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 (US) |
---|---|
Pages (from-to) | 318-332 |
Number of pages | 15 |
Journal | Alzheimer's and Dementia |
Volume | 19 |
Issue number | 1 |
DOIs | |
State | Accepted/In press - 2022 |
Keywords
- cerebrospinal fluid
- clinical trials
- dementia
- dementia with Lewy bodies
- Lewy body dementia
- MRI neurodegeneration
- parkinsonism
- PET
- α-synuclein
ASJC Scopus subject areas
- Epidemiology
- Health Policy
- Developmental Neuroscience
- Clinical Neurology
- Geriatrics and Gerontology
- Cellular and Molecular Neuroscience
- Psychiatry and Mental health
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In: Alzheimer's and Dementia, Vol. 19, No. 1, 2022, p. 318-332.
Research output: Contribution to journal › Review article › peer-review
}
TY - JOUR
T1 - Dementia with Lewy bodies
T2 - Impact of co-pathologies and implications for clinical trial design
AU - the ISTAART Lewy body dementias Trial Methods Working Group
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.
N1 - Funding Information: This manuscript was facilitated by the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART), through the Lewy body dementias professional interest area (PIA). The views and opinions expressed by the authors in this publication represent those of the authors and do not necessarily reflect those of the greater PIA membership, ISTAART, or the Alzheimer's Association. The authors are particularly grateful for the support and diligence of Jodi Titiner and Chris Weber in supporting the Lewy body dementia (LBD) PIA and the production of this manuscript. JBT has been supported by the Edmond J. Safra and is the Harrison Endowed Scientific Director of the nantz National Alzheimer Center. MJG is supported by the “Miguel Servet” program [CP19/00031] and a research grant [PI20/00613] of the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). DF is supported by the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet; Center for Innovative Medicine (CIMED); the Swedish Brain Foundation; Demensfonden; Gun och Bertil Stohnes Stiftelse; Gamla Tjänarinnor; Karolinska Institutet Research Funding; and Karolinska Institutet Funding for Geriatric Diseases. RW is supported by a Wellcome Clinical Research Career Development Fellowship (205167/Z/16/Z). DA is a Royal Society Wolfson Research Merit Award Holder and would like to thank the Wolfson Foundation and the Royal Society for their support. Professor Aarsland is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. IMcK and JPT are supported by the NIHR Newcastle Biomedical Research Centre. SWS was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS; program #: 1ZIANS003154). BB is supported in part by NIH (grants P30 AG62677, U01 NS100620, U19 AG 071754, U54 NS110435), the Lewy Body Dementia Association, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, the Little Family Foundation, and Ted Turner and Family Foundation. JBL was supported through NIH (NINDS, U01NA100610 and National Institute on Aging, P30AG072959) and the Lewy Body Dementia Association (Research Center of Excellence program). SL is partly supported through NHMRC Investigator Grant #1195830. JK is partially supported by the Alzheimer's Research UK (Pump priming grant). CA, JK, and KWC have no funding sources to acknowledge. Funding Information: This manuscript was facilitated by the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART), through the Lewy body dementias professional interest area (PIA). The views and opinions expressed by the authors in this publication represent those of the authors and do not necessarily reflect those of the greater PIA membership, ISTAART, or the Alzheimer's Association. The authors are particularly grateful for the support and diligence of Jodi Titiner and Chris Weber in supporting the Lewy body dementia (LBD) PIA and the production of this manuscript. JBT has been supported by the Edmond J. Safra and is the Harrison Endowed Scientific Director of the nantz National Alzheimer Center. MJG is supported by the “Miguel Servet” program [CP19/00031] and a research grant [PI20/00613] of the Instituto de Salud Carlos III‐Fondo Europeo de Desarrollo Regional (ISCIII‐FEDER). DF is supported by the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet; Center for Innovative Medicine (CIMED); the Swedish Brain Foundation; Demensfonden; Gun och Bertil Stohnes Stiftelse; Gamla Tjänarinnor; Karolinska Institutet Research Funding; and Karolinska Institutet Funding for Geriatric Diseases. RW is supported by a Wellcome Clinical Research Career Development Fellowship (205167/Z/16/Z). DA is a Royal Society Wolfson Research Merit Award Holder and would like to thank the Wolfson Foundation and the Royal Society for their support. Professor Aarsland is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. IMcK and JPT are supported by the NIHR Newcastle Biomedical Research Centre. SWS was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS; program #: 1ZIANS003154). BB is supported in part by NIH (grants P30 AG62677, U01 NS100620, U19 AG 071754, U54 NS110435), the Lewy Body Dementia Association, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, the Little Family Foundation, and Ted Turner and Family Foundation. JBL was supported through NIH (NINDS, U01NA100610 and National Institute on Aging, P30AG072959) and the Lewy Body Dementia Association (Research Center of Excellence program). SL is partly supported through NHMRC Investigator Grant #1195830. JK is partially supported by the Alzheimer's Research UK (Pump priming grant). CA, JK, and KWC have no funding sources to acknowledge. Funding Information: DF, MJG, JK, IMcK, JPT, JBT, and KWC report no conflicts of interest. RW has received speaker fees from GE Healthcare and honoraria from Britannia. SWS serves on the scientific advisory council of the Lewy Body Dementia Association and received grants/contracts from Cerevel Therapeutics. DA has received research support and/or honoraria from Astra‐Zeneca, H. Lundbeck, Novartis Pharmaceuticals, and GE Health, and serves as paid consultant for H. Lundbeck, Eisai, and Axovant. BB has received research support for clinical trials from Alector, Biogen, and Transposon. He receives royalties from the publication of a book entitled (Cambridge Medicine). He serves on the Scientific Advisory Board of the Tau Consortium, which is funded by the Rainwater Charitable Foundation. JBL serves on the Lewy Body Dementia Association Scientific Advisory Council and the ISTAART Lewy Body Dementia Professional Interest Area (Vice Chair), receives Grant support from GE Healthcare, and served on an Advisory Board for Vaxxinity. SL has received research support and/or honoraria from Acceler8, Pharmaxis. CA has received research support and/or honoraria from F. Hoffmann‐La Roche Ltd, Zambonm, Nutricia, and Schwabe Farma Ibérica S.A.U, and meeting/travel support from Nutricia and Biogen. Author disclosures are available in the supporting information . Behavioral Neurology of Dementia Publisher Copyright: © 2022 the Alzheimer's Association.
PY - 2022
Y1 - 2022
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
UR - http://www.scopus.com/inward/record.url?scp=85141388904&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85141388904&partnerID=8YFLogxK
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 -