Research Criteria for the Behavioral Variant of Alzheimer Disease
Authors: Rik Ossenkoppele, Ellen H. Singleton, Colin Groot, Anke A. Dijkstra, Willem S. Eikelboom, William W. Seeley, Bruce Miller, Robert Jr Laforce, Philip Scheltens, Janne M. Papma, Gil D. Rabinovici, Yolande A. L. Pijnenburg
Journal: JAMA Neurology (2021)

<h3>Importance</h3> 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. <h3>Objective</h3> To perform a systematic review and meta-analysis of the bvAD literature and use the outcomes to propose research criteria for this syndrome. <h3>Data Sources</h3> A systematic literature search in PubMed/MEDLINE and Web of Science databases (from inception through April 7, 2021) was performed in duplicate. <h3>Study Selection</h3> 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). <h3>Data Extraction and Synthesis</h3> 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. <h3>Main Outcomes and Measures</h3> 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, [<sup>18</sup>F]fluorodeoxyglucose-positron emission tomography, perfusion single-photon emission computed tomography, amyloid positron emission tomography, and tau positron emission tomography). <h3>Results</h3> 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];<i>P</i> &lt; .001) and a trend toward less severe behavioral symptoms compared with bvFTD (SMD, −0.22 [95% CI, −0.47 to 0.04];<i>P</i> = .10). Meta-analyses of cognitive data indicated worse executive performance in bvAD vs tAD (SMD, −1.03 [95% CI, −1.74 to −0.32];<i>P</i> = .008) but not compared with bvFTD (SMD, −0.61 [95% CI, −1.75 to 0.53];<i>P</i> = .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];<i>P</i> = .08) but did not differ from tAD (SMD, 0.43 [95% CI, −0.46 to 1.33];<i>P</i> = .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. <h3>Conclusions and Relevance</h3> 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.