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Meta-Analysis
. 2022 Jan 1;79(1):48-60.
doi: 10.1001/jamaneurol.2021.4417.

Research Criteria for the Behavioral Variant of Alzheimer Disease: A Systematic Review and Meta-analysis

Rik Ossenkoppele  1   2 , Ellen H Singleton  1 , Colin Groot  1 , Anke A Dijkstra  3 , Willem S Eikelboom  4 , William W Seeley  5 , Bruce Miller  5 , Robert Jr Laforce  6 , Philip Scheltens  1 , Janne M Papma  4 , Gil D Rabinovici  5   7   8   9 , Yolande A L Pijnenburg  1
Affiliations
Meta-Analysis

Research Criteria for the Behavioral Variant of Alzheimer Disease: A Systematic Review and Meta-analysis

Rik Ossenkoppele et al. JAMA Neurol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rabinovici 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.

Figures

Figure 1.
Figure 1.. Meta-analyses of Behavioral and Neuropsychiatric Features
Results of meta-analyses on behavioral and neuropsychiatric total scores between the behavioral variant of Alzheimer disease (bvAD) and typical Alzheimer disease (tAD) (A) and bvAD and the behavioral variant of frontotemporal dementia (bvFTD) (B). Mean weighted percentages of participants per diagnostic group fulfilling specific bvFTD core clinical features proposed by Rascovsky et al (C) or presence of specific neuropsychiatric symptoms measured using the Neuropsychiatric Inventory (NPI) (D). DCQ indicates Dépistage Cognitif de Québec; FAB, Frontal Assessment Battery; PBAC, Philadelphia Brief Assessment of Cognition; SMD, standardized mean difference. aP < .05.
Figure 2.
Figure 2.. Meta-analyses of Cognitive Performance
Results of meta-analyses on Mini-Mental State Examination (MMSE; A and B), episodic memory (C and D), and executive function (E and F) for the contrast of behavioral variant of Alzheimer disease (bvAD) vs typical Alzheimer disease (tAD) and the behavioral variation of frontotemporal dementia (bvFTD). SMD indicates standardized mean difference.
Figure 3.
Figure 3.. Neuroimaging Features in the Behavioral Variant of Alzheimer Disease (bvAD)
A and B, Two cases that serve as examples of 2 distinct bvAD neuroimaging phenotypes: an Alzheimer disease–like atrophy and tau load pattern with relative frontal sparing and a more behavioral variant of frontotemporal dementia (bvFTD)–like atrophy and tau load pattern with both posterior and anterior involvement. The tau positron emission tomography (PET) scans were performed using [18F]flortaucipir, and magnetic resonance imaging (MRI) was conducted on a 3-T scanner. C-F, Proposed neuroimaging phenotypes as part of a spectrum that ranges from a typical Alzheimer disease regional distribution to a classical bvFTD regional distribution. The brain template images were obtained from https://smart.servier.com/. G, Literature-informed estimated distribution of the regional distribution in bvAD, indicating that typical AD and bvAD-AD–like patterns are more common than bvAD-bvFTD–like and typical bvFTD. FDG indicates fluorodeoxyglucose; SPECT, single-photon emission computed tomography; SUVR, standardized uptake value ratio.
See this image and copyright information in PMC

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