Dementia with Lewy bodies: impact of co-pathologies and implications for clinical trial design

Jon B. Toledo; Carla Abdelnour; Rimona S. Weil; Daniel Ferreira; Federico Rodriguez-Porcel; Andrea Pilotto; Kathryn A. Wyman-Chick; Michel J. Grothe; Joseph P. M. Kane; Angela Taylor; Arvid Rongve; Sonja Scholz; James B. Leverenz; Bradley F. Boeve; Dag Aarsland; Ian G. McKeith; Simon Lewis; Iracema Leroi; John P. Taylor; the ISTAART Lewy body dementias Trial Methods Working Group

doi:10.1002/alz.12814

Dementia with Lewy bodies: impact of co-pathologies and implications for clinical trial design

Jon B. Toledo^*, Carla Abdelnour, Rimona S. Weil, Daniel Ferreira, Federico Rodriguez-Porcel, Andrea Pilotto, Kathryn A. Wyman-Chick, Michel J. Grothe, Joseph P. M. Kane, Angela Taylor, Arvid Rongve, Sonja Scholz, James B. Leverenz, Bradley F. Boeve, Dag Aarsland, Ian G. McKeith, Simon Lewis, Iracema Leroi, John P. Taylor, the ISTAART Lewy body dementias Trial Methods Working Group

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

31 Citations (Scopus)

Abstract

Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies.

Original language	English
Pages (from-to)	318-332
Number of pages	15
Journal	Alzheimer's and Dementia
Volume	19
Issue number	1
DOIs	https://doi.org/10.1002/alz.12814
Publication status	Published - Jan 2023
Externally published	Yes

Keywords

cerebrospinal fluid
clinical trials
dementia
dementia with Lewy bodies
Lewy body dementia
MRI neurodegeneration
parkinsonism
PET
α-synuclein

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10.1002/alz.12814

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Toledo, J. B., Abdelnour, C., Weil, R. S., Ferreira, D., Rodriguez-Porcel, F., Pilotto, A., Wyman-Chick, K. A., Grothe, M. J., Kane, J. P. M., Taylor, A., Rongve, A., Scholz, S., Leverenz, J. B., Boeve, B. F., Aarsland, D., McKeith, I. G., Lewis, S., Leroi, I., Taylor, J. P., & the ISTAART Lewy body dementias Trial Methods Working Group (2023). Dementia with Lewy bodies: impact of co-pathologies and implications for clinical trial design. Alzheimer's and Dementia, 19(1), 318-332. https://doi.org/10.1002/alz.12814

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title = "Dementia with Lewy bodies: impact of co-pathologies and implications for clinical trial design",

abstract = "Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies.",

keywords = "cerebrospinal fluid, clinical trials, dementia, dementia with Lewy bodies, Lewy body dementia, MRI neurodegeneration, parkinsonism, PET, α-synuclein",

author = "Toledo, {Jon B.} and Carla Abdelnour and Weil, {Rimona S.} and Daniel Ferreira and Federico Rodriguez-Porcel and Andrea Pilotto and Wyman-Chick, {Kathryn A.} and Grothe, {Michel J.} and Kane, {Joseph P. M.} and Angela Taylor and Arvid Rongve and Sonja Scholz and Leverenz, {James B.} and Boeve, {Bradley F.} and Dag Aarsland and McKeith, {Ian G.} and Simon Lewis and Iracema Leroi and Taylor, {John P.} and {the ISTAART Lewy body dementias Trial Methods Working Group}",

year = "2023",

month = jan,

doi = "10.1002/alz.12814",

language = "English",

volume = "19",

pages = "318--332",

journal = "Alzheimer's and Dementia",

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Toledo, JB, Abdelnour, C, Weil, RS, Ferreira, D, Rodriguez-Porcel, F, Pilotto, A, Wyman-Chick, KA, Grothe, MJ, Kane, JPM, Taylor, A, Rongve, A, Scholz, S, Leverenz, JB, Boeve, BF, Aarsland, D, McKeith, IG, Lewis, S, Leroi, I, Taylor, JP & the ISTAART Lewy body dementias Trial Methods Working Group 2023, 'Dementia with Lewy bodies: impact of co-pathologies and implications for clinical trial design', Alzheimer's and Dementia, vol. 19, no. 1, pp. 318-332. https://doi.org/10.1002/alz.12814

TY - JOUR

T1 - Dementia with Lewy bodies

T2 - impact of co-pathologies and implications for clinical trial design

AU - Toledo, Jon B.

AU - Abdelnour, Carla

AU - Weil, Rimona S.

AU - Ferreira, Daniel

AU - Rodriguez-Porcel, Federico

AU - Pilotto, Andrea

AU - Wyman-Chick, Kathryn A.

AU - Grothe, Michel J.

AU - Kane, Joseph P. M.

AU - Taylor, Angela

AU - Rongve, Arvid

AU - Scholz, Sonja

AU - Leverenz, James B.

AU - Boeve, Bradley F.

AU - Aarsland, Dag

AU - McKeith, Ian G.

AU - Lewis, Simon

AU - Leroi, Iracema

AU - Taylor, John P.

AU - the ISTAART Lewy body dementias Trial Methods Working Group

PY - 2023/1

Y1 - 2023/1

N2 - Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies.

AB - Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies.

KW - cerebrospinal fluid

KW - clinical trials

KW - dementia

KW - dementia with Lewy bodies

KW - Lewy body dementia

KW - MRI neurodegeneration

KW - parkinsonism

KW - PET

KW - α-synuclein

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U2 - 10.1002/alz.12814

DO - 10.1002/alz.12814

M3 - Review article

C2 - 36239924

AN - SCOPUS:85141388904

SN - 1552-5260

VL - 19

SP - 318

EP - 332

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 1

ER -

Dementia with Lewy bodies: impact of co-pathologies and implications for clinical trial design

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Keywords

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