Top

Published in:

Open Access 01-05-2015 | Position Paper

PART is part of Alzheimer disease

Authors: Charles Duyckaerts, Heiko Braak, Jean-Pierre Brion, Luc Buée, Kelly Del Tredici, Michel Goedert, Glenda Halliday, Manuela Neumann, Maria Grazia Spillantini, Markus Tolnay, Toshiki Uchihara

Published in: Acta Neuropathologica | Issue 5/2015

Abstract

It has been proposed that tau aggregation confined to entorhinal cortex and hippocampus, with no or only minimal Aβ deposition, should be considered as a ‘primary age-related tauopathy’ (PART) that is not integral to the continuum of sporadic Alzheimer disease (AD). Here, we examine the evidence that PART has a pathogenic mechanism and a prognosis which differ from those of AD. We contend that no specific property of the entorhinal–hippocampal tau pathology makes it possible to predict either a limited progression or the development of AD, and that biochemical differences await an evidence base. On the other hand, entorhinal–hippocampal tau pathology is an invariant feature of AD and is always associated with its development. Rather than creating a separate disease entity, we recommend the continued use of an analytical approach based on NFT stages and Aβ phases with no inference about hypothetical disease processes.

Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404. doi:10.1007/s00401-006-0127-z CrossRefPubMedCentralPubMed

Braak H, Braak E (1992) The human entorhinal cortex: normal morphology and lamina-specific pathology in various diseases. Neurosci Res 15:6–31CrossRefPubMed

Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969. doi:10.1097/NEN.0b013e318232a379 CrossRefPubMed

Braak H, Del Tredici K (2014) Are cases with tau pathology occurring in the absence of Aβ deposits part of the AD-related pathological process? Acta Neuropathol 128:767–772. doi:10.1007/s00401-014-1356-1 CrossRefPubMed

Braak H, Del Tredici K (2015) Neuroanatomy and pathology of sporadic Alzheimer’s Disease. Adv Anat Embryol Cell Biol 215:1–162. doi:10.1007/978-3-319-12679-1 CrossRefPubMed

Clavaguera F, Akatsu H, Fraser G, Crowther Ra, Frank S, Hench J, Probst A, Winkler DT, Reichwald J, Staufenbiel M, Ghetti B, Goedert M, Tolnay M (2013) Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci 110:9535–9540. doi:10.1073/pnas.1301175110 CrossRefPubMedCentralPubMed

Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913. doi:10.1038/ncb1901 CrossRefPubMedCentralPubMed

Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, Arnold SE, Attems J, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Gearing M, Grinberg LT, Hof PR, Hyman BT, Jellinger K, Jicha GA, Kovacs GG, Knopman DS, Kofler J, Kukull WA, Mackenzie IR, Masliah E, Mckee A, Montine TJ, Murray ME, Neltner JH, Santa-maria I, Seeley W, Serrano-Pozo A, Shelanski ML, Stein T, Takao M, Thal DR, Toledo JB, Troncoso JC, Vonsattel JP, White CL 3rd, Wisniewski T, Woltjer RL, Yamada M, Nelson PT (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128:755–766. doi:10.1007/s00401-014-1349-0 CrossRefPubMed

Delacourte A, Sergeant N, Champain D, Wattez A, Maurage CA, Lebert F, Pasquier F, David JP (2002) Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer’s disease. Neurology 59:398–407CrossRefPubMed

10.

Delaère P, He Y, Fayet G, Duyckaerts C, Hauw J-J (1993) ßA4 deposits are constant in the brain of the oldest old : an immunocytochemical study of 20 French centenarians. Neurobiol Aging 14:191–194CrossRefPubMed

11.

Dugger BN, Hidalgo JA, Chiarolanza G, Mariner M, Henry-Watson J, Sue LI, Beach TG (2013) The distribution of phosphorylated tau in spinal cords of Alzheimer’s disease and non-demented individuals. J Alzheimers Dis 34:529–536. doi:10.3233/JAD-121864 PubMedCentralPubMed

12.

Dujardin S, Lécolle K, Caillierez R, Bégard S, Zommer N, Lachaud C, Carrier S, Dufour N, Aurégan G, Winderickx J, Hantraye P, Déglon N, Colin M, Buée L (2014) Neuron-to-neuron wild-type tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies. Acta Neuropathol Commun 2:14. doi:10.1186/2051-5960-2-14 CrossRefPubMedCentralPubMed

13.

Elbaz A, Ross OA, Ioannidis JPA, Soto-Ortolaza AI, Moisan F, Aasly J, Annesi G, Bozi M, Brighina L, Chartier-Harlin M-C, Destée A, Ferrarese C, Ferraris A, Gibson JM, Gispert S, Hadjigeorgiou GM, Jasinska-Myga B, Klein C, Krüger R, Lambert J-C, Lohmann K, van de Loo S, Loriot M-A, Lynch T, Mellick GD, Mutez E, Nilsson C, Opala G, Puschmann A, Quattrone A, Sharma M, Silburn PA, Stefanis L, Uitti RJ, Valente EM, Vilariño-Güell C, Wirdefeldt K, Wszolek ZK, Xiromerisiou G, Maraganore DM, Farrer MJ (2011) Independent and joint effects of the MAPT and SNCA genes in Parkinson disease. Ann Neurol 69:778–792. doi:10.1002/ana.22321 CrossRefPubMedCentralPubMed

14.

Ghebremedhin E, Schultz C, Braak E, Braak H (1998) High frequency of apolipoprotein E ε4 allele in young individuals with very mild Alzheimer’ s disease-related neurofibrillary changes. Exp Neurol 155:152–155CrossRef

15.

Goedert M, Falcon B, Clavaguera F, Tolnay M (2014) Prion-like mechanisms in the pathogenesis of tauopathies and synucleinopathies. Curr Neurol Neurosci Rep 14:495. doi:10.1007/s11910-014-0495-z CrossRefPubMed

16.

Grinberg LT, Rüb U, Ferretti REL, Nitrini R, Farfel JM, Polichiso L, Gierga K, Jacob-Filho W, Heinsen H (2009) The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer’s disease. A precocious onset? Neuropathol Appl Neurobiol 35:406–416. doi:10.1111/j.1365-2990.2009.00997.x CrossRefPubMed

17.

Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8:1–13. doi:10.1016/j.jalz.2011.10.007 CrossRefPubMedCentralPubMed

18.

Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM-Y (2013) Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J Neurosci 33:1024–1037. doi:10.1523/JNEUROSCI.2642-12.2013 CrossRefPubMedCentralPubMed

19.

Jack CR (2014) PART and SNAP. Acta Neuropathol 128:773–776. doi:10.1007/s00401-014-1362-3 CrossRef

20.

Jack CR, Wiste HJ, Weigand SD, Rocca WA, Knopman DS, Mielke MM, Lowe VJ, Senjem ML, Gunter JL, Preboske GM, Pankratz VS, Vemuri P, Petersen RC (2014) Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50–89 years: a cross-sectional study. Lancet Neurol 13:997–1005. doi:10.1016/S1474-4422(14)70194-2 CrossRefPubMed

21.

Knopman DS, Jack CR, Wiste HJ, Weigand SD, Vemuri P, Lowe VJ, Kantarci K, Gunter JL, Senjem ML, Mielke MM, Roberts RO, Boeve BF, Petersen RC (2013) Brain injury biomarkers are not dependent on β-amyloid in normal elderly. Ann Neurol 73:472–480. doi:10.1002/ana.23816 CrossRefPubMedCentralPubMed

22.

Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV, Hyman BT (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11. doi:10.1007/s00401-011-0910-3 CrossRefPubMedCentralPubMed

23.

Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW (2011) Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol 10:785–796. doi:10.1016/S1474-4422(11)70156-9 CrossRefPubMedCentralPubMed

24.

Myers AJ, Kaleem M, Marlowe L, Pittman AM, Lees AJ, Fung HC, Duckworth J, Leung D, Gibson A, Morris CM, de Silva R, Hardy J (2005) The H1c haplotype at the MAPT locus is associated with Alzheimer’s disease. Hum Mol Genet 14:2399–2404. doi:10.1093/hmg/ddi241 CrossRefPubMed

25.

Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292. doi:10.1016/j.jalz.2011.03.003 CrossRefPubMedCentralPubMed

26.

Thal DR, Rüb U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800CrossRefPubMed

27.

Wider C, Ross OA, Nishioka K, Heckman MG, Vilariño-Güell C, Jasinska-Myga B, Erketin-Taner N, Rademakers R, Graff-Radford NR, Mash DC, Papapetropoulos S, Duara R, Uchikado H, Wszolek ZK, Farrer MJ, Dickson DW (2012) An evaluation of the impact of MAPT, SNCA and APOE on the burden of Alzheimer’s and Lewy body pathology. J Neurol Neurosurg Psychiatry 83:424–429. doi:10.1136/jnnp-2011-301413 CrossRefPubMedCentralPubMed

Title: PART is part of Alzheimer disease
Authors: Charles Duyckaerts
Heiko Braak
Jean-Pierre Brion
Luc Buée
Kelly Del Tredici
Michel Goedert
Glenda Halliday
Manuela Neumann
Maria Grazia Spillantini
Markus Tolnay
Toshiki Uchihara
Publication date: 01-05-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 5/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-015-1390-7

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

PART is part of Alzheimer disease

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2015

Does the difference between PART and Alzheimer’s disease lie in the age-related changes in cerebral arteries that trigger the accumulation of Aβ and propagation of tau?

Neuropathologically mixed Alzheimer’s and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes

The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients

Acknowledgement to referees

Soluble VCAM-1 impairs human brain endothelial barrier integrity via integrin α-4-transduced outside-in signalling

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups