Dataset Information

Anticholinergic drugs and forebrain magnetic resonance imaging changes in cognitively normal people and those with mild cognitive impairment.

ABSTRACT:

Background and purpose

Anticholinergic (AC) medication use is associated with cognitive decline and dementia, which may be related to an AC-induced central hypocholinergic state, but the exact mechanisms remain to be understood. We aimed to further elucidate the putative link between AC drug prescription, cognition, and structural and functional impairment of the forebrain cholinergic nucleus basalis of Meynert (NBM).

Methods

Cognitively normal (CN; n = 344) and mildly cognitively impaired (MCI; n = 224) Alzheimer's Disease Neuroimaging Initiative Phase 3 participants with good quality 3-T magnetic resonance imaging were included. Structural (regional gray matter [GM] density) and functional NBM integrity (functional connectivity [FC]) were compared between those on AC medication for > 1 year (AC⁺ ) and those without (AC^- ) in each condition. AC burden was classed as mild, moderate, or severe.

Results

MCI AC⁺ participants (0.55 ± 0.03) showed lower NBM GM density compared to MCI AC^- participants (0.56 ± 0.03, p = 0.002), but there was no structural AC effect in CN. NBM FC was lower in CN AC⁺ versus CN AC^- (3.6 ± 0.5 vs. 3.9 ± 0.6, p = 0.001), and in MCI AC⁺ versus MCI AC^- (3.3 ± 0.2 vs. 3.7 ± 0.5, p < 0.001), with larger effect size in MCI. NBM FC partially mediated the association between AC medication burden and cognition.

Conclusions

Our findings provide novel support for a detrimental effect of mild AC medication on the forebrain cholinergic system characterized as functional central hypocholinergic that partially mediated AC-related cognitive impairment. Moreover, structural tissue damage suggests neurodegeneration, and larger effect sizes in MCI point to enhanced susceptibility for AC medication in those at risk of dementia.

SUBMITTER: Meng D

PROVIDER: S-EPMC9304308 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFew studies have addressed whether anticholinergic (AC) medications for overactive bladder (OAB) cause cognitive decline in individuals with existing cognitive impairment, and whether the APOE ε4 gene increases this risk.ObjectiveTo determine whether OAB AC use is associated with a clinically relevant change in cognitive measures among adults with normal and abnormal cognition.Design setting and participantsThis was a retrospective cohort study using data from the National Alzheimer's Coordinating Center. Patients were enrolled at specialized centers in the USA between 2005 and 2019. Patients with existing OAB AC use, missing APOE ε4 status, and confounding neurologic diagnoses were excluded. New users of an OAB AC were matched 1:1 to patients not taking an OAB AC using propensity scores.InterventionNew use of oxybutynin, tolterodine, solifenacin, trospium, darifenacin, or fesoterodine.Outcome measurements and statistical analysisThe outcome was a change in cognitive function, measured as a ≥1-point increase on the Clinical Dementia Rating (CDR) instrument or a ≥3-point decrease on the Mini-Mental State Examination (MMSE). Conditional logistic regression with odds ratios (ORs) was conducted. We also tested for APOE ε4 effect modification.Results and limitationsAmong 18 835 eligible patients, 782 matched pairs were identified. The most common OAB ACs were oxybutynin (38%) and tolterodine (23%). There was no significant increase in the risk of a clinically relevant cognitive decline among OAB AC users (CDR: OR 1.38, 95% confidence interval [CI] 0.93-2.05; p = 0.11, MMSE: OR 1.06, 95% CI 0.79-1.43; p = 0.70). There was no significant interaction between APOE ε4 status and OAB AC use for the CDR (p = 0.38) or MMSE (p = 0.95) outcomes. Users of oxybutynin or tolterodine had numerically higher odds of a change on the CDR test (OR 1.65, 95% CI 0.98-2.77) that was close to statistical significance (p = 0.06). Limitations include the inability to determine medication dose or duration, and residual confounding.ConclusionsOAB AC use was not associated with a significant change in cognitive function among individuals with normal and abnormal cognition. Further research is necessary to determine if oxybutynin and tolterodine are significantly more likely to cause cognitive decline.Patient summaryUse of a specific class of overactive bladder medication was not associated with negative changes in brain function among patients with either normal or abnormal function. A genetic risk factor for Alzheimer's disease did not predispose individuals to cognitive decline when taking these drugs. Two of the drugs (oxybutynin and tolterodine) may lead to a higher risk of cognitive decline in comparison to other drugs, and this needs further research.