Difference between revisions of "Neurodegenerative diseases"
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==Progressive supranuclear palsy== | ==Progressive supranuclear palsy== | ||
*Commonly abbreviated ''PSP''. | |||
===General=== | ===General=== | ||
*[[AKA]] ''Steele-Richardson-Olszewski syndrome''. | *[[AKA]] ''Steele-Richardson-Olszewski syndrome''. | ||
*Diagnosis: clinical.<ref name=psp_emedicine>URL: [http://emedicine.medscape.com/article/1151430-overview http://emedicine.medscape.com/article/1151430-overview]. Accessed on: 11 November 2010.</ref> | *Diagnosis: clinical.<ref name=psp_emedicine>URL: [http://emedicine.medscape.com/article/1151430-overview http://emedicine.medscape.com/article/1151430-overview]. Accessed on: 11 November 2010.</ref> | ||
Revision as of 05:11, 2 August 2011
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).
- Creutzfeldt-Jakob disease (PrP).
Taupathies:
- Progressive supranuclear palsy.
- Pick's disease.
Synucleinopathies:[2]
- Parkinson disease.
- Dementia with Lewy bodies.
- Multiple system atrophy.
TDP-43 proteinopathies:
- Amyotrophic alteral sclerosis.
- Frontotemporal lobar degeneration with ubiquitinated inclusions.
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 | parkinsonism | globose neurofibrillary tangles in neurons, 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 with ubiquitinated inclusions |
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
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
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).
Amyloidoses
Alzheimer disease
General
- Onset: episodic memory loss.
- Diagnosis is clinical & pathologic.
- Pathologic finding alone are not diagnostic.
- Trisomy 21 (Down syndrome) - increases risk.[9]
Gross
Features:
- Temporal atrophy, esp. hippocampus.
- Dilation of:
- Lateral ventricles.
- Third ventricle.
Gross/microscopic - disease spread by NF tangles (staging):[10]
- 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)[11], tangle (washington.edu).[12]
- Dementia severity correlates better with NF tangles number than senile plaque number.[13]
- Senile 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.
- There is a staging system for plaques I (mild), II (moderate), III (severe).
- Image: Senile plaques (utah.edu).[14]
- Consists of two components:
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
Etiology:[15]
- Misfolded cell-surface protein called PrP(C).
Includes:[15]
- Creutzfeldt-Jakob disease (CJD).
- Sporadic fatal insomnia (sFI).
Creutzfeldt-Jakob disease
General
- Commonly abbreviated as CJD.
- Rare.
- Incurable disease.
- Usually diagnosed clinically.
- Characteristic findings:
- Very rapid decline (3-4 months).
- Characteristic (cortex findings on) neuroradiology.
- Characteristic findings:
Variant Creutzfeldt-Jakob disease (vCJD)
- Associated with bovine spongiform encephalopathy.
- Should sample: spleen, lymph nodes, tonsils.[16]
Microscopic
Features:
- Spongy appearance (cytoplasmic vacuolization[17]).
Images:
Lewy body diseases
DDx:
- Parkinson's disease.
- Dementia with Lewy bodies.
Etiology:
- Alpha-synuclein.
Clinical features of Dementia with Lewy bodies:
- Parkinsonian features.
- Hallucinations (visual).
- Progressive cognitive decline with fluctuations.
Parkinson disease
General
- Common.
Clinical TRAP:[18]
- Tremor.
- Rigidity.
- Akinesia.
- Postural instability.
Gross
Features:[19]
- Abnormally pale substantia nigra.
- Pigmentation increases with age.
Notes:
- Substantia nigra is a midbrain structure.
- Image: Midbrain - schematic (WC).
Microscopic
Features:[19]
- Loss of pigmented (catecholaminergic) neurons in the substantia nigra.
- 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.
Alpha-synucleinopathies
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).[20]
- Inclusions in oligodendrocytes.[21]
Progressive supranuclear palsy
- Commonly abbreviated PSP.
General
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.
Other
Huntington disease
General
- Autosomal dominant inheritance.
- Mutation: unstable CAG repeat.[26]
Gross
- Missing caudate.[27]
Image: Huntington's disease (ouhsc.edu).
Binswanger's 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.
Amyotrophic lateral sclerosis
- Abbreviated ALS.
General
- AKA Lou Gehrig's disease.
- TDP-43 proteinopathy.
Clinical:
- Weakness.
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.
- ↑ TN06 PS19
- ↑ 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.
- ↑ 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.
- ↑ 15.0 15.1 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/.
- ↑ 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.
- ↑ URL: http://www.nysslha.org/i4a/pages/index.cfm?pageid=3519. Accessed on: 30 March 2011.
- ↑ 19.0 19.1 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.
- ↑ 22.0 22.1 URL: http://emedicine.medscape.com/article/1151430-overview. Accessed on: 11 November 2010.
- ↑ 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.
- ↑ Kumar P, Kalonia H, Kumar A (2010). "Huntington's disease: pathogenesis to animal models". Pharmacol Rep 62 (1): 1–14. PMID 20360611.
- ↑ URL: http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q07-Ans.htm. Accessed on: 29 October 2010.