Neurodegenerative diseases

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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.

Molecular schema of neurodegenerative disorders:[1]

 
 
 
 
 
 
Neurodegenerative
disorders
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amyloidoses
 
Tauopathies
 
α-synucleinopathies
 
TDP-43
 

Common diseases

Amyloidoses:

  • 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 (FTLD) with
ubiquitinated inclusions 		TDP-43 cortex, basal ganglia dementia, focal cortical syndromes histology? Image?

Immunohistochemistry

Alpha-synuclein

Look for:

  • Lewy bodies (seen in Parkinson's d., Dementia with Lewy bodies) = round cytoplasmic eosinophilic body +/- pale halo.

Tau

  • AT8 = stains phosphorylated tau.[4]
    • AT = anti-tau.
    • Stains tau 4R and tau 3R.[5]

TDP-43

  • May accumulate due to a progranulin mutation.

Microscopic

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:

  1. Neurofibrillary tangles.
  2. Senile plaques.
    • Consists of two components:
      1. Centre - radiates.
        • Consists of Abeta amyloid
      2. Neurites - swollen axons.
    • 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]

Notes:

  • Abeta amyloid:
    • Derived from amyloid precursor protein (APP).
      • APP:
        • Rapid axonal transport - useful as a marker of axonal injury.
        • Function currently not known.
  • 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.

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:

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.

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

  • AKA Steele-Richardson-Olszewski syndrome.
  • Diagnosis: clinical.[22]

Microscopic

Features:[1][22][23]

  • 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.
    • Granular eosinophilic material adjacent to nuclei; once thought to be pathognomonic for PSP.[24][25]

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. ↑ 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.
  2. ↑ Uversky, VN. (Oct 2008). "Alpha-synuclein misfolding and neurodegenerative diseases.". Curr Protein Pept Sci 9 (5): 507-40. PMID 18855701.
  3. ↑ MUN. 15 November 2010.
  4. ↑ 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/.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ URL: http://dictionary.reference.com/browse/skein. Accessed on: 20 November 2010.
  8. ↑ TN06 PS19
  9. ↑ 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.
  10. ↑ Braak H, Braak E, Bohl J (1993). "Staging of Alzheimer-related cortical destruction". Eur. Neurol. 33 (6): 403–8. PMID 8307060.
  11. ↑ URL: http://www.pakmed.net/academic/age/alz/alz030.htm. Accessed on: 12 November 2010.
  12. ↑ URL: http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm. Accessed on: 13 November 2010.
  13. ↑ 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.
  14. ↑ URL: http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/npfrm.html. Accessed on: 5 December 2010.
  15. ↑ 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/.
  16. ↑ 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.
  17. ↑ URL: http://moon.ouhsc.edu/kfung/jty1/opaq/PathQuiz/N0I002-PQ01-M.htm. Accessed on: 19 October 2010.
  18. ↑ URL: http://www.nysslha.org/i4a/pages/index.cfm?pageid=3519. Accessed on: 30 March 2011.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ MUN. 16 November 2010.
  22. ↑ 22.0 22.1 URL: http://emedicine.medscape.com/article/1151430-overview. Accessed on: 11 November 2010.
  23. ↑ 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.
  24. ↑ URL: http://neuropathologyblog.blogspot.com/2008/03/grumose-degeneration-in-cerebellar.html. Accessed on: 4 December 2010.
  25. ↑ 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.
  26. ↑ Kumar P, Kalonia H, Kumar A (2010). "Huntington's disease: pathogenesis to animal models". Pharmacol Rep 62 (1): 1–14. PMID 20360611.
  27. ↑ URL: http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q07-Ans.htm. Accessed on: 29 October 2010.
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