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

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 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, [18F]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.

Investigating Heterogeneity and Neuroanatomic Correlates of Longitudinal Clinical Decline in Atypical Alzheimer Disease

“…Future studies with more follow-up will help to further elucidate patterns of clinical progression in atypical AD. Other atypical variants of AD, including the dysexecutive 49 and behavioral 50 variants of AD, have now been recognized, and it will be important to determine whether our findings generalize to these other variants. Previous studies have shown that clinical disease progression differs between both LPA and PCA and the typical amnestic variant of AD, 41,51 but a cohort of typical AD with these same clinical tests is not available to include in this study.…”

Social cognition deficits and its biometric signatures in the behavioral variant of Alzheimer’s disease

“…Nevertheless, our results suggest that specific social cognition tests and biometrics may be valuable in the clinical diagnosis of bvAD, such as the Ekman 60 faces test, Interpersonal Reactivity Index and Social Norms Questionnaire and eye movement patterns. The introduction of the first set of research criteria for bvAD [16] may greatly improve the general recognition of bvAD and the addition of the aforementioned tools may increase the diagnostic accuracy of bvAD even further in the future.…”

“…All bvAD cases fulfilled >2/6 core clinical criteria for bvFTD [18] in combination with amyloid-beta positivity based on CSF or PET examinations (see Table S1). According to recently proposed research criteria, all bvAD cases met criteria for at least "possible bvAD" (i.e., clinical bvAD in combination with positive amyloid-beta biomarkers [3], see table S1 for an overview of bvFTD symptoms in bvAD cases). In the same period, we consecutively included patients with "typical AD" (defined as amyloid-beta positive patients with MCI or AD dementia with an amnestic-predominant presentation) and patients with probable bvFTD according to the Rascovsky criteria [18] and with a negative amyloid status.…”

“…The behavioral variant of Alzheimer’s disease (bvAD) is a rare and atypical variant of Alzheimer’s disease (AD), characterized by early and predominant behavioral and personality changes with underlying AD pathology [1-3]. The clinical phenotype of bvAD overlaps substantially with that of the behavioral variant of frontotemporal dementia (bvFTD)[3]. bvFTD is characterized by a wide variety of social cognition deficits that are thought to underlie the behavioral disturbances [4].…”

“…We hypothesized that bvAD would show intermediate social cognition performance compared with bvFTD and typical AD (i.e. worse than tAD and better than bvFTD), based on the similar yet milder behavioral profile in bvAD compared with bvFTD [16].…”