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

Supplementary Online Content

Risacher SL, McDonald BC, Tallman EF, et al; Alzheimer’s Disease Neuroimaging Initiative. Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults. JAMA Neurol. Published online April 18, 2016. doi:10.1001/jamaneurol.2016.0580.

eAppendix. Methods

eTable 1. Medications With Medium or High Anticholinergic Activity Used in the Included ADNI and IMAS Samples

eTable 2. Medications Used in Calculating the Total Anticholinergic Burden Score in the Included ADNI and IMAS Samples

eTable 3. Indiana Memory and Aging Study Demographics (Mean (SD))

eFigure 1. Association of AC medication use with general cognition in the IMAS

eFigure 2. Association of AC medication use with brain atrophy in the IMAS

eFigure 3. Association of the total AC burden score and general cognition and brain atrophy measures in the IMAS

This supplementary material has been provided by the authors to give readers additional information about their work.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 eMethods

Alzheimer’s Disease Neuroimaging Initiative (ADNI)

ADNI was launched in 2003 by the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the Food and Drug Administration (FDA), private pharmaceutical companies and non- profit organizations, as a $60 million, 5-year public-private partnership. The primary goal of ADNI has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer’s disease (AD). Determination of sensitive and specific markers of very early AD progression is intended to aid researchers and clinicians to develop new treatments and monitor their effectiveness, as well as lessen the time and cost of clinical trials.

The Principal Investigator of this initiative is Michael W. Weiner, MD, VA Medical Center and University of California-San Francisco. ADNI is the result of efforts of many co-investigators from a broad range of academic institutions and private corporations, and subjects have been recruited from over 50 sites across the U.S. and Canada. The initial goal of ADNI was to recruit 800 subjects but ADNI has been followed by ADNI-GO and ADNI- 2. To date these three protocols have recruited over 1500 adults, ages 55 to 90, to participate in the research, consisting of cognitively normal older individuals, people with early or late MCI, and people with early AD. The follow up duration of each group is specified in the protocols for ADNI-1, ADNI-2 and ADNI-GO. Subjects originally recruited for ADNI-1 and ADNI-GO had the option to be followed in ADNI-2. Further information can be found at http://www.adni-info.org/ and in previous reports24-29.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 eTable 1. Medications with Medium or High Anticholinergic Activity Used in the Included ADNI and IMAS Samples*

Generic Name Selected Brand Name(s) Atropine Sal-Tropine Chlorpheniramine Chlor-Trimeton, Chlor-Tab, Aller-Chlor Chlorpromazine Thorazine Cyproheptadine Periactin, Peritol Darifenacin Enablex Dicyclomine Bentyl Dimenhydrinate Dramamine, Gravol, others Benadryl, Sominex, Diphenhist, Wal-Dryl, Hydramine, Tylenol PM, Diphenhydramine Advil PM, Aleve PM, others Doxepin Silenor, Zonalon, Prudoxin Hyoscyamine Anaspaz, Levsin Loperamide Immodium Meclizine/Buclizine Antivert, Bonine, Verticalm Methocarbamol Robaxin Nortriptyline Pamelor, Aventyl Oxybutynin Ditropan, Lyrinel, Novitropan Paroxetine Paxil Rantidine Zantac, Deprizine Solifenacin Vesicare Tolterodine Detrol, Detrusitol Trospium Spasmex, Sanctura *Medications listed in 18 or as medium/high activity on at least one of the following lists: a) Anticholinergic burden list (http://www.agingbraincare.org/uploads/products/ACB_scale_- _legal_size.pdf; http://www.bmedreport.com/wp-content/uploads/2011/06/Drugs-on-the-Anticholinergic- Burden-ACB-scale.jpg). b) Pharmacist’s Letter (http://pharmacistsletter.therapeuticresearch.com/pl/ArticleDD.aspx?nidchk=1&cs=&s=PL&pt=5&fpt=2&d d=271223&pb=PRL).

Downloaded From: https://jamanetwork.com/ on 09/28/2021 eTable 2. Medications Used in Calculating the Total Anticholinergic Burden Score in the Included ADNI and IMAS Samples**

Generic Name Brand Name ACB Score Alprazolam Xanax 1 Atenolol Tenormin 1 Atropine Sal-Tropine 3 Buproprion Wellbutrin, Zyban 1 Cetirizine Zyrtec 1 Chlorpheniramine Chlor-Trimeton, Chlor-Tab, Aller-Chlor 3 Chlorthalidone Diuril, Hygroton, Thialitone 1 Codeine Vicodin, Contin, others 1 Cyproheptadine Periactin, Peritol 2 Darifenacin Enablex 3 Dexchlorpheniramine Polaramine 3 Diazepam Valium 1 Dicyclomine Bentyl 3 Digoxin Lanoxin, Digitek 1 Dimenhydrinate Dramamine, Gravol, others 3 Benadryl, Sominex, Diphenhist, Wal-Dryl, Hydramine, Tylenol Diphenhydramine 3 PM, Advil PM, Aleve PM, others Doxepin Silenor, Zonalon, Prudoxin 3 Furosemide Lasix 1 Hydrocortisone Cortef, Cortaid 1 Hyoscyamine Anaspaz, Levsin 3 Isosorbide Isordil, Ismo 1 Levocetirizine Xyzal 1 Loperamide Immodium 1 Meclizine/Buclizine Antivert, Bonine, Verticalm 3 Methocarbamol Robaxin 3 Metoprolol Lopressor, Toprol 1 Nifedipine Procardia, Adalat 1 Nortriptyline Pamelor, Aventyl 3 Oxybutynin Ditropan, Lyrinel, Novitropan 3 Paroxetine Paxil 3 Prednisone Deltasone, Sterapred 1 Rantidine Zantac, Deprizine 1 Solifenacin Vesicare 3 Theophylline Theodur, Uniphyl, Theolair, Slo-bid 1 Timolol maleate Timoptic, Betimol 1 Tolterodine Detrol, Detrusitol 3 Trazodone Desyrel, Oleptro 1 Triamterene Dyrenium 1 Trospium Spasmex, Sanctura 3 Venlafaxine Effexor 1 Warfarin Coumadin 1 **Medications listed in the anticholinergic burden list (http://www.agingbraincare.org/uploads/products/ACB_scale_-_legal_size.pdf; http://www.bmedreport.com/wp-content/uploads/2011/06/Drugs-on-the-Anticholinergic-Burden-ACB- scale.jpg).

Downloaded From: https://jamanetwork.com/ on 09/28/2021 eTable 3. Indiana Memory and Aging Study Demographics (Mean (SD))

Participants, No. AC- AC+ p-value (n=41) (n=8) Age, mean (SD), y 70.2 (7.1) 73.6 (10.3) .25 Sex Male 13 3 .75 Female 28 5 Education, mean (SD), y 17.1 (1.9) 16.9 (2.5) .78 Handedness Right 41 8 n/a Left 0 0 APOE ε4 positive, % of participants* 40.0% 12.5% .14 Non-Hispanic white, % of participants 90.2% 100.0% .36 Medications, mean (SD), Total No. 2.9 (2.1) 6.0 (2.8) .001 Comorbid conditions, mean (SD), Total No. 1.1 (0.9) 1.8 (1.6) .12 Transient ischemic attack No 41 8 n/a Yes 0 0 Myocardial infarction No 41 8 n/a Yes 0 0 Cardiac surgery No 41 6 .001 Yes 0 2 Hypertension No 32 5 .35 Yes 9 3 Hyperlipidemia No 21 5 .65 Yes 18 3 Diabetes No 39 8 .52 Yes 2 0 Sleep apnea No 39 8 .52 Yes 2 0

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Other vascular conditions (eg, atrial fibrillation) No 38 5 .02 Yes 3 3 Anxiety No 39 7 .41 Yes 2 1 Depression No 36 7 0.98 Yes 5 1 Insomnia No 41 8 n/a Yes 0 0 ADD or ADHD No 41 8 n/a Yes 0 0 Other psychiatric condition (eg, posttraumatic stress disorder) No 41 8 n/a Yes 0 0 Concussion No 37 7 .82 Yes 4 1

* One participant (AC-) missing APOE genotype. AC = anticholinergic; AC- = participant not taking AC medication with medium or high AC activity; AC+ = participant taking AC medication with medium or high AC activity; ADD/ADHD = attention deficit disorder/attention deficit hyperactivity disorder; APOE = apolipoprotein E; SD = standard deviation.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 eFigure 1. Association of AC medication use with general cognition in the IMAS

Cognitively normal older adults taking one or more medications with medium or high anticholinergic (AC) activity (n=8) showed poorer general cognition than those not taking these medications (n=41; p=0.030). The general cognitive test z-score includes adjusted scores on the Mini-Mental State Exam (MMSE), Mattis Dementia Rating Scale (DRS), and/or Montreal Cognitive Assessment (MoCA). AC = anticholinergic; AC- = participant not taking AC medication with medium or high AC activity; AC+ = participant taking AC medication with medium or high AC activity.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 eFigure 2. Association of AC medication use with brain atrophy in the IMAS

Cognitively normal older adults taking one or more medications with medium or high anticholinergic (AC) activity (n=8) showed significantly reduced bilateral mean medial temporal lobe cortical thickness (A; p=0.014) and a trend for reduced bilateral overall mean temporal lobe cortical thickness (B; p=0.054). AC = anticholinergic; AC- = participant not taking AC medication with medium or high AC activity; AC+ = participant taking AC medication with medium or high AC activity.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 eFigure 3. Association of the total AC burden score and general cognition and brain atrophy measures in the IMAS

A trend for poorer general cognition and greater brain atrophy with higher total AC burden score was observed in the IMAS study. When including all participants, a trend for a significant negative association between total AC burden score and general cognition

(A; rs=-0.239, p=0.098) was observed. In addition, a significant association was observed between total AC burden score and

bilateral mean medial temporal lobe cortical thickness (B; rs=-0.313, p=0.032). However, when excluding those with a total AC

burden score of 0, general cognition was significantly negatively associated total AC burden score (C; rs=-0.625, p=0.004) and there

was a trend for a negative association between total AC burden score and bilateral mean temporal lobe cortical thickness (D; rs=- 0.428, p=0.068). AC = anticholinergic; AC- = participant not taking AC medication with medium or high AC activity; AC+ = participant taking AC medication with medium or high AC activity.

Downloaded From: https://jamanetwork.com/ on 09/28/2021