TY - JOUR
T1 - Research Criteria for the Behavioral Variant of Alzheimer Disease
T2 - A Systematic Review and Meta-analysis
AU - Ossenkoppele, Rik
AU - Singleton, Ellen H.
AU - Groot, Colin
AU - Dijkstra, Anke A.
AU - Eikelboom, Willem S.
AU - Seeley, William W.
AU - Miller, Bruce
AU - Laforce, Robert Jr
AU - Scheltens, Philip
AU - Papma, Janne M.
AU - Rabinovici, Gil D.
AU - Pijnenburg, Yolande A. L.
N1 - Funding Information: reported grants from National Institutes of Health, Alzheimer’s Association, and Rainwater Charitable Foundation during the conduct of the study; grants from Avid Radiopharmaceuticals, GE Healthcare, Life Molecular Imaging, and Genentech and personal fees from Genentech, Eisai, Roche, and Johnson & Johnson outside the submitted work. Dr Seeley reported personal fees from BridgeBio, GLG Council, Guidepoint Global, and Corcept Therapeutics outside the submitted work. Dr Miller reported grants from National Institutes of Health/ National Institute of Aging and University of California, San Francisco/Quest Diagnostics outside the submitted work; and royalties from Cambridge University Press, Guilford Publications Inc, Johns Hopkins Press, Oxford University Press, Taylor & Francis Group, Elsevier Inc, and UpToDate. Dr Scheltens reported receiving consultancy fees (paid to the institution) from AC Immune, Alkermes, Alnylam, Alzheon, Anavex, Biogen, Brainstorm Cell, Cortexyme, Denali, EIP, ImmunoBrain Checkpoint, GemVax, Genentech, Green Valley, Novartis, Novo Nordisk, PeopleBio, Renew LLC, and Roche; being a principal investigator with AC Immune, CogRx, FUJI-film/Toyama, IONIS, UCB, and Vivoryon; being a part-time employee of Life Sciences Partners Amsterdam; and being on the boards of Brain Research Center and New Amsterdam Pharma. Dr Papma reported grants from ZonMw Memorabel and Alzheimer Nederland during the conduct of the study. No other disclosures were reported. Funding Information: funding from the Netherlands Organization for Health Research and Development (70-73305-98-1214 [Drs Ossenkoppele and Papma]). Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research programme of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. Research at University of California, San Francisco, is supported by the National Institutes of Health (grants P30-AG062422 [Drs Miller and Rabinovici], P01-AG019724 [Drs Miller and Rabinovici], R35 AG072362 [Dr Rabinovici], R01-AG038791 [Dr Rabinovici], and R01 AG045611 [Dr Rabinovici]) and the Rainwater Charitable Foundation (Dr Rabinovici). Research at Centre Hospitalier Universitaire de Québec is supported by the Chaire de Recherche sur les Aphasies Primaires Progressives–Fondation de la Famille Lemaire (Dr Laforce). Publisher Copyright: © 2022 American Medical Association. All rights reserved.
PY - 2022
Y1 - 2022
N2 - Importance: The behavioral variant of Alzheimer disease (bvAD) is characterized by early and predominant behavioral deficits caused by AD pathology. This AD phenotype is insufficiently understood and lacks standardized clinical criteria, limiting reliability and reproducibility of diagnosis and scientific reporting. Objective: To perform a systematic review and meta-analysis of the bvAD literature and use the outcomes to propose research criteria for this syndrome. Data Sources: A systematic literature search in PubMed/MEDLINE and Web of Science databases (from inception through April 7, 2021) was performed in duplicate. Study Selection: Studies reporting on behavioral, neuropsychological, or neuroimaging features in bvAD and, when available, providing comparisons with typical amnestic-predominant AD (tAD) or behavioral variant frontotemporal dementia (bvFTD). Data Extraction and Synthesis: This analysis involved random-effects meta-analyses on group-level study results of clinical data and systematic review of the neuroimaging literature. The study was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Main Outcomes and Measures: Behavioral symptoms (neuropsychiatric symptoms and bvFTD core clinical criteria), cognitive function (global cognition, episodic memory, and executive functioning), and neuroimaging features (structural magnetic resonance imaging, [18F]fluorodeoxyglucose-positron emission tomography, perfusion single-photon emission computed tomography, amyloid positron emission tomography, and tau positron emission tomography). Results: The search led to the assessment of 83 studies, including 13 suitable for meta-analysis. Data were collected for 591 patients with bvAD. There was moderate to substantial heterogeneity and moderate risk of bias across studies. Cases with bvAD showed more severe behavioral symptoms than tAD (standardized mean difference [SMD], 1.16 [95% CI, 0.74-1.59]; P <.001) and a trend toward less severe behavioral symptoms compared with bvFTD (SMD, -0.22 [95% CI, -0.47 to 0.04]; P =.10). Meta-analyses of cognitive data indicated worse executive performance in bvAD vs tAD (SMD, -1.03 [95% CI, -1.74 to -0.32]; P =.008) but not compared with bvFTD (SMD, -0.61 [95% CI, -1.75 to 0.53]; P =.29). Cases with bvAD showed a nonsignificant difference of worse memory performance compared with bvFTD (SMD, -1.31 [95% CI, -2.75 to 0.14]; P =.08) but did not differ from tAD (SMD, 0.43 [95% CI, -0.46 to 1.33]; P =.34). The neuroimaging literature revealed 2 distinct bvAD neuroimaging phenotypes: an AD-like pattern with relative frontal sparing and a relatively more bvFTD-like pattern characterized by additional anterior involvement, with the AD-like pattern being more prevalent. Conclusions and Relevance: These data indicate that bvAD is clinically most similar to bvFTD, while it shares most pathophysiological features with tAD. Based on these insights, we propose research criteria for bvAD aimed at improving the consistency and reliability of future research and aiding the clinical assessment of this AD phenotype.
AB - Importance: The behavioral variant of Alzheimer disease (bvAD) is characterized by early and predominant behavioral deficits caused by AD pathology. This AD phenotype is insufficiently understood and lacks standardized clinical criteria, limiting reliability and reproducibility of diagnosis and scientific reporting. Objective: To perform a systematic review and meta-analysis of the bvAD literature and use the outcomes to propose research criteria for this syndrome. Data Sources: A systematic literature search in PubMed/MEDLINE and Web of Science databases (from inception through April 7, 2021) was performed in duplicate. Study Selection: Studies reporting on behavioral, neuropsychological, or neuroimaging features in bvAD and, when available, providing comparisons with typical amnestic-predominant AD (tAD) or behavioral variant frontotemporal dementia (bvFTD). Data Extraction and Synthesis: This analysis involved random-effects meta-analyses on group-level study results of clinical data and systematic review of the neuroimaging literature. The study was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Main Outcomes and Measures: Behavioral symptoms (neuropsychiatric symptoms and bvFTD core clinical criteria), cognitive function (global cognition, episodic memory, and executive functioning), and neuroimaging features (structural magnetic resonance imaging, [18F]fluorodeoxyglucose-positron emission tomography, perfusion single-photon emission computed tomography, amyloid positron emission tomography, and tau positron emission tomography). Results: The search led to the assessment of 83 studies, including 13 suitable for meta-analysis. Data were collected for 591 patients with bvAD. There was moderate to substantial heterogeneity and moderate risk of bias across studies. Cases with bvAD showed more severe behavioral symptoms than tAD (standardized mean difference [SMD], 1.16 [95% CI, 0.74-1.59]; P <.001) and a trend toward less severe behavioral symptoms compared with bvFTD (SMD, -0.22 [95% CI, -0.47 to 0.04]; P =.10). Meta-analyses of cognitive data indicated worse executive performance in bvAD vs tAD (SMD, -1.03 [95% CI, -1.74 to -0.32]; P =.008) but not compared with bvFTD (SMD, -0.61 [95% CI, -1.75 to 0.53]; P =.29). Cases with bvAD showed a nonsignificant difference of worse memory performance compared with bvFTD (SMD, -1.31 [95% CI, -2.75 to 0.14]; P =.08) but did not differ from tAD (SMD, 0.43 [95% CI, -0.46 to 1.33]; P =.34). The neuroimaging literature revealed 2 distinct bvAD neuroimaging phenotypes: an AD-like pattern with relative frontal sparing and a relatively more bvFTD-like pattern characterized by additional anterior involvement, with the AD-like pattern being more prevalent. Conclusions and Relevance: These data indicate that bvAD is clinically most similar to bvFTD, while it shares most pathophysiological features with tAD. Based on these insights, we propose research criteria for bvAD aimed at improving the consistency and reliability of future research and aiding the clinical assessment of this AD phenotype.
UR - http://www.scopus.com/inward/record.url?scp=85120737803&partnerID=8YFLogxK
U2 - https://doi.org/10.1001/jamaneurol.2021.4417
DO - https://doi.org/10.1001/jamaneurol.2021.4417
M3 - Review article
C2 - 34870696
SN - 2168-6149
VL - 79
SP - 48
EP - 60
JO - JAMA Neurology
JF - JAMA Neurology
IS - 1
ER -