Cerebrovascular and Alzheimer's disease biomarkers in dementia with Lewy bodies and other dementias

Anna Rennie¹, Urban Ekman^{1

2}, Sara Shams^{3

4

5}, Lina Rydén^{6

7}, Jessica Samuelsson^{6

7}, Anna Zettergren^{6

7}, Silke Kern^{6

7

8}, Ketil Oppedal^{9

10

11}, Frédéric Blanc^{12

13}, Jakub Hort¹⁴, Sara Garcia-Ptacek^{1

15}, Angelo Antonini¹⁶, Afina W Lemstra^{17

18}, Alessandro Padovani¹⁹, Milica Gregoric Kramberger^{1

20

21}, Irena Rektorová²², Zuzana Walker^{23

24}, Jón Snædal²⁵, Matteo Pardini^{26

27}, John-Paul Taylor²⁸, Laura Bonanni²⁹, Tobias Granberg^{3

4}, Dag Aarsland^{9

30}, Ingmar Skoog^{6

7

8}, Lars-Olof Wahlund¹, Miia Kivipelto^{1

15

31

32}, Eric Westman^{1

33}, Daniel Ferreira^{1

34}

Affiliations

¹ Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77 Stockholm, Sweden.
² Medical Unit, Allied Health Professionals Women´s Health, Karolinska University Hospital, 171 76 Stockholm, Sweden.
³ Department of Radiology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
⁴ Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
⁵ Department of Radiology, Stanford University, Stanford, 94305-5105 CA, USA.
⁶ Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, 431 41 Mölndal, Sweden.
⁷ Centre for Ageing and Health (AgeCap), University of Gothenburg, 413 46 Gothenburg, Sweden.
⁸ Psychiatry, Cognition and Old Age Psychiatry Clinic, Region Västra Götaland, Sahlgrenska University Hospital, 431 41 Gothenburg, Sweden.
⁹ Center for Age-Related Medicine, Stavanger University Hospital, 4011 Stavanger, Norway.
¹⁰ Stavanger Medical Imaging Laboratory (SMIL), Department of Radiology, Stavanger University Hospital, 4016 Stavanger, Norway.
¹¹ The Norwegian Centre for Movement Disorders, Stavanger University Hospital, 4011 Stavanger, Norway.
¹² Day Hospital of Geriatrics, Memory Resource and Research Centre (CM2R) of Strasbourg, Department of Geriatrics, Hopitaux Universitaires de Strasbourg, 67098 Strasbourg, France.
¹³ ICube Laboratory and Federation de Medecine Translationnelle de Strasbourg (FMTS), University of Strasbourg and French National Centre for Scientific Research (CNRS), Team Imagerie Multimodale Integrative en Sante (IMIS)/ICONE, 67000 Strasbourg, France.
¹⁴ Memory Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, 150 06 Prague, Czech Republic.
¹⁵ Aging and Inflammation Theme, Karolinska University Hospital, 171 76 Stockholm, Sweden.
¹⁶ Parkinson and Movement Disorders Unit, Study Center on Neurodegeneration (CESNE), 35129 Padova, Italy.
¹⁷ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location Vumc, 1081 HV Amsterdam, The Netherlands.
¹⁸ Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location Vumc, 1081 HV Amsterdam, The Netherlands.
¹⁹ Neurology Unit, Department of Clinical and Experimental Sciences (DSCS), University of Brescia, 25123 Brescia, Italy.
²⁰ Department of Neurology, University Medical Center, 1000 Ljubljana, Slovenia.
²¹ Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia.
²² Applied Neuroscience Research Group, CEITEC, Masaryk University, 625 00 Brno, Czech Republic.
²³ Division of Psychiatry, University College London, W1T 7NF London, UK.
²⁴ St Margaret's Hospital, Essex Partnership University NHS Foundation Trust, CM16 6TN Essex, UK.
²⁵ Memory Clinic, Landspitali, 105 Reykjavik, Iceland.
²⁶ Department of Neurology, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.
²⁷ Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, 16132 Genoa, Italy.
²⁸ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE1 7RU Newcastle upon Tyne, UK.
²⁹ Department of Medicine, Aging Sciences University G. d'Annunzio of Chieti-Pescara Chieti, 66100 Chieti, Italy.
³⁰ Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, SE5 8AF London, UK.
³¹ Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, SW7 2AZ London, UK.
³² Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70211 Kuopio, Finland.
³³ Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, SE5 8AF London, UK.
³⁴ Facultad de Ciencias de la Salud, Universidad Fernando Pessoa Canarias, 35016 Las Palmas, España.

PMID: 39291165
PMCID: PMC11406466
DOI: 10.1093/braincomms/fcae290

Cerebrovascular and Alzheimer's disease biomarkers in dementia with Lewy bodies and other dementias

Anna Rennie et al. Brain Commun. 2024.

. 2024 Aug 28;6(5):fcae290.

doi: 10.1093/braincomms/fcae290. eCollection 2024.

Authors

Affiliations

¹ Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77 Stockholm, Sweden.
² Medical Unit, Allied Health Professionals Women´s Health, Karolinska University Hospital, 171 76 Stockholm, Sweden.
³ Department of Radiology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
⁴ Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
⁵ Department of Radiology, Stanford University, Stanford, 94305-5105 CA, USA.
⁶ Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, 431 41 Mölndal, Sweden.
⁷ Centre for Ageing and Health (AgeCap), University of Gothenburg, 413 46 Gothenburg, Sweden.
⁸ Psychiatry, Cognition and Old Age Psychiatry Clinic, Region Västra Götaland, Sahlgrenska University Hospital, 431 41 Gothenburg, Sweden.
⁹ Center for Age-Related Medicine, Stavanger University Hospital, 4011 Stavanger, Norway.
¹⁰ Stavanger Medical Imaging Laboratory (SMIL), Department of Radiology, Stavanger University Hospital, 4016 Stavanger, Norway.
¹¹ The Norwegian Centre for Movement Disorders, Stavanger University Hospital, 4011 Stavanger, Norway.
¹² Day Hospital of Geriatrics, Memory Resource and Research Centre (CM2R) of Strasbourg, Department of Geriatrics, Hopitaux Universitaires de Strasbourg, 67098 Strasbourg, France.
¹³ ICube Laboratory and Federation de Medecine Translationnelle de Strasbourg (FMTS), University of Strasbourg and French National Centre for Scientific Research (CNRS), Team Imagerie Multimodale Integrative en Sante (IMIS)/ICONE, 67000 Strasbourg, France.
¹⁴ Memory Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, 150 06 Prague, Czech Republic.
¹⁵ Aging and Inflammation Theme, Karolinska University Hospital, 171 76 Stockholm, Sweden.
¹⁶ Parkinson and Movement Disorders Unit, Study Center on Neurodegeneration (CESNE), 35129 Padova, Italy.
¹⁷ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location Vumc, 1081 HV Amsterdam, The Netherlands.
¹⁸ Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location Vumc, 1081 HV Amsterdam, The Netherlands.
¹⁹ Neurology Unit, Department of Clinical and Experimental Sciences (DSCS), University of Brescia, 25123 Brescia, Italy.
²⁰ Department of Neurology, University Medical Center, 1000 Ljubljana, Slovenia.
²¹ Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia.
²² Applied Neuroscience Research Group, CEITEC, Masaryk University, 625 00 Brno, Czech Republic.
²³ Division of Psychiatry, University College London, W1T 7NF London, UK.
²⁴ St Margaret's Hospital, Essex Partnership University NHS Foundation Trust, CM16 6TN Essex, UK.
²⁵ Memory Clinic, Landspitali, 105 Reykjavik, Iceland.
²⁶ Department of Neurology, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.
²⁷ Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, 16132 Genoa, Italy.
²⁸ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE1 7RU Newcastle upon Tyne, UK.
²⁹ Department of Medicine, Aging Sciences University G. d'Annunzio of Chieti-Pescara Chieti, 66100 Chieti, Italy.
³⁰ Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, SE5 8AF London, UK.
³¹ Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, SW7 2AZ London, UK.
³² Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70211 Kuopio, Finland.
³³ Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, SE5 8AF London, UK.
³⁴ Facultad de Ciencias de la Salud, Universidad Fernando Pessoa Canarias, 35016 Las Palmas, España.

PMID: 39291165
PMCID: PMC11406466
DOI: 10.1093/braincomms/fcae290

Abstract

Co-pathologies are common in dementia with Lewy bodies and other dementia disorders. We investigated cerebrovascular and Alzheimer's disease co-pathologies in patients with dementia with Lewy bodies in comparison with patients with mild cognitive impairment, Alzheimer's disease, mixed dementia, vascular dementia or Parkinson's disease with dementia and cognitively unimpaired participants. We assessed the association of biomarkers of cerebrovascular and Alzheimer's disease co-pathologies with medial temporal atrophy and global cognitive performance. Additionally, we evaluated whether the findings were specific to dementia with Lewy bodies. We gathered a multi-cohort dataset of 4549 participants (dementia with Lewy bodies = 331, cognitively unimpaired = 1505, mild cognitive impairment = 1489, Alzheimer's disease = 708, mixed dementia = 268, vascular dementia = 148, Parkinson's disease with dementia = 120) from the MemClin Study, Karolinska Imaging in Dementia Study, Gothenburg H70 Birth Cohort Studies and the European DLB Consortium. Cerebrovascular co-pathology was assessed with visual ratings of white matter hyperintensities using the Fazekas scale through structural imaging. Alzheimer's disease biomarkers of β-amyloid and phosphorylated tau were assessed in the cerebrospinal fluid for a subsample (N = 2191). Medial temporal atrophy was assessed with visual ratings and global cognition with the mini-mental state examination. Differences and associations were assessed through regression models, including interaction terms. In dementia with Lewy bodies, 43% had a high white matter hyperintensity load, which was significantly higher than that in cognitively unimpaired (14%), mild cognitive impairment (26%) and Alzheimer's disease (27%), but lower than that in vascular dementia (62%). In dementia with Lewy bodies, white matter hyperintensities were associated with medial temporal atrophy, and the interaction term showed that this association was stronger than that in cognitively unimpaired and mixed dementia. However, the association between white matter hyperintensities and medial temporal atrophy was non-significant when β-amyloid was included in the model. Instead, β-amyloid predicted medial temporal atrophy in dementia with Lewy bodies, in contrast to the findings in mild cognitive impairment where medial temporal atrophy scores were independent of β-amyloid. Dementia with Lewy bodies had the lowest performance on global cognition, but this was not associated with white matter hyperintensities. In Alzheimer's disease, global cognitive performance was lower in patients with more white matter hyperintensities. We conclude that white matter hyperintensities are common in dementia with Lewy bodies and are associated with more atrophy in medial temporal lobes, but this association depended on β-amyloid-related pathology in our cohort. The associations between biomarkers were overall stronger in dementia with Lewy bodies than in some of the other diagnostic groups.

Keywords: atrophy; imaging; multi-cohort; naturalistic cohort.

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Conflict of interest statement

A.R., U.E., S.S., L.R., J.S., A.Z., K.O., J.H., S.G-P., A.A., A.W.L., A.P., M.G.K., I.R., Z.W., J.G.S., M.P., L.B., T.G., I.S., L.-O.W. and E.W. has nothing to disclose. S.K. has served at scientific advisory boards and/or as a consultant for Geras Solutions, Optoceutics, Biogen and Bioarctic F.B. has served as national coordinator and principal investigator for clinical trials sponsored by Biogen, Roche, Axovant and Eisai. J.-P.T. has received speaker fees from GE Healthcare D.A. has received research support and/or honoraria from AstraZeneca, H. Lundbeck, Novartis Pharmaceuticals and GE Health and served as a paid consultant for H. Lundbeck, Eisai and Evonik. M.K. has an advisory board membership for BioArctic, Biogen, Combinostics and Nestlé and has received speaking and lecture fees for Biogen, Nestlé, Nutricia and Roche. D.F. consults for BioArctic and has received honoraria from Esteve.

Figures

**Figure 1**
**White matter hyperintensities (WMHs) across diagnoses.** Odds ratios from a logistic regression model. Panel A shows examples of low and high WMHs. Panel B displays absolute frequencies of high WMH load (Fazekas scores 2 and 3). Panel C shows odds ratios based on logistic regression with the dementia with Lewy bodies group as reference. Model adjusted for age and sex. χ²(8, N = 4549) = 634.82, P < 0.001. In the logistic regression model, the WMH variable is dichotomous and was coded as a high WMH load (Fazekas scores 2 and 3) versus a low WMH load (Fazekas scores 0 and 1). Dot reflects the estimate (odds ratio) and whiskers the 95% confidence interval. Significant results compared to dementia with Lewy bodies do not cross the black line.

**Figure 2**
**Medial temporal atrophy (MTA) across diagnoses.** Odds ratios from a logistic regression model. Panel A shows examples of low and high MTA. Panel B displays absolute frequencies of MTA (cut-offs are age adjusted). Panel C shows odds ratios based on logistic regression with the dementia with Lewy bodies group as a reference. Absolute frequencies of MTA, odds ratios based on logistic regression with the dementia with Lewy bodies as a reference group. Model adjusted for age and sex, χ²(8, N = 3508)= 324.72, P < 0.001. Dot reflects the estimate and whiskers the 95% confidence interval. Significant results compared to dementia with Lewy bodies do not cross the black line.

**Figure 3**
**Results from the logistic regression models in Table 3.** Interactions between biomarkers and the diagnostic group on the prediction of MTA. Only statistically significant interactions displayed. Displayed is the percent in each category with a high degree of MTA. (A) Interaction of the diagnostic group and WMHs on MTA; dementia with Lewy bodies in comparison with cognitively unimpaired and mixed dementia. The model is adjusted for age and sex, and main effects of the diagnostic group and WMHs are also fitted in addition to the interaction term. Omnibus statistics, χ²(15, N = 3508) = 414.55, P < 0.001. (B) Interaction of the diagnostic group and Aβ on MTA; dementia with Lewy bodies in comparison with mild cognitive impairment. The model is adjusted for age and sex, and main effects of the diagnostic group and MTA are also fitted in addition to the interaction term. Omnibus statistics, χ²(13, N = 1477) = 137.77, P < 0.001. MTA, medial temporal atrophy; WMH, white matter hyperintensities.

**Figure 4**
**Results from the linear regression models in Table 3.** Interaction between WMHs and diagnosis on MMSE. Only the statistically significant interaction displayed with fitted values of individual observations. Dementia with Lewy bodies in comparison to Alzheimer’s disease. The model is adjusted for age, sex and education, and main effects of diagnosis and WMHs are also fitted in addition to the interaction term. Omnibus statistics, F(16, 2707) = 164.4, adjusted R² = 0.49, P < 0.001.

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Cerebrovascular and Alzheimer's disease biomarkers in dementia with Lewy bodies and other dementias

Affiliations

Cerebrovascular and Alzheimer's disease biomarkers in dementia with Lewy bodies and other dementias

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources