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. 2021 Sep:105:252-261.
doi: 10.1016/j.neurobiolaging.2021.04.029. Epub 2021 May 14.

Cerebrovascular disease, neurodegeneration, and clinical phenotype in dementia with Lewy bodies

Daniel Ferreira  1 , Zuzana Nedelska  2 , Jonathan Graff-Radford  3 , Scott A Przybelski  4 , Timothy G Lesnick  4 , Christopher G Schwarz  5 , Hugo Botha  3 , Matthew L Senjem  6 , Julie A Fields  7 , David S Knopman  3 , Rodolfo Savica  3 , Tanis J Ferman  8 , Neill R Graff-Radford  9 , Val J Lowe  5 , Clifford R Jack  5 , Ronald C Petersen  3 , Afina W Lemstra  10 , Marleen van de Beek  10 , Frederik Barkhof  11 , Frederic Blanc  12 , Paulo Loureiro de Sousa  12 , Nathalie Philippi  12 , Benjamin Cretin  12 , Catherine Demuynck  12 , Jakub Hort  13 , Ketil Oppedal  14 , Bradley F Boeve  3 , Dag Aarsland  15 , Eric Westman  16 , Kejal Kantarci  17
Affiliations

Cerebrovascular disease, neurodegeneration, and clinical phenotype in dementia with Lewy bodies

Daniel Ferreira et al. Neurobiol Aging. 2021 Sep.

Abstract

We investigated whether cerebrovascular disease contributes to neurodegeneration and clinical phenotype in dementia with Lewy bodies (DLB). Regional cortical thickness and subcortical gray matter volumes were estimated from structural magnetic resonance imaging (MRI) in 165 DLB patients. Cortical and subcortical infarcts were recorded and white matter hyperintensities (WMHs) were assessed. Subcortical only infarcts were more frequent (13.3%) than cortical only infarcts (3.1%) or both subcortical and cortical infarcts (2.4%). Infarcts, irrespective of type, were associated with WMHs. A higher WMH volume was associated with thinner orbitofrontal, retrosplenial, and posterior cingulate cortices, smaller thalamus and pallidum, and larger caudate volume. A higher WMH volume was associated with the presence of visual hallucinations and lower global cognitive performance, and tended to be associated with the absence of probable rapid eye movement sleep behavior disorder. Presence of infarcts was associated with the absence of parkinsonism. We conclude that cerebrovascular disease is associated with gray matter neurodegeneration in patients with probable DLB, which may have implications for the multifactorial treatment of probable DLB.

Keywords: Cerebrovascular disease; Dementia with Lewy bodies (DLB); Magnetic resonance imaging; Neurodegeneration; White matter hyperintensities; infarcts.

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Conflict of interest statement

CONFLICTS OF INTEREST

D Ferreira, SA Przybelski, TG Lesnick, AW Lemstra, Z Nedelska, CG Schwarz, H Botha, ML Senjem, JA Fields, DS Knopman, R Savica, NR Graff-Radford, RC Petersen, J Hort, K Oppedal, and E Westman report no disclosures relevant to the manuscript. J Graff-Radford receives research support from NIH. T Ferman receives funding from the Mangurian Foundation for Lewy body research and NIH. VJ Lowe serves as a consultant for AVID Radiopharmaceuticals, Bayer Schering Pharma, Eisai Inc, Philips Molecular Imaging, and Piramal Imaging and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, the NIH (NIA, NCI), and the MN Partnership for Biotechnology and Medical Genomics. CR Jack has consulted for Lily, serves on an independent data monitoring board for Roche, and as a speaker for Eisai, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. F Blanc, has served as national coordinator and principal investigator for clinical trials sponsored by Biogen, Roche, Axovant and Eisai. BF Boeve has served as an investigator for clinical trials sponsored by Biogen and Alector. He receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program and the Little Family Foundation. D Aarsland has received research support and/or honoraria from AstraZeneca, H. Lundbeck, Novartis Pharmaceuticals and GE Health, and served as paid consultant for H. Lundbeck, Eisai and Evonik. K Kantarci serves on the data safety monitoring board for Takeda Global Research and Development Center, Inc.; receives research support from Avid Radiopharmaceuticals and Eli Lilly, and receives funding from NIH and Alzheimer’s Drug Discovery Foundation.

Figures

Figure 1.
Figure 1.. Visual examples of mild, moderate, and severe WMH burden
The mild WMH burden category includes the two lower volume categories corresponding to WMHs 1 to 7 cm3 large (first volume category), and WMHs 8 to 17 cm3 large (second volume category). The moderate WMH burden category includes the two intermediate volume categories corresponding to WMHs 18 to 23 cm3 large (third volume category), and WMHs 24 to 35 cm3 large (fourth volume category). The severe WMH burden category includes the two higher volume categories corresponding to WMHs 36 to 47 cm3 large (fifth volume category), and WMHs 48 cm3 or larger (sixth volume category). Abbreviations: WMH = white matter hyperintensities.
Figure 2.
Figure 2.. Infarcts and WMHs
(A) Pie chart displaying percentage of DLB patients with only cortical infarcts (in red), only subcortical infarcts (in green), or both cortical and subcortical infarcts (in blue). (B) Histogram displaying the distribution of the six WMH volume categories (bars) colored by WMH burden (mild, moderate, and severe), as follows: WMHs 1 to 7 cm3 large (first volume category), 8 to 17 cm3 large (second volume category), 18 to 23 cm3 large (third volume category), 24 to 35 cm3 large (fourth volume category), 36 to 47 cm3 large (fifth volume category), and 48 cm3 or larger (sixth volume category) (please see also Figure 1). Abbreviations: WMHs = white matter hyperintensities.
Figure 3.
Figure 3.. Infarcts within mild, moderate, and severe WMH burden
The association between infarcts and WMH burden. Abbreviations: WMH = white matter hyperintensities.
Figure 4.
Figure 4.. The association of infarcts and WMHs with clinical features
Odds-Ratios and p-values for infarcts and WMHs from a linear mixed model with center as a blocking variable included as a random effect in the models, and age and sex adjustment. Significant p-values (≤0.05) are displayed in red. Abbreviations: RBD = rapid eye movement sleep behavior disorder; WMHs = white matter hyperintensities volume; OR = odds-ratios.
Figure 5.
Figure 5.. The association of WMHs with cortical thickness and subcortical gray matter volumes
(A) Red areas represent combined results from two models: the cluster of cortical regions with the highest estimates from a linear mixed effects model with WMHs as a fixed effect variable and center as a random variable, adjusted for age and sex; plus all the significant regions from a linear mixed effects model for subcortical volume ROIs with WMHs as a fixed effect variable and center as a random variable, adjusted for age, sex, and total intracranial volume (please see Supplementary Figure 1 for forest plot results including estimates, confidence intervals, and both uncorrected and FDR-adjusted p-values). (B) A schematic representation of the cholinergic system. Abbreviations: A = anterior; FDR = False Discovery Rate; GM = gray matter; L = left; P = posterior; R = right; WMHs = white matter hyperintensities.
See this image and copyright information in PMC

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