Cortical microstructural abnormalities in dementia with Lewy bodies and their associations with Alzheimer's disease copathologies

Elijah Mak; Robert I Reid; Scott A Przybelski; Angela J Fought; Timothy G Lesnick; Christopher G Schwarz; Matthew L Senjem; Sheelakumari Raghavan; Prashanthi Vemuri; Clifford R Jack Jr; Hoon Ki Min; Manoj K Jain; Toji Miyagawa; Leah K Forsberg; Julie A Fields; Rodolfo Savica; Jonathan Graff-Radford; David T Jones; Hugo Botha; Erik K St Louis; David S Knopman; Vijay K Ramanan; Dennis W Dickson; Neill R Graff-Radford; Gregory S Day; Tanis J Ferman; Ronald C Petersen; Val J Lowe; Bradley F Boeve; John T O'Brien; Kejal Kantarci

doi:10.1038/s41531-025-00944-x

Cortical microstructural abnormalities in dementia with Lewy bodies and their associations with Alzheimer's disease copathologies

NPJ Parkinsons Dis. 2025 May 12;11(1):124. doi: 10.1038/s41531-025-00944-x.

Authors

Elijah Mak^{1

2}, Robert I Reid^{3

4}, Scott A Przybelski⁵, Angela J Fought⁵, Timothy G Lesnick⁵, Christopher G Schwarz³, Matthew L Senjem^{3

4}, Sheelakumari Raghavan³, Prashanthi Vemuri³, Clifford R Jack Jr³, Hoon Ki Min³, Manoj K Jain⁶, Toji Miyagawa⁷, Leah K Forsberg⁷, Julie A Fields⁸, Rodolfo Savica⁷, Jonathan Graff-Radford⁷, David T Jones⁷, Hugo Botha⁷, Erik K St Louis^{7

8

9}, David S Knopman⁷, Vijay K Ramanan⁷, Dennis W Dickson¹⁰, Neill R Graff-Radford¹¹, Gregory S Day¹¹, Tanis J Ferman¹², Ronald C Petersen^{5

7}, Val J Lowe³, Bradley F Boeve⁷, John T O'Brien¹³, Kejal Kantarci³

Affiliations

¹ Department of Radiology, Mayo Clinic, Rochester, MN, USA. mak.elijah@mayo.edu.
² Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. mak.elijah@mayo.edu.
³ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
⁴ Department of Information Technology, Mayo Clinic, Rochester, MN, USA.
⁵ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
⁶ Department of Radiology, Mayo Clinic, Jacksonville, FL, USA.
⁷ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁸ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
⁹ Center for Sleep Medicine, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
¹⁰ Laboratory of Medicine and Pathology, Mayo Clinic in Florida, Jacksonville, FL, USA.
¹¹ Department of Neurology, Mayo Clinic in Florida, Jacksonville, FL, USA.
¹² Department of Psychiatry and Psychology, Mayo Clinic in Florida, Jacksonville, FL, USA.
¹³ Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.

Abstract

Dementia with Lewy bodies (DLB) frequently coexists with Alzheimer's disease pathology, yet the pattern of cortical microstructural injury and its relationship with amyloid, tau, and cerebrovascular pathologies remains unclear. We applied neurite orientation dispersion and density imaging (NODDI) to assess cortical microstructural integrity in 57 individuals within the DLB spectrum and 57 age- and sex-matched cognitively unimpaired controls by quantifying mean diffusivity (MD), tissue-weighted neurite density index (tNDI), orientation dispersion index (ODI), and free water fraction (FWF). Amyloid and tau levels were measured using PiB and Flortaucipir PET imaging. Compared to controls, DLB exhibited increased MD and FWF, reduced tNDI across multiple regions, and focal ODI reductions in the occipital cortex. Structural equation modeling revealed that APOE genotype influenced amyloid levels, which elevated tau, leading to microstructural injury. These findings highlight the role of AD pathology in DLB neurodegeneration, advocating for multi-target therapeutic approaches addressing both AD and DLB-specific pathologies.

Abstract

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