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Original Investigation |

Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults

Shannon L. Risacher, PhD1,2; Brenna C. McDonald, PsyD, MBA1,2,3; Eileen F. Tallman, BS1,2; John D. West, MS1,2; Martin R. Farlow, MD2,3; Fredrick W. Unverzagt, PhD2,4; Sujuan Gao, PhD2,5; Malaz Boustani, MD, MPH2,6,7,8; Paul K. Crane, MD, MPH9; Ronald C. Petersen, MD, PhD10; Clifford R. Jack Jr, MD11; William J. Jagust, MD12; Paul S. Aisen, MD13; Michael W. Weiner, MD14,15; Andrew J. Saykin, PsyD1,2 ; for the Alzheimer’s Disease Neuroimaging Initiative
[+] Author Affiliations
1Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indiana University Health Neuroscience Center, Indianapolis
2Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis
3Department of Neurology, Indiana University School of Medicine, Indianapolis
4Department of Psychiatry, Indiana University School of Medicine, Indianapolis
5Department of Biostatistics, Indiana University School of Medicine, Indianapolis
6Indiana University Center for Aging Research, Indianapolis
7Regenstrief Institute Inc, Indianapolis, Indiana
8Eskenzai Health, Indianapolis, Indiana
9Department of Internal Medicine, University of Washington, Seattle
10Department of Neurology, Mayo Clinic, Rochester, Minnesota
11Department of Radiology, Mayo Clinic, Rochester, Minnesota
12Department of Neurology, University of California–Berkeley, Berkeley
13Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego
14Departments of Radiology, Medicine, and Psychiatry, University of California–San Francisco, San Francisco
15Department of Veterans Affairs Medical Center, San Francisco, California
JAMA Neurol. 2016;73(6):721-732. doi:10.1001/jamaneurol.2016.0580.
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Importance  The use of anticholinergic (AC) medication is linked to cognitive impairment and an increased risk of dementia. To our knowledge, this is the first study to investigate the association between AC medication use and neuroimaging biomarkers of brain metabolism and atrophy as a proxy for understanding the underlying biology of the clinical effects of AC medications.

Objective  To assess the association between AC medication use and cognition, glucose metabolism, and brain atrophy in cognitively normal older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Indiana Memory and Aging Study (IMAS).

Design, Setting, and Participants  The ADNI and IMAS are longitudinal studies with cognitive, neuroimaging, and other data collected at regular intervals in clinical and academic research settings. For the participants in the ADNI, visits are repeated 3, 6, and 12 months after the baseline visit and then annually. For the participants in the IMAS, visits are repeated every 18 months after the baseline visit (402 cognitively normal older adults in the ADNI and 49 cognitively normal older adults in the IMAS were included in the present analysis). Participants were either taking (hereafter referred to as the AC+ participants [52 from the ADNI and 8 from the IMAS]) or not taking (hereafter referred to as the AC participants [350 from the ADNI and 41 from the IMAS]) at least 1 medication with medium or high AC activity. Data analysis for this study was performed in November 2015.

Main Outcomes and Measures  Cognitive scores, mean fludeoxyglucose F 18 standardized uptake value ratio (participants from the ADNI only), and brain atrophy measures from structural magnetic resonance imaging were compared between AC+ participants and AC participants after adjusting for potential confounders. The total AC burden score was calculated and was related to target measures. The association of AC use and longitudinal clinical decline (mean [SD] follow-up period, 32.1 [24.7] months [range, 6-108 months]) was examined using Cox regression.

Results  The 52 AC+ participants (mean [SD] age, 73.3 [6.6] years) from the ADNI showed lower mean scores on Weschler Memory Scale–Revised Logical Memory Immediate Recall (raw mean scores: 13.27 for AC+ participants and 14.16 for AC participants; P = .04) and the Trail Making Test Part B (raw mean scores: 97.85 seconds for AC+ participants and 82.61 seconds for AC participants; P = .04) and a lower executive function composite score (raw mean scores: 0.58 for AC+ participants and 0.78 for AC participants; P = .04) than the 350 AC participants (mean [SD] age, 73.3 [5.8] years) from the ADNI. Reduced total cortical volume and temporal lobe cortical thickness and greater lateral ventricle and inferior lateral ventricle volumes were seen in the AC+ participants relative to the AC participants.

Conclusions and Relevance  The use of AC medication was associated with increased brain atrophy and dysfunction and clinical decline. Thus, use of AC medication among older adults should likely be discouraged if alternative therapies are available.

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Figure 1.
Association of Anticholinergic (AC) Medication Use With Cognition and Glucose Metabolism Among Participants From the Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Cognitively normal older adults taking 1 or more medications with medium or high AC activity (referred to as AC+ participants [n = 52]) showed poorer cognition than those not taking these medications (referred to as AC participants [n = 350]), including a lower score on the Weschler Memory Scale–Revised Logical Memory Immediate Recall (P = .04 [A]), the Trail Making Test Part B (TMT-B) (P = .04 [B]), and an executive function composite (P = .04, with transient ischemic attack, myocardial infarction, and diabetes as additional covariates [C]). Glucose hypometabolism, as measured by the fluorodeoxyglucose F 18–positron emission tomographic (FDG-PET) standardized uptake value ratio (SUVR), was also observed in the bilateral hippocampus (P = .02, with anxiety as an additional covariate [D]) and in a global cortical region of interest of AC+ participants (n = 43) relative to AC participants (n = 286), generated from an analysis of cognitively normal participants who show greater glucose metabolism than participants with AD from the full ADNI 1 cohort (P = .03, with other vascular conditions and concussion as additional covariates [E]). Error bars indicate SD.

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Figure 2.
Effect of Anticholinergic (AC) Medication Use on Brain Atrophy Measures

Cognitively normal older adults taking 1 or more medications with medium or high anticholinergic activity (referred to as AC+ participants [n = 35]) showed more brain atrophy than participants not taking these medications (referred to as AC participants [n = 251]). Reduced total cortex volume (P = .02 [A]), increased bilateral lateral ventricle volume (P = .01 [B]), and increased inferior lateral ventricle volume (P < .001 [C]) were observed in AC+ participants relative to AC participants. Furthermore, reduced bilateral temporal lobe (P = .02, with concussion as an additional covariate [D]) and medial temporal lobe (P = .02, with concussion and cardiac surgery as additional covariates [E]) cortical thicknesses were also observed. Error bars indicate SD.

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Figure 3.
Association of Total Anticholinergic (AC) Burden Score and Brain Atrophy

The total AC burden score was significantly associated with both cognition and brain atrophy. Specifically, a higher total AC burden score was associated with poorer performance on the Trail Making Test Part B (TMT-B) (r = 0.137; P = .01, with transient ischemic attack and total number of medications as additional covariates [A]) and greater inferior lateral ventricle (r = 0.126; P = .03 [B]) and lateral ventricle volumes (r = 0.145; P = .01 [C]). Inferior lateral ventricle volume was still significantly associated with the total AC burden score after excluding participants with a total AC burden score of 0 (r = 0.331; P < .001 [E]). The TMT-B score (r = 0.146; P = .06 [D]) and lateral ventricle volume showed nonsignificant trend associations with the total AC burden score after excluding those with a total AC burden score of 0 (r = 0.152; P = .10 [F]).

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Figure 4.
Effect of Anticholinergic (AC) Medication Use on Clinical Conversion

A, A significant association between AC use and future progression of Alzheimer’s Disease Neuroimaging Initiative participants to mild cognitive impairment and/or Alzheimer disease was observed (P = .01; hazard ratio [HR], 2.47; with total number of medications, cardiac surgery, total number of comorbid conditions, and other psychiatric conditions as additional covariates). B, When evaluating the interaction between AC use and Aβ positivity, we found that participants taking 1 or more medications with medium or high AC activity who are positive for Aβ on florbetapir F-18–positron emission tomographic (PET) scans or cerebrospinal fluid (CSF) samples (referred to as AC+ and Aβ+ participants) showed a higher risk of conversion relative to participants not taking these medications who are negative for Aβ on florbetapir F-18–PET scans or CSF samples (referred to as AC and Aβ participants) (P < .001; HR, 7.73; with cardiac surgery and other psychiatric conditions as additional covariates) and participants who are positive for either AC use or Aβ (P = .001; HR, 4.24).

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