Parietal white matter lesions in Alzheimer’s disease are associated with cortical neurodegenerative pathology, but not with small vessel disease

Kirsty E. McAleese, Lauren Walker, Sophie Graham, Elisa L.J. Moya, Mary Johnson, Daniel Erskine, Sean J. Colloby, Madhurima Dey, Carmen Martin-Ruiz, John Paul Taylor, Alan J. Thomas, Ian G. McKeith, Charles DeCarli, Johannes Attems

Research output: Contribution to journalArticle

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Abstract

Cerebral white matter lesions (WML) encompass axonal loss and demyelination, and the pathogenesis is assumed to be small vessel disease (SVD)-related ischemia. However, WML may also result from the activation of Wallerian degeneration as a consequence of cortical Alzheimer’s disease (AD) pathology, i.e. hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) deposition. WML seen in AD have a posterior predominance compared to non-demented individuals but it is unclear whether the pathological and molecular signatures of WML differ between these two groups. We investigated differences in the composition and aetiology of parietal WML from AD and non-demented controls. Parietal WML tissue from 55 human post-mortem brains (AD, n = 27; non-demented controls, n = 28) were quantitatively assessed for axonal loss and demyelination, as well as for cortical HPτ and Aβ burden and SVD. Biochemical assessment included Wallerian degeneration protease calpain and the myelin-associated glycoprotein (MAG) to proteolipid protein (PLP) ratio (MAG:PLP) as a measure of hypoperfusion. WML severity was associated with both axonal loss and demyelination in AD, but only with demyelination in controls. Calpain was significantly increased in WML tissue in AD, whereas MAG:PLP was significantly reduced in controls. Calpain levels were associated with increasing amounts of cortical AD-pathology but not SVD. We conclude that parietal WML seen in AD differ in their pathological composition and aetiology compared to WML seen in aged controls: WML seen in AD may be associated with Wallerian degeneration that is triggered by cortical AD-pathology, whereas WML in aged controls are due to ischaemia. Hence, parietal WML as seen on MRI should not invariably be interpreted as a surrogate biomarker for SVD as they may be indicative of cortical AD-pathology, and therefore, AD should also be considered as the main underlying cause for cognitive impairment in cases with parietal WML.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Jun 21 2017

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Alzheimer Disease
Pathology
Myelin-Associated Glycoprotein
Demyelinating Diseases
Wallerian Degeneration
Proteolipids
Calpain
White Matter
Ischemia
Proteins
Brain Diseases
Amyloid
Peptide Hydrolases
Biomarkers

Keywords

  • Alzheimer’s disease
  • Hyperphosphorylated tau
  • Small vessel disease
  • Wallerian degeneration
  • White matter hyperintensity
  • White matter lesion

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Parietal white matter lesions in Alzheimer’s disease are associated with cortical neurodegenerative pathology, but not with small vessel disease. / McAleese, Kirsty E.; Walker, Lauren; Graham, Sophie; Moya, Elisa L.J.; Johnson, Mary; Erskine, Daniel; Colloby, Sean J.; Dey, Madhurima; Martin-Ruiz, Carmen; Taylor, John Paul; Thomas, Alan J.; McKeith, Ian G.; DeCarli, Charles; Attems, Johannes.

In: Acta Neuropathologica, 21.06.2017, p. 1-15.

Research output: Contribution to journalArticle

McAleese, KE, Walker, L, Graham, S, Moya, ELJ, Johnson, M, Erskine, D, Colloby, SJ, Dey, M, Martin-Ruiz, C, Taylor, JP, Thomas, AJ, McKeith, IG, DeCarli, C & Attems, J 2017, 'Parietal white matter lesions in Alzheimer’s disease are associated with cortical neurodegenerative pathology, but not with small vessel disease', Acta Neuropathologica, pp. 1-15. https://doi.org/10.1007/s00401-017-1738-2
McAleese, Kirsty E. ; Walker, Lauren ; Graham, Sophie ; Moya, Elisa L.J. ; Johnson, Mary ; Erskine, Daniel ; Colloby, Sean J. ; Dey, Madhurima ; Martin-Ruiz, Carmen ; Taylor, John Paul ; Thomas, Alan J. ; McKeith, Ian G. ; DeCarli, Charles ; Attems, Johannes. / Parietal white matter lesions in Alzheimer’s disease are associated with cortical neurodegenerative pathology, but not with small vessel disease. In: Acta Neuropathologica. 2017 ; pp. 1-15.
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AU - Martin-Ruiz, Carmen

AU - Taylor, John Paul

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