TY - JOUR
T1 - Association of the ATN Research Framework with Clinical Profile, Cognitive Decline, and Mortality in Patients with Dementia with Lewy Bodies
AU - van de Beek, Marleen
AU - Ooms, Floor A. H.
AU - Ebenau, Jarith L.
AU - Barkhof, Frederik
AU - Scheltens, Philip
AU - Teunissen, Charlotte E.
AU - van Harten, Argonde C.
AU - van der Flier, Wiesje M.
AU - Lemstra, Afina W.
N1 - Funding Information: M. van de Beek, F.A.H. Ooms, and J.L. Ebenau report no disclosures relevant to the manuscript. P. Scheltens has acquired grant support (for the institution) from Biogen and in the past 2 years has received consultancy/speaker fees (paid to the institution) from Probiodrug Biogen, EIP Pharma, and Merck AG. F. Barkhof is a consultant for Biogen Idec, Janssen Alzheimer Immunotherapy, Bayer-Schering, Merck-Serono, Roche, Novartis, Genzume, and Sanofi-Aventis; has received sponsorship from European Commission−Horizon 2020, National Institute for Health Research–University College London Hospitals Biomedical Research Centre, Scottish Multiple Sclerosis Register, TEVA, Novartis, and Toshiba; and serves on the editorial boards of Radiology, Brain, Neuroradiology, Multiple Sclerosis Journal, and Neurology®. A.C. van Harten reports no disclosures relevant to the manuscript. C.E. Teunissen serves on the advisory board of Roche; performed contract research for Boehringer, Roche, Toyama Fujifilm, Esai and Probiodrug; obtained a grant with ADxNeurosciences; and received lecture fees from Biogen and Axon Neurosciences. W.M. van der Flier's research programs have been funded by ZonMW, the Netherlands Organization of Scientific Research, Alzheimer Nederland, Cardiovascular Onderzoek Nederland, Stichting Dioraphte, Gieskes-Strijbis fonds, Pasman stichting, Boehringer Ingelheim, Life-MI, AVID, Biogen MA, and Combinostics, with all funding is paid to the institution. A.L. Lemstra has received funding from Stichting Dioraphte, Alzheimer Nederland, and ZonMW Memorabel (project 733050509). Go to Neurology.org/N for full disclosures. Funding Information: Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Drs. van der Flier, Scheltens, and Teunissen are recipients of ABOARD, which is a public–private partnership receiving funding from ZonMW (73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP allowance; LSHM20106). Dr. van der Flier holds the Pasman chair. Dr. Barkhof is supported by the NIHR biomedical research center at UCLH. Dr. Teunissen is supported by the European Commission (Marie Curie International Training Network; JPND), the Dutch Research Council (ZonMW), The Weston Brain Institute, and Alzheimer Netherlands. Publisher Copyright: © American Academy of Neurology.
PY - 2022/3/22
Y1 - 2022/3/22
N2 - Background and ObjectivesThe ATN framework has been developed to categorize biological processes within the Alzheimer disease (AD) continuum. Because AD pathology often coincides with dementia with Lewy bodies (DLB), we aimed to investigate the distribution of ATN profiles in DLB and associate ATN profiles in DLB with prognosis.MethodsWe included 202 patients with DLB from the Amsterdam Dementia Cohort (68±7 years; 19% female; Mini-Mental State Examination 24 ± 3; abnormal DAT-SPECT 105/119). Patients were classified into 8 profiles according to the ATN framework, using CSF β-amyloid (Aβ)42 (A), CSF p-tau (T), and medial temporal atrophy scores (N). We compared presence of clinical symptoms in ATN profiles and used linear mixed models to analyze decline on cognitive tests (follow-up 3±2 years for n = 139). Mortality risk was assessed using Cox proportional hazards analysis. Analyses were performed on the 8 profiles as well as 3 clustered categories (normal AD biomarkers, non-AD pathologic change, and AD continuum).ResultsFifty (25%) patients with DLB had normal AD biomarkers (A-T-N-), 37 (18%) had non-AD pathologic change (A-T+N- 10%, A-T-N+ 6%, A-T+N+ 3%), and 115 (57%) were classified within the AD continuum (A+T-N- 20%, A+T+N- 16%, A+T-N+ 10%, A+T+N+ 9%). A+T+N+ patients were older and least often had REM sleep behavior disorder symptoms. Parkinsonism was more often present in A+T- compared to A-T+ patients (independent of N). Compared to patients with normal AD biomarkers, patients in A+ categories showed steeper decline on memory tests and higher mortality risk. Cognitive decline and mortality did not differ between non-AD pathologic change and normal AD biomarkers.DiscussionIn our DLB cohort, we found clinically relevant associations between ATN categories and disease manifestation. Patients within the AD continuum had steeper cognitive decline and shorter survival. Implementing the ATN framework within patients with DLB aids in subtyping patients based on underlying biological processes and could provide targets for future treatment strategies (for example, AD-modifying treatment). Expanding the framework by incorporating markers for α-synucleinopathy would improve the use of the framework to characterize patients with dementia with mixed pathology, which could enhance proper stratification of patients for therapeutic trials.
AB - Background and ObjectivesThe ATN framework has been developed to categorize biological processes within the Alzheimer disease (AD) continuum. Because AD pathology often coincides with dementia with Lewy bodies (DLB), we aimed to investigate the distribution of ATN profiles in DLB and associate ATN profiles in DLB with prognosis.MethodsWe included 202 patients with DLB from the Amsterdam Dementia Cohort (68±7 years; 19% female; Mini-Mental State Examination 24 ± 3; abnormal DAT-SPECT 105/119). Patients were classified into 8 profiles according to the ATN framework, using CSF β-amyloid (Aβ)42 (A), CSF p-tau (T), and medial temporal atrophy scores (N). We compared presence of clinical symptoms in ATN profiles and used linear mixed models to analyze decline on cognitive tests (follow-up 3±2 years for n = 139). Mortality risk was assessed using Cox proportional hazards analysis. Analyses were performed on the 8 profiles as well as 3 clustered categories (normal AD biomarkers, non-AD pathologic change, and AD continuum).ResultsFifty (25%) patients with DLB had normal AD biomarkers (A-T-N-), 37 (18%) had non-AD pathologic change (A-T+N- 10%, A-T-N+ 6%, A-T+N+ 3%), and 115 (57%) were classified within the AD continuum (A+T-N- 20%, A+T+N- 16%, A+T-N+ 10%, A+T+N+ 9%). A+T+N+ patients were older and least often had REM sleep behavior disorder symptoms. Parkinsonism was more often present in A+T- compared to A-T+ patients (independent of N). Compared to patients with normal AD biomarkers, patients in A+ categories showed steeper decline on memory tests and higher mortality risk. Cognitive decline and mortality did not differ between non-AD pathologic change and normal AD biomarkers.DiscussionIn our DLB cohort, we found clinically relevant associations between ATN categories and disease manifestation. Patients within the AD continuum had steeper cognitive decline and shorter survival. Implementing the ATN framework within patients with DLB aids in subtyping patients based on underlying biological processes and could provide targets for future treatment strategies (for example, AD-modifying treatment). Expanding the framework by incorporating markers for α-synucleinopathy would improve the use of the framework to characterize patients with dementia with mixed pathology, which could enhance proper stratification of patients for therapeutic trials.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85127729409&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/35074893
U2 - https://doi.org/10.1212/WNL.0000000000200048
DO - https://doi.org/10.1212/WNL.0000000000200048
M3 - Article
C2 - 35074893
SN - 0028-3878
VL - 98
SP - E1262-E1272
JO - Neurology
JF - Neurology
IS - 12
ER -