Benzodiazepine use and neuroimaging markers of Alzheimer's disease in nondemented older individuals: an MRI and 18F Florbetapir PET study in the MEMENTO cohort

Abstract

Recent evidence suggests an association between benzodiazepines (BZDs) use and lower brain amyloid load, a hallmark of AD pathophysiology. Other AD-related markers include hippocampal atrophy, but the effect of BZDs on hippocampal volume remains unclear. We aimed at 1) replicating findings on BZDs use and brain amyloid load and 2) investigating associations between BZDs use and hippocampal volume, in the MEMENTO clinical cohort of nondemented older adults with isolated memory complaint or light cognitive impairment at baseline. Total Standardized Uptake Value Ratio (SUVR) of brain amyloid load and hippocampal volume (HV) were obtained, respectively, from ¹⁸F Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI), and compared between BZD chronic users and nonusers using multiple linear regressions adjusted for age, sex, educational level, ApoE ε4 genotype, cognitive and neuropsychiatric assessments, history of major depressive episodes and antidepressant intake. BZD users were more likely to manifest symptoms of depression, anxiety and apathy. In the MRI subgroup, BZD users were also more frequently females with low education and greater clinical impairments as assessed with the clinical dementia rating scale. Short- versus long-acting BZDs, Z-drugs versus non-Z-drugs BZDs, as well as dose and duration of BZD use, were also considered in the analyses. Total SUVR and HV were significantly lower and larger, respectively, in BZD users (n = 38 in the PET subgroup and n = 331 in the MRI subgroup) than in nonusers (n = 251 in the PET subgroup and n = 1840 in the MRI subgroup), with a medium (Cohen's d = -0.43) and low (Cohen's d = 0.10) effect size, respectively. Short-acting BZDs and Z-drugs were more significantly associated with larger HV. We found no effect of dose and duration of BZD use. Our results support the involvement of the GABAergic system as a potential target for blocking AD-related pathophysiology, possibly via reduction in neuronal activity and neuroinflammation. Future longitudinal studies may confirm the causal effect of BZDs to block amyloid accumulation and hippocampal atrophy.

Fig. 1. Scatterplots of the individual total amyloid SUVR in BZD users and nonusers.

BZD: Benzodiazepine; SUVR: standardized uptake value ratio. Thresholds for amyloid positivity with the PET imaging processing used in the MEMENTO cohort were 0.79 (liberal threshold) and 0.88 (conservative threshold) [17]. The total amyloid load was significantly lower in BZD users compared to BZD nonusers (beta = −0.073, p = 0.042) after controlling for age, sex, educational level, CDR, MMSE, NPI scores (depression, anxiety and apathy) history of major depressive episodes, history of antidepressant intake and ApoE ε4.

Fig. 2. Scatterplots of the individual HV in BZD users and nonusers.

BZD Benzodiazepine, HV hippocampal volume, TIV total intracranial volume. The hippocampal volume (ratio of the sum of the left and right hippocampal volumes over TIV, multiplied by 1000 to facilitate interpretation) was significantly larger in BZD users compared to BZD nonusers (beta = 0.072, p = 0.027) after controlling for age, sex, educational level, CDR, MMSE, NPI scores (depression, anxiety and apathy) history of major depressive episodes, history of antidepressant intake and ApoE ε4, type of MRI.