: inferior aspect of brain.
- Stage V-VI: limbic system.
Microscopic
Features:
- Neurofibrillary tangles.
- Consists of tau.
- Location: hippocampus, cerebral cortex, hypothalamus.
- Images: tangles - schematic (pakmed.net)[19], tangle (washington.edu).[20]
- Dementia severity correlates better with NF tangles number than senile plaque number.[21]
- Senile plaques (AKA neuritic plaques).
- Consists of two components:
- Centre - radiates.
- Consists of Abeta amyloid
- Neurites - swollen axons.
- Centre - radiates.
- Considered to be more specific for Alzheimer's than NF tangles.
- How to remember: senile plaques = specific.
- There is a staging system for plaques I (mild), II (moderate), III (severe).
- Images: senile plaques (utah.edu)[22] senile plaques - beta-APP - high mag. (WC).
- Consists of two components:
- Neuron loss.
- +/-Cerebral amyloid angiopathy.
Notes:
- Abeta amyloid:
- Derived from amyloid precursor protein (APP).
- APP:
- Rapid axonal transport - useful as a marker of axonal injury.
- Function currently not known.
- APP:
- Derived from amyloid precursor protein (APP).
- Tau:
- Important in microtubule assembly.
Prion diseases
General
Etiology:[23]
- Misfolded cell-surface protein called PrPSC.
- This is derived from the protein PrPC encoded by the PRNP gene.
Includes:
- Creutzfeldt-Jakob disease (CJD).
- Sporadic fatal insomnia (sFI).[23]
- Fatal familial insomnia (FFI).[24][25]
- Gestmann-Straussler-Scheinker syndrome (GSS) - due to PRNP gene mutations.[26]
IHC
PrPC:[24]
- Congo red +ve.
- PAS +ve.
Creutzfeldt-Jakob disease
- Commonly abbreviated as CJD.
General
- Rare.
- Incurable disease.
Usually diagnosed clinically:
- Characteristic findings:
- Very rapid decline (3-4 months).
- Characteristic (cortex findings on) neuroradiology.
Variant Creutzfeldt-Jakob disease
- Abbreviated vCJD.
General
- Associated with bovine spongiform encephalopathy (AKA mad cow disease).
- Should sample: spleen, lymph nodes, tonsils.[27]
Microscopic
Features:
- Spongy appearance (cytoplasmic vacuolization[28]).
Note:
- Spongiform changes may be seen in ALS, Alzheimer's disease and Lewy body disease (e.g. Parkinson disease); however, the changes are only in the upper cortex and not diffuse.[29]
Images:
Alpha-synucleinopathies
Includes the Lewy body diseases Parkinson's disease and Dementia with Lewy bodies.
Dementia with Lewy bodies
General
Clinical features:
- Parkinsonian features.
- Hallucinations (visual).
- Progressive cognitive decline with fluctuations.
Microscopic
Features:
IHC
- Alpha-synuclein +ve.
Parkinson disease
General
- Common - often sporadic.
- May be genetic.
Clinical TRAP:[30]
- Tremor.
- Rigidity.
- Akinesia.
- Postural instability.
Genetics:[31]
Gross
Features:[34]
- Abnormally pale substantia nigra.
- Pigmentation increases with age.
- Pale locus ceruleus.
Notes:
- Substantia nigra is a midbrain structure.
- Image: Midbrain - schematic (WC).
Microscopic
Features:[34]
- Loss of pigmented (catecholaminergic) neurons in the substantia nigra and locus ceruleus.
- Gliosis - due to neuron loss.
- Lewy bodies (in remaining neurons) - key feature.
- Eosinophilic cytoplasmic inclusion with "dense" (darker) core and pale (surrounding) halo.
- Consist of filaments composed of alpha-synuclein.
- Eosinophilic cytoplasmic inclusion with "dense" (darker) core and pale (surrounding) halo.
IHC
- Alpha-synuclein +ve.
Multiple system atrophy
General
Clinical findings variable:
- Parkinsonism (stiatonigral degeneration).
- Ataxia (olivo-panto-cerebellar degeneration).
Microscopic
Features:
- Alpha-synuclein-rich glial cytoplasmic inclusions (finding at autopsy).[35]
- Inclusions in oligodendrocytes.[36]
Tauopathies
Progressive supranuclear palsy
- Commonly abbreviated PSP.
- AKA Steele-Richardson-Olszewski syndrome.
General
- Diagnosis - clinical.[37]
Clinical:
- Impaired control of gaze, esp. difficulty looking up and down (supranuclear palsy).[38]
- Parkinsonism.[11]
Microscopic
- Globose neurofibrillary tangles in neurons.
- Coiled bodies in oligodendrocytes.
- Wire coil-like structure around the nucleus.
- Tufted astrocytes.
- Near impossible to see without IHC - specifically AT8.
- Cellular processes filled with crap.
- Star-like appearance; looks like a road network where all the roads lead to one place (Parisian star).
- Grumose degeneration of the cerebellar dentate nucleus.
Images:
Pick disease
General
- Dementia.
Gross
Microscopic
Features:[42]
- Pick cells = large ballooned neurons.
- Pick bodies = round, homogenous, intracytoplasmic inclusions, size ~10 micrometers.
Image(s):
Other
Chronic traumatic encephalopathy
- Abbreviated CTE.
Main article: Chronic traumatic encephalopathy
Huntington disease
General
- Autosomal dominant inheritance.
- Mutation in Huntington gene (HTT):[45]
- 11-34 CAG repeat = normal.[46]
- >42 CAG repeat = Huntington disease.
Clinical:[47]
- Early onset dementia.
- Involuntary movements (chorea) - both arms and legs.
- Behaviour changes, e.g. grimacing.
- Speech changes.
Gross
Note:
- A normal caudate bulges into the ventricle.
Images:
Microscopic
Features:[47]
- Neuron loss.
- Gliosis.
Binswanger disease
General
- Multi-infarct dementia affecting subcortical white matter.
- Waste-basket diagnosis; diagnosed if CADASIL and amyloidosis have been excluded.
- Diagnosis has been controversial -- most with this entity (in the past) were diagnosed with Alzheimer's disease.
Microscopic
Features:
- Subcortical lesions that replace the myelin consisting of macrophages.
Frontotemporal lobar degeneration with ubiquitinated inclusions
Abbreviated FTLD with ubiquitinated inclusions or FTLD-TDP43.
General
- There are several forms of frontotemporal dementia.
- Related to amyotrophic lateral sclerosis (ALS); also a TDP-43 pathology.[50]
- There are several subtypes of FTLD with TDP-43.
Gross
- Frontal and temporal lobe atrophy.
Image:
Amyotrophic lateral sclerosis
- Abbreviated ALS.
General
- AKA Lou Gehrig's disease.
- TDP-43 proteinopathy.
- Characterized by motor neuron death.
- May be familial and associated with SOD1 gene.[51]
Clinical:
- Weakness.
Microscopic
Features:[51]
- Motor neurons with Bunina bodies.
- PAS positive cytoplasmic inclusions.
- Motor neuron loss + reactive gliosis + neurogenic muscular atrophy.
Images:
Hallervorden-Spatz disease
- AKA pantothenate kinase-associated neurodegeneration.
General
- Uncommon.
Microscopic
Features:[53]
- Axonal spheroids.
- Iron deposition.
Images:
Stains
- Prussian blue +ve.
See also
References
- ↑ 1.0 1.1 1.2 1.3 Dickson DW (2009). "Neuropathology of non-Alzheimer degenerative disorders". Int J Clin Exp Pathol 3 (1): 1–23. PMC 2776269. PMID 19918325. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776269/?tool=pubmed.
- ↑ Uversky, VN. (Oct 2008). "Alpha-synuclein misfolding and neurodegenerative diseases.". Curr Protein Pept Sci 9 (5): 507-40. PMID 18855701.
- ↑ MUN. 15 November 2010.
- ↑ 4.0 4.1 Seelaar H, Klijnsma KY, de Koning I, et al. (May 2010). "Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration". J. Neurol. 257 (5): 747–53. doi:10.1007/s00415-009-5404-z. PMC 2864899. PMID 19946779. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864899/.
- ↑ Kumaran R, Kingsbury A, Coulter I, et al. (October 2007). "DJ-1 (PARK7) is associated with 3R and 4R tau neuronal and glial inclusions in neurodegenerative disorders". Neurobiol. Dis. 28 (1): 122–32. doi:10.1016/j.nbd.2007.07.012. PMID 17719794.
- ↑ Geser F, Brandmeir NJ, Kwong LK, et al. (May 2008). "Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis". Arch. Neurol. 65 (5): 636–41. doi:10.1001/archneur.65.5.636. PMID 18474740.
- ↑ URL: http://dictionary.reference.com/browse/skein. Accessed on: 20 November 2010.
- ↑ Shiau, Carolyn; Toren, Andrew (2006). Toronto Notes 2006: Comprehensive Medical Reference (Review for MCCQE 1 and USMLE Step 2) (22nd edition (2006) ed.). Toronto Notes for Medical Students, Inc.. pp. PS19. ISBN 978-0968592861.
- ↑ Tuite, PJ.; Krawczewski, K. (Apr 2007). "Parkinsonism: a review-of-systems approach to diagnosis.". Semin Neurol 27 (2): 113-22. doi:10.1055/s-2007-971174. PMID 17390256.
- ↑ Ahmed, Z.; Asi, YT.; Sailer, A.; Lees, AJ.; Houlden, H.; Revesz, T.; Holton, JL. (Nov 2011). "Review: The neuropathology, pathophysiology and genetics of multiple system atrophy.". Neuropathol Appl Neurobiol. doi:10.1111/j.1365-2990.2011.01234.x. PMID 22074330.
- ↑ 11.0 11.1 Bertram, K.; Williams, DR. (Apr 2012). "Visual hallucinations in the differential diagnosis of parkinsonism.". J Neurol Neurosurg Psychiatry 83 (4): 448-52. doi:10.1136/jnnp-2011-300980. PMID 22228724.
- ↑ Mahmoud, F.; Tampi, RR. (Oct 2011). "Valproic Acid-Induced Parkinsonism in the Elderly: A Comprehensive Review of the Literature.". Am J Geriatr Pharmacother. doi:10.1016/j.amjopharm.2011.09.002. PMID 21993183.
- ↑ Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 674-5. ISBN 978-1416054542.
- ↑ Nieuwenhuis-Mark, RE.. "Diagnosing Alzheimer's dementia in Down syndrome: problems and possible solutions.". Res Dev Disabil 30 (5): 827-38. doi:10.1016/j.ridd.2009.01.010. PMID 19269132.
- ↑ Online 'Mendelian Inheritance in Man' (OMIM) 104311
- ↑ Online 'Mendelian Inheritance in Man' (OMIM) 600759
- ↑ Online 'Mendelian Inheritance in Man' (OMIM) 107741
- ↑ Braak H, Braak E, Bohl J (1993). "Staging of Alzheimer-related cortical destruction". Eur. Neurol. 33 (6): 403–8. PMID 8307060.
- ↑ URL: http://www.pakmed.net/academic/age/alz/alz030.htm. Accessed on: 12 November 2010.
- ↑ URL: http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm. Accessed on: 13 November 2010.
- ↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1317. ISBN 978-1416031215.
- ↑ URL: http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/npfrm.html. Accessed on: 5 December 2010.
- ↑ 23.0 23.1 Watts JC, Balachandran A, Westaway D (March 2006). "The expanding universe of prion diseases". PLoS Pathog. 2 (3): e26. doi:10.1371/journal.ppat.0020026. PMC 1434791. PMID 16609731. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1434791/.
- ↑ 24.0 24.1 Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 672. ISBN 978-1416054542.
- ↑ Online 'Mendelian Inheritance in Man' (OMIM) 600072
- ↑ Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 671. ISBN 978-1416054542.
- ↑ Burton, Julian L.; Rutty, Guy N. (2010). The Hospital Autopsy A Manual of Fundamental Autopsy Practice (3rd ed.). Oxford University Press. pp. 83. ISBN 978-0340965146.
- ↑ URL: http://moon.ouhsc.edu/kfung/jty1/opaq/PathQuiz/N0I002-PQ01-M.htm. Accessed on: 19 October 2010.
- ↑ Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 419 Q4. ISBN 978-1416025887.
- ↑ URL: http://www.nysslha.org/i4a/pages/index.cfm?pageid=3519. Accessed on: 30 March 2011.
- ↑ Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 677. ISBN 978-1416054542.
- ↑ Online 'Mendelian Inheritance in Man' (OMIM) 609007
- ↑ Online 'Mendelian Inheritance in Man' (OMIM) 602544
- ↑ 34.0 34.1 Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1319. ISBN 978-1416031215.
- ↑ Wenning, GK.; Stefanova, N.; Jellinger, KA.; Poewe, W.; Schlossmacher, MG. (Sep 2008). "Multiple system atrophy: a primary oligodendrogliopathy.". Ann Neurol 64 (3): 239-46. doi:10.1002/ana.21465. PMID 18825660.
- ↑ MUN. 16 November 2010.
- ↑ 37.0 37.1 URL: http://emedicine.medscape.com/article/1151430-overview. Accessed on: 11 November 2010.
- ↑ Levy, R. (Jun 2011). "[Progressive supranuclear palsy: what's new?].". Geriatr Psychol Neuropsychiatr Vieil 9 (2): 191-201. doi:10.1684/pnv.2011.0271. PMID 21690028.
- ↑ Williams DR, Lees AJ (March 2009). "Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges". Lancet Neurol 8 (3): 270–9. doi:10.1016/S1474-4422(09)70042-0. PMID 19233037.
- ↑ URL: http://neuropathologyblog.blogspot.com/2008/03/grumose-degeneration-in-cerebellar.html. Accessed on: 4 December 2010.
- ↑ Yamanouchi H, Yokoo H, Yuhara Y, et al. (March 2002). "An autopsy case of ornithine transcarbamylase deficiency". Brain Dev. 24 (2): 91–4. PMID 11891099.
- ↑ 42.0 42.1 Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 676. ISBN 978-1416054542.
- ↑ URL: http://medical-dictionary.thefreedictionary.com/Walnut+Brain. Accessed on: 14 March 2012.
- ↑ Grossman, M. (Feb 2010). "Primary progressive aphasia: clinicopathological correlations.". Nat Rev Neurol 6 (2): 88-97. doi:10.1038/nrneurol.2009.216. PMID 20139998.
- ↑ Kumar P, Kalonia H, Kumar A (2010). "Huntington's disease: pathogenesis to animal models". Pharmacol Rep 62 (1): 1–14. PMID 20360611.
- ↑ Online 'Mendelian Inheritance in Man' (OMIM) 613004
- ↑ 47.0 47.1 Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 415 Q44. ISBN 978-1416025887.
- ↑ URL: http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q07-Ans.htm. Accessed on: 29 October 2010.
- ↑ URL: http://path.upmc.edu/cases/case117/gross.html. Accessed on: 3 January 2012.
- ↑ Online 'Mendelian Inheritance in Man' (OMIM) 105400
- ↑ 51.0 51.1 Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 679. ISBN 978-1416054542.
- ↑ URL: http://pathology.mc.duke.edu/neuropath/CNSlecture4/CNSlecture4.htm. Accessed on: 30 August 2011.
- ↑ URL: http://path.upmc.edu/cases/case207/dx.html. Accessed on: 11 January 2012.