Behavioral Variant Alzheimer Similar Clinically to BV Frontotemporal Dementia, Pathophysiologically to Typical Alzheimer

Rik Ossenkoppele, PhD

Although Alzheimer disease (AD) is a disease that can manifest with both amnestic and nonamnestic clinical presentations, findings published in JAMA Neurology indicated that behavioral variant AD (bvAD) is most clinically similar to behavioral variant frontotemporal dementia (bvFTD), while sharing most pathophysiological features with typical AD (tAD).

Lead author Rik Ossenkoppele, PhD, Department of Neurology, Vrije Universiteit Amsterdam, and colleagues conducted a systematic review and meta-analysis to understand the associations between bvAD and tAD, and bvAD and bvFTD in terms of clinical presentation and neuroimaging signatures. At the conclusion of the analysis, the investigators proposed research criteria for improving the consistency and reliability of future research of bvAD.

A total of 13 studies that reported on behavioral, neuropsychological, or neuroimaging features in bvAD were included in the meta-analysis. Clinical characteristics, which included behavioral features and neuropsychiatric symptoms were extracted using bvFTD criteria and Neuropsychiatric Inventory (NPI), respectively. At the conclusion of the analysis, patients with bvAD demonstrated more severe behavioral and neuropsychiatric symptoms than those with tAD (standardized mean difference [SMD], 1.16 [95% CI, 0.74-1.59]; P <.001). In comparison with bvFTD, there was a nonsignificant difference in severe behavioral/neuropsychiatric symptoms (SMD, –0.22 [95% CI, –0.47 to 0.04]; P = .10).

Neuropsychological characteristics were evaluated using Mini-Mental State Examination (MMSE) and memory and executive function tests. At initial assessment of bvAD, patients demonstrated no differences on MMSE compared to those with tAD (SMD, –0.18 [95% CI, –0.56 to 0.20]; P = .35) and those with bvFTD (SMD, –0.22 [95% CI, –0.78 to 0.35]; P = .46). Worse executive performance was found for patients with bvAD when compared with tAD (SMD, –1.03 [95% CI, –1.74 to –0.32]; P = .008), but not when compared with bvFTD (SMD, –0.61 [95% CI, –1.75 to 0.53]; P = .29).

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Using 16 structural MRI studies, 2 distinct bvAD neuroimaging phenotypes were distilled from the literature. They were characterized by either relative frontal sparing, which was more AD-like, or by both posterior and anterior involvement, which resembled bvFTD. Investigators proposed that these phenotypes occur on a continuum, with the more AD-like phenotype being most prevalent.

The meta-analyses on neuropathological data indicated no differences between bvAD and tAD on burden of amyloid-ß across frontal regions (SMD, 0.23 [95% CI, –0.36 to 0.81]; P = .45), medial temporal lobe (SMD, –0.06 [95% CI, –0.65 to 0.53]; P = .84) or occipital cortex (SMD, –0.16 [95% CI, –1.05 to 0.73]; P = .73). Tau burden, measured in 4 studies, did not differ between the 2 groups across frontal regions (SMD, –0.05 [95% CI, –0.56 to 0.46]; P = .84), medial temporal lobe (SMD, 0.32 [95% CI, –0.19 to 0.83]; P = .22) or occipital cortex (SMD, –0.36 [95% CI, –0.95 to 0.23]; P = .24).

Based on results from the systematic review and meta-analysis, the investigators provided research for bvAD. They included 4 levels, the first (clinical bvAD) which can be established solely based on clinical information, while levels 2 and 3 (possible bvAD and probable bvAD) add biomarker confirmation of amyloid-ß and tau pathology. The fourth level (definite bvAD) is assigned through histopathological or genetic confirmation of AD in conjunction with a bvAD clinical syndrome.

Clinical bvAD, can be characterized by early, persistent, predominant and progressive change or exacerbation of at least 2 of 5 core behavioral features, as well as documented impairment in executive functions. The features include behavioral disinhibition; apathy or inertia; loss of empathy or sympathy; preservative, stereotyped, or compulsive or ritualistic behavior; or hyperorality and dietary changes. Patients will not meet these criteria if behavioral deficits are accounted for by another concurrent neurological or nonneurological medical comorbidity, a known genetic variant associated with the familial behavioral variant of frontotemporal dementia (FTD), or the use of medication. Supportive features, although not mandatory, included presence of hallucinations and/or delusions and AD-specific and/or behavioral variant of FTD-specific neuroimaging features on MRI or CT scan.

Possible bvAD cases were characterized as meeting criteria for clinical bvAD and showing presence of ß-amyloid pathology on amyloid PET and/or in cerebrospinal fluid (CSF). This group also had tau pathology CSF and/or plasma. In comparison, probable bvAD were cases that met criteria for both clinical or possible bvAD, with additional in vivo tau PET evidence for the presence of neocortical tau aggregates. Definite bvAD meets the criteria for clinical bvAD, possible bvAD, or probable bvAD, and has the presence of AD. This presence is established by histopathological indication of AD as the primary pathology on biopsy or at autopsy, or a presence of a known genetic variant associated with familial AD.

"There are several promising novel biomarkers and behavioral features that could be included in future bvAD criteria, such as more objective measurements of behavior, such as social cognition in conjunction with biometric information (eg, eye tracking, face reading, galvanic skin response) or blood-based biomarkers of AD pathology (eg, phosphorylated tau, amyloid-β) and neurodegeneration (eg, neurofilament light chain)," the study authors wrote. "Furthermore, the diagnostic utility of potential bvAD-specific features (eg, relatively preserved disease insight, presence of hallucinations, and delusions) or measures of disease severity (eg, the frontotemporal lobar degeneration-modified Clinical Dementia Rating scale) should be further investigated."

REFERENCE

Ossenkoppele R, Singleton EH, Groot C. Reseach criteria for the behavioral variant of Alzheimer disease. JAMA Neurol. 2022;79(1):48-60. doi:10.1001/jamaneurol.2021.4417