Alzheimer’s disease (AD) is a heterogeneous disease that can manifest with both amnestic and non-amnestic clinical presentations. Several atypical (i.e., non-memory predominant) variants of AD have been described, including posterior cortical atrophy, logopenic variant of primary progressive aphasia, corticobasal syndrome due to AD, and dysexecutive AD.
Behavioral variant Alzheimer ’s disease (bvAD) represents another rare variant of AD that is characterized by early and predominant behavioral deficits and personality changes caused by AD pathology. The clinical syndrome of bvAD substantially overlaps with that of behavioral variant frontotemporal dementia (bvFTD) and approximately 10% to 40% of clinically diagnosed bvFTD cases have positive AD biomarkers and/or neuropathologically confirmed AD. This highlights an important diagnostic challenge, which is even more pertinent with the recent accelerated approval of aducanumab by the US Food and Drug Administration to reduce brain β-amyloid in early symptomatic AD.
Although bvEA is recognized as a clinical entity in recent diagnostic and research criteria for AD dementia, there are currently no criteria that provide specific recommendations for the diagnosis of bvEA. This contrasts with other AD variants and limits the reliable and reproducible classification of bvEA as well as uniform scientific reporting.
The current literature on bvEA includes relatively few studies with typically small sample sizes that have reported several inconsistent findings. To better understand the bvEA phenotype, a systematic review and meta-analysis of the bvEA clinical, neuroimaging, and neuropathology literature was performed and the results were applied to develop research criteria. With this work, we aim to improve the consistency and reliability of future research and potentially assist in the clinical evaluation of bvEA.
| Methods |
A systematic literature search was conducted in the PubMed/MEDLINE and Web of Science databases (from inception to April 7, 2021) in duplicate.
Studies report on behavioral, neuropsychological, or neuroimaging features in bvAD and, where available, provide comparisons with typical amnestic-predominant AD (tEA) or behavioral variant frontotemporal dementia (bvFTD).
This analysis involved random-effects meta-analyses on the results of cluster-level studies of clinical data and a systematic review of the neuroimaging literature. The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
| Results |
Main 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, fluorodeoxyglucose-positron emission tomography, positron emission tomography computed tomography). perfusion single photon, amyloid positron emission tomography and tau positron emission tomography).
The search led to the evaluation of 83 studies, including 13 suitable for meta-analysis. Data were collected from 591 patients with bvEA. There was moderate to significant heterogeneity and moderate risk of bias between studies.
Cases with bvEA showed more severe behavioral symptoms than tEA (standardized mean difference [SMD], 1.16 [95% CI, 0.74-1.59]; P < .001) and a trend toward less behavioral symptoms. severe 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 bvEA versus tEA (SMD, −1.03 [95% CI, −1.74 to −0.32]; P = .008), but not in comparison with bvFTD (SMD, −0.61 [95% CI, −1.75 to 0.53]; P = .29).
Cases with bvEA showed a nonsignificant difference in worse memory performance compared with bvFTD (SMD, −1.31 [95% CI, −2.75 to 0.14]; P = .08), but not differed from tEA (SMD, 0.43 [95% CI, −0.46 to 1.33]; P = .34).
The neuroimaging literature revealed 2 distinct neuroimaging phenotypes of bvAD: 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 common.
| Discussion |
In this systematic review and meta-analysis, we found that bvEA is more clinically reminiscent of bvFTD, while sharing most pathophysiological features with tEA. Based on these perspectives, we provide research criteria for bvEA intended to improve the consistency and reliability of future research and assist in future clinical evaluations.
> Systematic review and meta-analysis
The behavioral variant Alzheimer’s disease (bvAD) phenotype typically presents at an early age (mean [SD] age, 62.0 [7.3] years at diagnosis), is found more frequently in men than in women (61.7% vs 38.2%, in line with bvFTD but in contrast to tEA), and has a lower APOEε4 transporter frequency compared to tEA (47.5% vs 66.1%99) .
Clinically, bvEA shows a milder behavioral profile compared to bvFTD, with less compulsivity and hyperorality but a higher prevalence of neuropsychiatric symptoms, such as agitation, delusions, and hallucinations.
By definition, behavioral variant Alzheimer’s disease (bvAD) shows greater impairment on a variety of behavioral and neuropsychiatric measures compared to tAD.
The directionality of findings in meta-analyses of cognitive data suggests that bvEA might show greater memory and executive function deficits compared to bvFTD and relatively better memory function and worse executive functioning compared to tEA, but more research is needed in cohorts. larger to confirm the importance of these findings.
Neuroimaging methods were too heterogeneous across studies to perform a formal meta-analysis, but a systematic review revealed 2 distinct phenotypes of brain atrophy, hypometabolism, and tau pathology in bvEA, with many cases likely occurring on a continuum.
The neuroimaging phenotype of the most prevalent behavioral variant Alzheimer’s disease (bvAD) is an AD-like pattern involving bilateral temporoparietal regions with limited involvement of the frontal cortex. This observation is consistent with this meta-analysis on neuropathological data showing that bvEA patients were indistinguishable from tEA patients in both β-amyloid and tau burden and spatial distribution.
The other phenotype of bvEA is characterized by a neuroimaging pattern more similar to that of bvFTD, including posterior and anterior regions (e.g., anterior cingulate cortex, frontal insula, temporal poles) located in brain networks (e.g., the salience network) that are activated during socioemotional information processing.
> Research criteria for bvEA
The main objective was to propose research criteria for behavioral variant Alzheimer’s disease (bvAD) guided by the results of the systematic review and meta-analyses.
The criteria are based on consensus among all authors, including neurologists, neuropsychologists, neuropathologists, and neuroscientists.
Several issues deserve further explanation.
First, both the literature and the authors’ clinical experience align with the notion that bvEA is a combined cognitive and behavioral clinical syndrome.
Furthermore, this meta-analysis suggests that episodic memory performance in bvEA is intermediate between tEA and bvFTD, while bvEA shows greater executive dysfunction compared to bvFTD.
To improve the discriminatory accuracy between bvEA and bvFTD, it is mandatory to objectively confirm impairment in memory or executive domains. To achieve this, a comprehensive neuropsychological evaluation is recommended rather than the use of relatively rudimentary dementia screening tests.
Additionally, 2 of 5 behavioral features of the diagnostic criteria for bvFTD (i.e., disinhibition, apathy, lack of empathy, compulsivity, and hyperorality) must be present.
Note that the sixth criterion (i.e., a dysexecutive neuropsychological profile) was removed because documented memory and/or executive function deficits are required for a diagnosis.
Second, despite the clinically significant differences between bvEA and bvFTD and tEA, it is considered premature to include hallucinations and delusions in the basic research criteria because these observations were derived from only 2 studies. Instead, they were added as supporting characteristics, and future prospective studies are needed to evaluate whether they should be incorporated into the core criteria for bvEA.
Third, most AD variants have a clear neurodegenerative signature on MRI and/or FDG-PET that corresponds to their clinical phenotype, such as left hemispheric predominance in the logopenic variant of primary or progressive aphasia. occipitotemporal or occipitoparietal damage in posterior cortical atrophy. However, the neuroimaging literature in bvEA is very inconsistent. Some studies (mainly case studies or case series) showed anterior neurodegenerative patterns resembling bvFTD, but most group studies showed a combination of anterior and posterior involvement or a predominantly posterior pattern.
Fourth, evidence of β-amyloid pathology provided by PET, cerebrospinal fluid, or plasma biomarkers may improve the diagnosis from clinical bvEA to possible bvEA. Positive β-amyloid biomarkers substantially increase the likelihood that AD is the primary causal mechanism, but given its limited specificity, the possibility that β-amyloid is a comorbid pathology cannot be ruled out.
> Limitations
There are several limitations. First, bvEA is a rare AD phenotype that has, for the most part, been described in single case studies and case series. Therefore, the bvEA literature consists of relatively few cohort studies generally characterized by modest sample sizes, resulting in reduced statistical power to detect differences between bvEA vs bvFTD and tEA. This was further complicated by significant heterogeneity in patient samples and outcome measures and subsequent substantial risk of bias between studies.
Second, the variability between neuroimaging studies did not allow for a meta-analytic approach; therefore, we interpret this literature using a systematic review.
Third, in the behavioral, cognitive, and neuropathological meta-analyses, outcome measures from comparable but different studies were combined, such as different neuropsychological tests for memory and executive functions, questionnaires for neuropsychiatric/behavioral characteristics, or staining and region selection methods. brain for histopathological analysis. assessment of β-amyloid and tau.
Fourth, possible copathologies (e.g., Lewy bodies) that may contribute to the clinical phenotype were not taken into account.
Fifth, classification of possible bvEA and probable bvEA may be influenced by inherent differences in the diagnostic accuracy of various amyloid and tau PET tracers, as well as cerebrospinal fluid and plasma analyses, and centers likely vary in reliability. of the interpretation of their biomarker results.
Sixth, there was only limited data on the behavioral presentations of AD in various populations.
| Conclusion |
Although the existence of behavioral variant Alzheimer’s disease (bvAD) is recognized in the most recent diagnostic and research criteria for AD dementia, there is currently no set of criteria that provides specific recommendations for the diagnosis of bvAD.
The present systematic review and meta-analysis of the current literature on bvEA indicates that bvEA is clinically more similar to bvFTD, while sharing most of the pathophysiological features with tEA. Based on these insights, first research criteria for bvEA are provided aimed at improving the consistency and reliability of future research and potentially facilitating clinical evaluation of bvEA.
