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:

Synucleinopathies:[2]

TDP-43 proteinopathies:

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

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

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:

  1. Neurofibrillary tangles.
  2. Senile plaques (AKA neuritic plaques).
  3. Neuron loss.
  4. +/-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.
  • 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:

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]

  • LRRK2 gene[32] - autosomal dominant.
  • PARK2 gene (parkin)[33] - autosomal recessive.

Gross

Features:[34]

  • Abnormally pale substantia nigra.
    • Pigmentation increases with age.
  • Pale locus ceruleus.

Notes:

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.

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

Features:[1][37][39]

  • 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.[40][41]

Images:

Pick disease

General

  • Dementia.

Gross

  • Frontal and temporal lobe atrophy.[42]
    • May be called "walnut brain"[43] - as it resembles a walnut.

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.

General

  • Due to head trauma - usually repetitive.
    • Seen in American football and boxing.
      • The in the context of boxing it is known as dementia pugilistica; pugil is boxer in Latin.[45]
  • May be associated with motor neuron disease.[46]

Microscopic

Features:[47]

  • Wall-to-wall neurofibrillary tangles.
    • Common in olfactory bulb, mammillary bodies, hippocampus.
    • Usually perivascular.
    • Often superficial (unlike Alzheimer disease) and at the deep aspect of sulci.

IHC

  • Increased TDP-43 staining.

Note:

  • ALS associated with trauma brain injuries.[48]

Huntington disease

General

  • Autosomal dominant inheritance.
  • Mutation in Huntington gene (HTT):[49]
    • 11-34 CAG repeat = normal.[50]
    • >42 CAG repeat = Huntington disease.

Clinical:[51]

  • Early onset dementia.
  • Involuntary movements (chorea) - both arms and legs.
  • Behaviour changes, e.g. grimacing.
  • Speech changes.

Gross

  • Severe caudate atrophy.[52]
    • Prominent frontal horns of the lateral ventricles.[53]

Note:

  • A normal caudate bulges into the ventricle.

Images:

Microscopic

Features:[51]

  • 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.[54]
    • 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.[55]

Clinical:

  • Weakness.

Microscopic

Features:[55]

  • 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:[57]

  • Axonal spheroids.
  • Iron deposition.

Images:

Stains

  • Prussian blue +ve.

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. ↑ 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.
  9. ↑ 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.
  10. ↑ 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. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 104311
  16. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 600759
  17. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 107741
  18. ↑ Braak H, Braak E, Bohl J (1993). "Staging of Alzheimer-related cortical destruction". Eur. Neurol. 33 (6): 403–8. PMID 8307060.
  19. ↑ URL: http://www.pakmed.net/academic/age/alz/alz030.htm. Accessed on: 12 November 2010.
  20. ↑ URL: http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm. Accessed on: 13 November 2010.
  21. ↑ 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.
  22. ↑ URL: http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/npfrm.html. Accessed on: 5 December 2010.
  23. ↑ 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. ↑ 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.
  25. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 600072
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ URL: http://moon.ouhsc.edu/kfung/jty1/opaq/PathQuiz/N0I002-PQ01-M.htm. Accessed on: 19 October 2010.
  29. ↑ Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 419 Q4. ISBN 978-1416025887.
  30. ↑ URL: http://www.nysslha.org/i4a/pages/index.cfm?pageid=3519. Accessed on: 30 March 2011.
  31. ↑ 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.
  32. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 609007
  33. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 602544
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ MUN. 16 November 2010.
  37. ↑ 37.0 37.1 URL: http://emedicine.medscape.com/article/1151430-overview. Accessed on: 11 November 2010.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ URL: http://neuropathologyblog.blogspot.com/2008/03/grumose-degeneration-in-cerebellar.html. Accessed on: 4 December 2010.
  41. ↑ 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. ↑ 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.
  43. ↑ URL: http://medical-dictionary.thefreedictionary.com/Walnut+Brain. Accessed on: 14 March 2012.
  44. ↑ Grossman, M. (Feb 2010). "Primary progressive aphasia: clinicopathological correlations.". Nat Rev Neurol 6 (2): 88-97. doi:10.1038/nrneurol.2009.216. PMID 20139998.
  45. ↑ URL: http://dictionary.reference.com/browse/pugilism. Accessed on: 21 November 2011.
  46. ↑ Daneshvar, DH.; Riley, DO.; Nowinski, CJ.; McKee, AC.; Stern, RA.; Cantu, RC. (Nov 2011). "Long-term consequences: effects on normal development profile after concussion.". Phys Med Rehabil Clin N Am 22 (4): 683-700. doi:10.1016/j.pmr.2011.08.009. PMID 22050943.
  47. ↑ Stern, RA.; Riley, DO.; Daneshvar, DH.; Nowinski, CJ.; Cantu, RC.; McKee, AC. (Oct 2011). "Long-term Consequences of Repetitive Brain Trauma: Chronic Traumatic Encephalopathy.". PM R 3 (10 Suppl 2): S460-7. doi:10.1016/j.pmrj.2011.08.008. PMID 22035690.
  48. ↑ Costanza, A.; Weber, K.; Gandy, S.; Bouras, C.; Hof, PR.; Giannakopoulos, P.; Canuto, A. (Oct 2011). "Review: Contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates.". Neuropathol Appl Neurobiol 37 (6): 570-84. doi:10.1111/j.1365-2990.2011.01186.x. PMID 21696410.
  49. ↑ Kumar P, Kalonia H, Kumar A (2010). "Huntington's disease: pathogenesis to animal models". Pharmacol Rep 62 (1): 1–14. PMID 20360611.
  50. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 613004
  51. ↑ 51.0 51.1 Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 415 Q44. ISBN 978-1416025887.
  52. ↑ URL: http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q07-Ans.htm. Accessed on: 29 October 2010.
  53. ↑ URL: http://path.upmc.edu/cases/case117/gross.html. Accessed on: 3 January 2012.
  54. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 105400
  55. ↑ 55.0 55.1 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.
  56. ↑ URL: http://pathology.mc.duke.edu/neuropath/CNSlecture4/CNSlecture4.htm. Accessed on: 30 August 2011.
  57. ↑ URL: http://path.upmc.edu/cases/case207/dx.html. Accessed on: 11 January 2012.
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