Acta Neuropathologica

, Volume 120, Issue 3, pp 327–341 | Cite as

Brain biopsy in dementia: clinical indications and diagnostic approach

  • Jonathan M. Schott
  • Lilla Reiniger
  • Maria Thom
  • Janice L. Holton
  • Joan Grieve
  • Sebastian Brandner
  • Jason D. Warren
  • Tamas Revesz


Brain biopsy may be performed to make a definitive diagnosis in patients with rapidly progressive dementia. To assess the value of this procedure, we previously studied 90 consecutive cerebral biopsies performed in the tertiary referral centre of the National Hospital for Neurology and Neurosurgery, Queen Square between 1989 and 2003 (6 biopsies/year). Fifty-seven percent of all biopsies were diagnostic with Alzheimer’s disease (18%), Creutzfeldt–Jakob disease (CJD) (12%) and inflammatory disorders (9%) being the most frequent. In the non-diagnostic group and for the series as a whole non-specific gliosis was the commonest diagnosis (37%). Treatment was altered because of information obtained from neuropathological findings in 11% of cases. To identify changes in practice that may have occurred due to recent advances in clinical assessment and improved histopathological techniques, we performed a follow-up study of 19 brain biopsies (~3 cases/year) carried out for a dementing illness in the same centre between 2004 and 2009. These data suggest that brain biopsy may be less frequently used to help clinical diagnosis whilst its diagnostic yield increased from 57 to 74%. The commonest diagnosis was CJD, mostly suspected during life. Amongst the diagnoses, there were two cases of vasculitis and two cases of primary neurodegenerative dementia. These data suggest that improved clinical selection criteria supported by advances in diagnostic testing may result in brain biopsy being less frequently required, although it may still provide useful diagnostic information in difficult cases. We propose algorithms to aid the clinician in selecting appropriate patients for a biopsy and the neuropathologist in assessing a biopsy specimen.



We are grateful to Dr. Peter Rudge, Dr. Robin Lachmann and Dr. Elaine Murphy for helpful discussions and Dr. Tammaryn Lashley for performing FUS and TDP-43 immunohistochemistry. JMS is a UK HEFCE Lecturer. JDW is in receipt of a Wellcome Intermediate Clinical Fellowship. TR and JLH are recipients of a research grant from the Alzheimer’s Research Trust. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme. The Dementia Research Centre is an Alzheimer’s Research Trust Coordinating Centre.


  1. 1.
    Al-Araji A, Kidd DP (2009) Neuro-Behcet’s disease: epidemiology, clinical characteristics, and management. Lancet Neurol 8:192–204CrossRefPubMedGoogle Scholar
  2. 2.
    Ball M, Braak H, Coleman P et al (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. Neurobiol Aging 18:S1–S2CrossRefGoogle Scholar
  3. 3.
    Basu N, WATTS R, Bajema I et al (2010) EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis. Ann Rheum Dis (Epub ahead of print)Google Scholar
  4. 4.
    Birnbaum J, Hellmann DB (2009) Primary angiitis of the central nervous system. Arch Neurol 66:704–709CrossRefPubMedGoogle Scholar
  5. 5.
    Blennow K, Zetterberg H (2009) Cerebrospinal fluid biomarkers for Alzheimer’s disease. J Alzheimers Dis 18:413–417PubMedGoogle Scholar
  6. 6.
    Brunnstrom H, Dictor M, Nilsson C, Gulich D, Englund E (2009) A 76-year-old man with cognitive and neurological symptoms. Brain Pathol 19:731–734CrossRefPubMedGoogle Scholar
  7. 7.
    Cairns NJ, Bigio EH, Mackenzie IR et al (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22CrossRefPubMedGoogle Scholar
  8. 8.
    Cairns NJ, Zhukareva V, Uryu K et al (2004) Alpha-internexin is present in the pathological inclusions of neuronal intermediate filament inclusion disease. Am J Pathol 164:2153–2161PubMedGoogle Scholar
  9. 9.
    Capellari S, Vital C, Parchi P et al (1997) Familial prion disease with a novel 144-bp insertion in the prion protein gene in a Basque family. Neurology 49:133–141PubMedGoogle Scholar
  10. 10.
    Caselli RJ, Boeve BF, Scheithauer BW, O’Duffy JD, Hunder GG (1999) Nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM): a reversible form of encephalopathy. Neurology 53:1579–1581PubMedGoogle Scholar
  11. 11.
    de Silva R, Lashley T, Gibb G et al (2003) Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies. Neuropathol Appl Neurobiol 29:288–302CrossRefPubMedGoogle Scholar
  12. 12.
    Dickson DW, Fujishiro H, Orr C et al (2009) Neuropathology of non-motor features of Parkinson disease. Parkinsonism Relat Disord 15(Suppl 3):S1–S5CrossRefPubMedGoogle Scholar
  13. 13.
    Dulai MS, Park CY, Howell WD et al (2008) CNS T-cell lymphoma: an under-recognized entity? Acta Neuropathol 115:345–356CrossRefPubMedGoogle Scholar
  14. 14.
    Duna GF, Calabrese LH (1995) Limitations of invasive modalities in the diagnosis of primary angiitis of the central nervous system. J Rheumatol 22:662–667PubMedGoogle Scholar
  15. 15.
    Duna GF, Calabrese LH (2005) Primary angiitis of the central nervous system. In: Kalimo H (ed) Cerebrovascular diseases. ISN Neuropath Press, Basel, pp 147–150Google Scholar
  16. 16.
    Esiri MM, Carter J, Ironside JW (2000) Prion protein immunoreactivity in brain samples from an unselected autopsy population: findings in 200 consecutive cases. Neuropathol Appl Neurobiol 26:273–284CrossRefPubMedGoogle Scholar
  17. 17.
    Geschwind MD, Shu H, Haman A, Sejvar JJ, Miller BL (2008) Rapidly progressive dementia. Ann Neurol 64:97–108CrossRefPubMedGoogle Scholar
  18. 18.
    Graus F, Saiz A, Dalmau J (2010) Antibodies and neuronal autoimmune disorders of the CNS. J Neurol 257:509–517CrossRefPubMedGoogle Scholar
  19. 19.
    Graus F, Saiz A, Lai M et al (2008) Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations. Neurology 71:930–936CrossRefPubMedGoogle Scholar
  20. 20.
    Hainfellner JA, Parchi P, Kitamoto T, Jarius C, Gambetti P, Budka H (1999) A novel phenotype in familial Creutzfeldt–Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein. Ann Neurol 45:812–816CrossRefPubMedGoogle Scholar
  21. 21.
    Hamilton RL (2000) Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 10:378–384CrossRefPubMedGoogle Scholar
  22. 22.
    Hayward PA, Bell JE, Ironside JW (1994) Prion protein immunocytochemistry: reliable protocols for the investigation of Creutzfeldt–Jakob disease. Neuropathol Appl Neurobiol 20:375–383CrossRefPubMedGoogle Scholar
  23. 23.
    Heath CA, Cooper SA, Murray K et al (2010) Validation of diagnostic criteria for variant Creutzfeldt–Jakob disease. Ann Neurol 67:761–770CrossRefPubMedGoogle Scholar
  24. 24.
    Ikemura M, Saito Y, Sengoku R et al (2008) Lewy body pathology involves cutaneous nerves. J Neuropathol Exp Neurol 67:945–953CrossRefPubMedGoogle Scholar
  25. 25.
    Irani SR, Bera K, Waters P et al (2010) N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 133:1655–1667CrossRefPubMedGoogle Scholar
  26. 26.
    Josephs KA, Holton JL, Rossor MN et al (2003) Neurofilament inclusion body disease: a new proteinopathy? Brain 126:2291–2303CrossRefPubMedGoogle Scholar
  27. 27.
    Josephs KA, Rubino FA, Dickson DW (2004) Nonvasculitic autoimmune inflammatory meningoencephalitis. Neuropathology 24:149–152CrossRefPubMedGoogle Scholar
  28. 28.
    Josephs KA, Whitwell JL, Knopman DS et al (2008) Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology 70:1850–1857CrossRefPubMedGoogle Scholar
  29. 29.
    Josephson SA, Papanastassiou AM, Berger MS et al (2007) The diagnostic utility of brain biopsy procedures in patients with rapidly deteriorating neurological conditions or dementia. J Neurosurg 106:72–75CrossRefPubMedGoogle Scholar
  30. 30.
    Kepes JJ, Malone DG, Griffin W, Moral LA, Yarde WL, Jones S (1995) Surgical “touch artefacts” of the cerebral cortex. An experimental study with light and electron microscopic analysis. Clin Neuropathol 14:86–92PubMedGoogle Scholar
  31. 31.
    Lantos PL, Cairns NJ, Khan MN et al (2002) Neuropathologic variation in frontotemporal dementia due to the intronic tau 10(+16) mutation. Neurology 58:1169–1175PubMedGoogle Scholar
  32. 32.
    Lashley T, Ahmed Z, Borroni B et al (2010) FUS pathology in frontotemporal lobar degenerations. Neuropathol Appl Neurobiol 36(Suppl 1):15Google Scholar
  33. 33.
    Lashley T, Holton JL, Gray E et al (2008) Cortical alpha-synuclein load is associated with amyloid-beta plaque burden in a subset of Parkinson’s disease patients. Acta Neuropathol 115:417–425CrossRefPubMedGoogle Scholar
  34. 34.
    Lucantoni C, De BP, Doglietto F et al (2009) Primary cerebral lymphomatoid granulomatosis: report of four cases and literature review. J Neurooncol 94:235–242CrossRefPubMedGoogle Scholar
  35. 35.
    Macfarlane RG, Wroe SJ, Collinge J, Yousry TA, Jager HR (2007) Neuroimaging findings in human prion disease. J Neurol Neurosurg Psychiatry 78:664–670CrossRefPubMedGoogle Scholar
  36. 36.
    Mackenzie IR, Neumann M, Bigio EH et al (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4CrossRefPubMedGoogle Scholar
  37. 37.
    Mackenzie IR, Neumann M, Bigio EH et al (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18CrossRefPubMedGoogle Scholar
  38. 38.
    Massey L, Lashley T, O’Sullivan SS et al (2008) TDP-43 proteinopathy in progressive supranuclear palsy (PSP). Mov Disord 23:100Google Scholar
  39. 39.
    Nakashima-Yasuda H, Uryu K, Robinson J et al (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol (Berl) 114:221–229CrossRefGoogle Scholar
  40. 40.
    Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931CrossRefPubMedGoogle Scholar
  41. 41.
    Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IR (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616CrossRefPubMedGoogle Scholar
  42. 42.
    Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133CrossRefPubMedGoogle Scholar
  43. 43.
    Paisan-Ruiz C, Li A, schneider s, et al. (2010) Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging (in press)Google Scholar
  44. 44.
    Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ (2002) Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology 58:1629–1634PubMedGoogle Scholar
  45. 45.
    Pletnikova O, West N, Lee MK et al (2005) Abeta deposition is associated with enhanced cortical alpha-synuclein lesions in Lewy body diseases. Neurobiol Aging 26:1183–1192CrossRefPubMedGoogle Scholar
  46. 46.
    Ponzoni M, Ferreri AJ (2006) Intravascular lymphoma: a neoplasm of ‘homeless’ lymphocytes? Hematol Oncol 24:105–112CrossRefPubMedGoogle Scholar
  47. 47.
    Reiniger L, Lukic A, Linehan J et al (2010) Tau, prions and Abeta: the triad of neurodegeneration. Acta Neuropathol (Epub ahead of print)Google Scholar
  48. 48.
    Revesz T, Holton JL, Lashley T et al (2009) Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropathol 118:115–130CrossRefPubMedGoogle Scholar
  49. 49.
    Salvarani C, Brown RD Jr, Calamia KT et al (2007) Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 62:442–451CrossRefPubMedGoogle Scholar
  50. 50.
    Scolding NJ (2009) Central nervous system vasculitis. Semin Immunopathol 31:527–536CrossRefPubMedGoogle Scholar
  51. 51.
    Scolding NJ, Joseph F, Kirby PA et al (2005) Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain 128:500–515CrossRefPubMedGoogle Scholar
  52. 52.
    Smith EE, Greenberg SM (2009) Beta-amyloid, blood vessels, and brain function. Stroke 40:2601–2606CrossRefPubMedGoogle Scholar
  53. 53.
    Tofaris GK, Revesz T, Jacques TS, Papacostas S, Chataway J (2007) Adult-onset neurodegeneration with brain iron accumulation and cortical alpha-synuclein and tau pathology: a distinct clinicopathological entity. Arch Neurol 64:280–282CrossRefPubMedGoogle Scholar
  54. 54.
    Uchikado H, Lin WL, DeLucia MW, Dickson DW (2006) Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol 65:685–697CrossRefPubMedGoogle Scholar
  55. 55.
    Uryu K, Nakashima-Yasuda H, Forman MS et al (2008) Concomitant TAR-DNA-Binding Protein 43 Pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67:555–564CrossRefPubMedGoogle Scholar
  56. 56.
    Van Everbroeck B, Boons J, Cras P (2005) Cerebrospinal fluid biomarkers in Creutzfeldt–Jakob disease. Clin Neurol Neurosurg 107:355–360CrossRefPubMedGoogle Scholar
  57. 57.
    Vanier MT (2010) Niemann–Pick disease type C. Orphanet J Rare Dis 5:16 (Epub ahead of print)Google Scholar
  58. 58.
    Vincent A, Buckley C, Schott JM et al (2004) Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 127:701–712CrossRefPubMedGoogle Scholar
  59. 59.
    Wadsworth JD, Powell C, Beck JA et al (2008) Molecular diagnosis of human prion disease. Methods Mol Biol 459:197–227CrossRefPubMedGoogle Scholar
  60. 60.
    Warren JD, Schott JM, Fox NC et al (2005) Brain biopsy in dementia. Brain 128:2016–2025CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Jonathan M. Schott
    • 1
  • Lilla Reiniger
    • 2
  • Maria Thom
    • 2
  • Janice L. Holton
    • 2
  • Joan Grieve
    • 3
  • Sebastian Brandner
    • 2
  • Jason D. Warren
    • 1
  • Tamas Revesz
    • 2
  1. 1.Dementia Research CentreThe National Hospital for Neurology and NeurosurgeryLondonUK
  2. 2.Division of Neuropathology, UCL Institute of NeurologyUniversity College LondonLondonUK
  3. 3.Department of NeurosurgeryThe National Hospital for Neurology and NeurosurgeryLondonUK

Personalised recommendations