Top

Published in:

Open Access 01-11-2019 | Alzheimer's Disease | Original Paper

Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85+

Authors: Anna Raunio, Karri Kaivola, Jarno Tuimala, Mia Kero, Minna Oinas, Tuomo Polvikoski, Anders Paetau, Pentti J. Tienari, Liisa Myllykangas

Published in: Acta Neuropathologica | Issue 5/2019

Abstract

According to a generally accepted concept Lewy-related pathology (LRP) follows hierarchical caudo-rostral progression. LRP is also frequently present concomitantly with Alzheimer’s disease (AD), and it has been hypothesized that AD-associated LRP forms a distinct type of α-synucleinopathy, where LRP originates in the amygdala. The frequency of distinct forms of LRP progression types has not been studied in a population-based setting. We investigated the distribution and progression of LRP and its relation to AD pathology and apolipoprotein (APOE) ε4 in a population-based sample of Finns aged over 85 years (N = 304). Samples from spinal cord to neocortical areas representing 11 anatomical sites without any hierarchical selection were analyzed immunohistochemically (α-synuclein antibody clone 5G4). LRP was present in 124 individuals (41%) and according to DLB Consortium guidelines 19 of them were categorized as brainstem, 10 amygdala-predominant, 41 limbic, and 43 diffuse neocortical type, whereas 11 could not be classified. To determine the LRP progression patterns, a systematic anatomical scoring was carried out by taking into account the densities of the semiquantitative LRP scores in each anatomic site. With this scoring 123 (99%) subjects could be classified into two progression pattern types: 67% showed caudo-rostral and 32% amygdala-based progression. The unsupervised statistical K-means cluster analysis was used as a supplementary test and supported the presence of two progression patterns and had a 90% overall concordance with the systematic anatomical scoring method. Severe Braak NFT stage, high CERAD score and APOE ε4 were significantly (all p < 0.00001) associated with amygdala-based, but not with caudo-rostral progression type (all p > 0.2). This population-based study demonstrates two distinct common LRP progression patterns in the very elderly population. The amygdala-based pattern was associated with APOE ε4 and AD pathology. The results confirm the previous progression hypotheses but also widen the concept of the AD-associated LRP.

Available only for authorised users

Alafuzoff I, Ince PG, Arzberger T, Al-Sarraj S, Bell J, Bodi I et al (2009) Staging/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe Consortium. Acta Neuropathol 117:635–652. https://doi.org/10.1007/s00401-009-0523-2 CrossRefPubMed

Arai Y, Yamazaki M, Mori O, Muramatsu H, Asano G, Katayama Y (2001) Alpha-synuclein-positive structures in cases with sporadic Alzheimer’s disease: morphology and its relationship to tau aggregation. Brain Res 888:287–296CrossRefPubMed

Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL et al (2010) Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119:689–702. https://doi.org/10.1007/s00401-010-0664-3 CrossRefPubMedPubMedCentral

Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelman M, Myers AJ et al (2014) Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias. PLoS Genet 10:e1004606. https://doi.org/10.1371/journal.pgen.1004606 CrossRefPubMedPubMedCentral

Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259CrossRef

Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211CrossRefPubMed

Bras J, Guerreiro R, Darwent L, Parkkinen L, Ansorge O, Escott-Price V, Hernandez DG et al (2014) Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum Mol Genet 23:6139–6146. https://doi.org/10.1093/hmg/ddu334 CrossRefPubMedPubMedCentral

Cersosimo MG (2018) Propagation of alpha-synuclein pathology from the olfactory bulb: possible role in the pathogenesis of dementia with Lewy bodies. Cell Tissue Res 373:233–243. https://doi.org/10.1007/s00441-017-2733-6 CrossRefPubMed

Dickson DW, Heckman MG, Murray ME, Soto AI, Walton RL, Diehl NN et al (2018) APOE ε4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology 91:e1182–e1195. https://doi.org/10.1212/wnl.0000000000006212 CrossRefPubMedPubMedCentral

10.

Dickson DW, Ruan D, Crystal H, Mark MH, Davies P, Kress Y et al (1991) Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer’s disease: light and electron microscopic immunocytochemistry of CA2-3 neurites specific to DLBD. Neurology 41:1402–1409CrossRefPubMed

11.

Dickson DW, Uchikado H, Fujishiro H, Tsuboi Y (2010) Evidence in favor of Braak staging of Parkinson’s disease. Mov Disord 25(Suppl 1):78. https://doi.org/10.1002/mds.22637 CrossRef

12.

Dugger BN, Dickson DW (2017) Pathology of neurodegenerative diseases. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a028035.a028035 CrossRefPubMedPubMedCentral

13.

Fujishiro H, Ferman TJ, Boeve BF, Smith GE, Graff-Radford NR, Uitti RJ et al (2008) Validation of the neuropathologic criteria of the third consortium for dementia with Lewy bodies for prospectively diagnosed cases. J Neuropathol Exp Neurol 67:649–656. https://doi.org/10.1097/NEN.0b013e31817d7a1d CrossRefPubMedPubMedCentral

14.

Goedert M, Spillantini MG, Del Tredici K, Braak H (2013) 100 years of Lewy pathology. Nat Rev Neurol 9:13–24. https://doi.org/10.1038/nrneurol.2012.242 CrossRefPubMed

15.

Guerreiro R, Escott-Price V, Darwent L, Parkkinen L, Ansorge O, Hernandez DG, Nalls MA et al (2016) Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson’s and Alzheimer’s diseases. Neurobiol Aging 38:214.e7–214.e10. https://doi.org/10.1016/j.neurobiolaging.2015.10.028 CrossRef

16.

Guerreiro R, Escott-Price V, Hernandez DG, Kun-Rodrigues C, Ross OA, Orme T et al (2019) Heritability and genetic variance of dementia with Lewy bodies. Neurobiol Dis 127:492–501. https://doi.org/10.1016/j.nbd.2019.04.004 CrossRefPubMed

17.

Guerreiro R, Ross OA, Kun-Rodrigues C, Hernandez DG, Orme T, Eicher JD et al (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64–74. https://doi.org/10.1016/s1474-4422(17)30400-3 CrossRefPubMed

18.

Hamilton RL (2000) Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 10:378–384CrossRefPubMed

19.

Hyman BT, Trojanowski JQ (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 56:1095–1097. https://doi.org/10.1097/00005072-199710000-00002 CrossRefPubMed

20.

Irwin DJ, Grossman M, Weintraub D, Hurtig HI, Duda JE, Xie SX et al (2017) Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis. Lancet Neurol 16:55–65. https://doi.org/10.1016/S1474-4422(16)30291-5 CrossRefPubMedPubMedCentral

21.

Jellinger KA (2018) Dementia with Lewy bodies and Parkinson’s disease-dementia: current concepts and controversies. J Neural Transm (Vienna) 125:615–650. https://doi.org/10.1007/s00702-017-1821-9 CrossRef

22.

Ketchen DJ, Shook CL (1996) The application of cluster analysis in strategic management research: an analysis and critique. Strateg Manag J 17:441–458. https://doi.org/10.1002/(sici)1097-0266(199606)17:6%3c441:Aid-smj819%3e3.0.Co;2-g CrossRef

23.

Kosaka K, Yoshimura M, Ikeda K, Budka H (1984) Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree—a new disease? Clin Neuropathol 3:185–192PubMed

24.

Kovacs GG, Breydo L, Green R, Kis V, Puska G, Lorincz P et al (2014) Intracellular processing of disease-associated alpha-synuclein in the human brain suggests prion-like cell-to-cell spread. Neurobiol Dis 69:76–92. https://doi.org/10.1016/j.nbd.2014.05.020 CrossRefPubMed

25.

Kovacs GG, Wagner U, Dumont B, Pikkarainen M, Osman AA, Streichenberger N et al (2012) An antibody with high reactivity for disease-associated alpha-synuclein reveals extensive brain pathology. Acta Neuropathol 124:37–50. https://doi.org/10.1007/s00401-012-0964-x CrossRefPubMed

26.

McKeith I, Cummings J (2005) Behavioural changes and psychological symptoms in dementia disorders. Lancet Neurol 4:735–742. https://doi.org/10.1016/s1474-4422(05)70219-2 CrossRefPubMed

27.

McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D et al (2017) Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology 89:88–100. https://doi.org/10.1212/WNL.0000000000004058 CrossRefPubMedPubMedCentral

28.

McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872. https://doi.org/10.1212/01.wnl.0000187889.17253.b1 CrossRefPubMed

29.

McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA et al (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113–1124CrossRef

30.

Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM et al (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486CrossRefPubMed

31.

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. https://doi.org/10.1016/S1474-4422(11)70156-9 CrossRefPubMedPubMedCentral

32.

Myllykangas L, Polvikoski T, Sulkava R, Verkkoniemi A, Crook R, Tienari PJ et al (1999) Genetic association of alpha2-macroglobulin with Alzheimer’s disease in a Finnish elderly population. Ann Neurol 46:382–390CrossRefPubMed

33.

Oinas M, Polvikoski T, Sulkava R, Myllykangas L, Juva K, Notkola IL et al (2009) Neuropathologic findings of dementia with Lewy bodies (DLB) in a population-based Vantaa 85+ study. J Alzheimers Dis 18:677–689. https://doi.org/10.3233/JAD-2009-1169 CrossRefPubMed

34.

Outeiro TF, Koss DJ, Erskine D, Walker L, Kurzawa-Akanbi M, Burn D et al (2019) Dementia with Lewy bodies: an update and outlook. Mol Neurodegener 14:5. https://doi.org/10.1186/s13024-019-0306-8 CrossRefPubMedPubMedCentral

35.

Peuralinna T, Myllykangas L, Oinas M, Nalls MA, Keage HA, Isoviita VM et al (2015) Genome-wide association study of neocortical Lewy-related pathology. Ann Clin Transl Neurol 2:920–931. https://doi.org/10.1002/acn3.231 CrossRefPubMedPubMedCentral

36.

Peuralinna T, Tanskanen M, Mäkelä M, Polvikoski T, Paetau A, Kalimo H et al (2011) APOE and AβPP gene variation in cortical and cerebrovascular amyloid-β pathology and Alzheimer’s disease: a population-based analysis. J Alzheimers Dis 26:377–385. https://doi.org/10.3233/JAD-2011-102049 CrossRefPubMedPubMedCentral

37.

Polvikoski T, Sulkava R, Myllykangas L, Notkola IL, Niinisto L, Verkkoniemi A et al (2001) Prevalence of Alzheimer’s disease in very elderly people: a prospective neuropathological study. Neurology 56:1690–1696CrossRefPubMed

38.

Rahimi J, Kovacs GG (2014) Prevalence of mixed pathologies in the aging brain. Alzheimers Res Ther. https://doi.org/10.1186/s13195-014-0082-1 CrossRefPubMedPubMedCentral

39.

Raunio A, Myllykangas L, Kero M, Polvikoski T, Paetau A, Oinas M (2017) Amygdala alpha-synuclein pathology in the population-based Vantaa 85+ study. J Alzheimers Dis 58:669–674. https://doi.org/10.3233/JAD-170104 CrossRefPubMedPubMedCentral

40.

Sabir MS, Blauwendraat C, Ahmed S, Serrano GE, Beach TG, Perkins M et al (2019) Assessment of APOE in atypical parkinsonism syndromes. Neurobiol Dis 127:142–146. https://doi.org/10.1016/j.nbd.2019.02.016 CrossRefPubMed

41.

Toledo JB, Gopal P, Raible K, Irwin DJ, Brettschneider J, Sedor S et al (2016) Pathological α-synuclein distribution in subjects with coincident Alzheimer’s and Lewy body pathology. Acta Neuropathol 131:393–409. https://doi.org/10.1007/s00401-015-1526-9 CrossRefPubMed

42.

Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA et al (2013) APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurol 70:223–228. https://doi.org/10.1001/jamaneurol.2013.600 CrossRefPubMedPubMedCentral

43.

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 65:685–697. https://doi.org/10.1097/01.jnen.0000225908.90052.07 CrossRefPubMedPubMedCentral

44.

Vann Jones SA, O’Brien JT (2014) The prevalence and incidence of dementia with Lewy bodies: a systematic review of population and clinical studies. Psychol Med 44:673–683. https://doi.org/10.1017/S0033291713000494 CrossRefPubMed

45.

Walker Z, Possin KL, Boeve BF, Aarsland D (2015) Lewy body dementias. Lancet 386:1683–1697. https://doi.org/10.1016/S0140-6736(15)00462-6 CrossRefPubMedPubMedCentral

46.

Wu Y-T, Beiser AS, Breteler MMB, Fratiglioni L, Helmer C, Hendrie HC et al (2017) The changing prevalence and incidence of dementia over time–current evidence. Nat Rev Neurol 13:327–339. https://doi.org/10.1038/nrneurol.2017.63 CrossRefPubMed

47.

Zaccai J, Brayne C, McKeith I, Matthews F, Ince PG (2008) Patterns and stages of alpha-synucleinopathy: relevance in a population-based cohort. Neurology 70:1042–1048. https://doi.org/10.1212/01.wnl.0000306697.48738.b6 CrossRefPubMed

Title: Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85+
Authors: Anna Raunio
Karri Kaivola
Jarno Tuimala
Mia Kero
Minna Oinas
Tuomo Polvikoski
Anders Paetau
Pentti J. Tienari
Liisa Myllykangas
Publication date: 01-11-2019
Publisher: Springer Berlin Heidelberg
Keywords: Alzheimer's Disease
Dementia
Alzheimer's Disease
Pathology
Dementia
Published in: Acta Neuropathologica / Issue 5/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02071-3

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85+

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2019

C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy

Splicing repression is a major function of TDP-43 in motor neurons

Routine RNA sequencing of formalin-fixed paraffin-embedded specimens in neuropathology diagnostics identifies diagnostically and therapeutically relevant gene fusions

On the journey to uncover the causes of selective cellular and regional vulnerability in neurodegeneration

Increased prevalence of granulovacuolar degeneration in C9orf72 mutation

The basis of clinicopathological heterogeneity in TDP-43 proteinopathy