Provisional research criteria for the behavioral variant of Alzheimer’s disease A systematic review and meta-analysis

ABSTRACT Importance The behavioral variant of Alzheimer’s 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 provisional research criteria for this syndrome. Data sources A systematic literature search in PubMed/Medline and Web-of-Science databases (from inception through April 7th, 2021, performed in duplicate) led to the assessment of 83 studies, including 13 suitable for meta-analysis. Study selection Studies reporting on behavioral, neuropsychological or neuroimaging features in bvAD, and, when available, providing comparisons with “typical” amnestic-predominant AD (tAD) or behavorial variant frontotemporal dementia (bvFTD). Data extraction and synthesis We performed random-effects meta-analyses on group-level study results of clinical data, and systematically reviewed the neuroimaging literature. Main outcome and measures Behavioral symptoms (neuropsychiatric symptoms and bvFTD core clinical criteria), cognitive function (global cognition, episodic memory and executive functioning) and neuroimaging features (structural MRI, [ 18 F]FDG-PET, perfusion SPECT, amyloid-PET and tau-PET). Results Data were collected for 591 patients with bvAD. There was moderate-to-substantial heterogeneity and moderate risk of bias across studies. bvAD showed more severe behavioral symptoms compared to tAD (standardized mean difference [SMD, 95% confidence interval]: 1.16[0.74–1.59], p<0.001), and a trend towards less severe behavioral symptoms compared to bvFTD (SMD:-0.22[-0.47–0.04], p=0.10). Meta-analyses of cognitive data indicated worse executive performance in bvAD versus tAD (SMD:-1.03[-1.74–-0.32], p<0.01), but not compared to bvFTD (SMD:-0.61[-1.75–0.53], p=0.29). bvAD showed a trend towards worse memory performance compared to bvFTD (SMD:-1.31[-2.75–0.14], p=0.08), but did not differ from tAD (SMD:0.43[-0.46–1.33], p=0.34). The neuroimaging literature revealed two distinct bvAD neuroimaging-phenotypes: an “AD-like” posterior-predominant pattern and a “bvFTD-like” anterior-predominant pattern, with the former being more prevalent. Conclusions and relevance Our data indicate that bvAD is clinically most similar to bvFTD, while it shares most pathophysiological features with tAD. Based on these insights, we propose provisional research criteria for bvAD aimed at improving the consistency and reliability of future research and aiding the clinical assessment of this AD phenotype. KEY POINTS Question How does the behavioral variant of Alzheimer’s disease (bvAD) relate to typical AD (tAD) and to behavioral variant frontotemporal dementia (bvFTD) in terms of clinical presentation and neuroimaging signatures? Findings In this systematic review and meta-analysis, we found that, at time of diagnosis, bvAD showed more severe neuropsychiatric symptoms and other behavioral deficits compared to tAD. Two distinct neuroimaging phenotypes were observed across reported bvAD cases: an “AD-like” posterior-predominant pattern and a “bvFTD-like” anterior-predominant pattern, with the posterior-predominant neuroimaging phenotype being the most prevalent across reported bvAD cases. Meaning bvAD is clinically most reminiscent of bvFTD, while it shares most pathophysiological features with tAD. The provisional research criteria are aimed at improving the consistency and reliability of future research, and potentially aid in the clinical assessment of bvAD.