Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults

Shannon L. Risacher; Brenna C. McDonald; Eileen F. Tallman; John D. West; Martin R. Farlow; Fredrick W. Unverzagt; Sujuan Gao; Malaz Boustani; Paul K. Crane; Ronald C. Petersen; Clifford R. Jack; William J. Jagust; Paul S. Aisen; Michael W. Weiner; Andrew J. Saykin; John Q. Trojanowki; Arthur W. Toga; Laurel Beckett; Robert C. Green; John Morris; Leslie M. Shaw; Zaven Khachaturian; Greg Sorensen; Maria Carrillo; Lew Kuller; Marc Raichle; Steven Paul; Peter Davies; Howard Fillit; Franz Hefti; Davie Holtzman; Marek Marsel Mesulam; William Potter; Peter J. Snyder; Adam Schwartz; Tom Montine; Ronald G. Thomas; Michael Donohue; Sarah Walter; Devon Gessert; Tamie Sather; Gus Jiminez; Archana B. Balasubramanian; Jennifer Mason; Iris Sim; Danielle Harvey; Matthew Bernstein; Sandra Weintraub; Borna Bonakdarpour; Jordan Grafman; Alzheimer's Disease Neuroimaging Initiative

doi:10.1001/jamaneurol.2016.0580

Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults

Shannon L. Risacher, Brenna C. McDonald, Eileen F. Tallman, John D. West, Martin R. Farlow, Fredrick W. Unverzagt, Sujuan Gao, Malaz Boustani, Paul K. Crane, Ronald C. Petersen, Clifford R. Jack, William J. Jagust, Paul S. Aisen, Michael W. Weiner, Andrew J. Saykin, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, John MorrisLeslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, Davie Holtzman, Marek Marsel Mesulam, William Potter, Peter J. Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Sandra Weintraub, Borna Bonakdarpour, Jordan Grafman, Alzheimer's Disease Neuroimaging Initiative

Research output: Contribution to journal › Article › peer-review

265 Scopus citations

Abstract

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 onWeschler 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.

Original language	English (US)
Pages (from-to)	721-732
Number of pages	12
Journal	JAMA Neurology
Volume	73
Issue number	6
DOIs	https://doi.org/10.1001/jamaneurol.2016.0580
State	Published - Jun 2016

Funding

Data collection and sharing for this project were funded by the ADNI (NIH grant U01 AG024904) and Department of Defense ADNI (Department of Defense awardW81XWH-12-2- 0012). The ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering, and through the generous contributions from the Alzheimer's Association, the Alzheimer's Drug Discovery Foundation, Araclon Biotech, BioClinica Inc, Biogen Idec Inc, Bristol-Myers Squibb Company, Eisai Inc, Elan Pharmaceuticals Inc, Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc, Fujirebio, GE Healthcare, IXICO Ltd, Janssen Alzheimer Immunotherapy Research and Development LLC, Johnson and Johnson Pharmaceutical Research and Development LLC, Medpace Inc, Merck and Company Inc,Meso Scale Diagnostics LLC, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc, Piramal Imaging, Servier, Synarc Inc, and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research are providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the NIH (http://www.fnih.org/). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. The ADNI data are disseminated by the Loni at the University of Southern California. The ADNI was also supported by NIH grants P30 AG010129 and K01 AG030514 and the Dana Foundation. Additional support for analyses included in the present report was provided by the following sources: the National Institute on Aging (grants R01 AG19771, P30 AG10133, and K01 AG049050), the Alzheimer's Association, the Indiana University Health-Indiana University School of Medicine Strategic Research Initiative, and the Indiana Clinical and Translational Sciences Institute.

ASJC Scopus subject areas

Clinical Neurology

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10.1001/jamaneurol.2016.0580

Cite this

Risacher, S. L., McDonald, B. C., Tallman, E. F., West, J. D., Farlow, M. R., Unverzagt, F. W., Gao, S., Boustani, M., Crane, P. K., Petersen, R. C., Jack, C. R., Jagust, W. J., Aisen, P. S., Weiner, M. W., Saykin, A. J., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., ... Alzheimer's Disease Neuroimaging Initiative (2016). Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults. JAMA Neurology, 73(6), 721-732. https://doi.org/10.1001/jamaneurol.2016.0580

@article{7ad1747ed9a9453b91ab5c2fc2b228bc,

title = "Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults",

abstract = "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 onWeschler 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.",

author = "Risacher, {Shannon L.} and McDonald, {Brenna C.} and Tallman, {Eileen F.} and West, {John D.} and Farlow, {Martin R.} and Unverzagt, {Fredrick W.} and Sujuan Gao and Malaz Boustani and Crane, {Paul K.} and Petersen, {Ronald C.} and Jack, {Clifford R.} and Jagust, {William J.} and Aisen, {Paul S.} and Weiner, {Michael W.} and Saykin, {Andrew J.} and Trojanowki, {John Q.} and Toga, {Arthur W.} and Laurel Beckett and Green, {Robert C.} and John Morris and Shaw, {Leslie M.} and Zaven Khachaturian and Greg Sorensen and Maria Carrillo and Lew Kuller and Marc Raichle and Steven Paul and Peter Davies and Howard Fillit and Franz Hefti and Davie Holtzman and Mesulam, {Marek Marsel} and William Potter and Snyder, {Peter J.} and Adam Schwartz and Tom Montine and Thomas, {Ronald G.} and Michael Donohue and Sarah Walter and Devon Gessert and Tamie Sather and Gus Jiminez and Balasubramanian, {Archana B.} and Jennifer Mason and Iris Sim and Danielle Harvey and Matthew Bernstein and Sandra Weintraub and Borna Bonakdarpour and Jordan Grafman and {Alzheimer's Disease Neuroimaging Initiative}",

year = "2016",

month = jun,

doi = "10.1001/jamaneurol.2016.0580",

language = "English (US)",

volume = "73",

pages = "721--732",

journal = "JAMA Neurology",

issn = "2168-6149",

publisher = "American Medical Association",

number = "6",

}

Risacher, SL, McDonald, BC, Tallman, EF, West, JD, Farlow, MR, Unverzagt, FW, Gao, S, Boustani, M, Crane, PK, Petersen, RC, Jack, CR, Jagust, WJ, Aisen, PS, Weiner, MW, Saykin, AJ, Trojanowki, JQ, Toga, AW, Beckett, L, Green, RC, Morris, J, Shaw, LM, Khachaturian, Z, Sorensen, G, Carrillo, M, Kuller, L, Raichle, M, Paul, S, Davies, P, Fillit, H, Hefti, F, Holtzman, D, Mesulam, MM, Potter, W, Snyder, PJ, Schwartz, A, Montine, T, Thomas, RG, Donohue, M, Walter, S, Gessert, D, Sather, T, Jiminez, G, Balasubramanian, AB, Mason, J, Sim, I, Harvey, D, Bernstein, M, Weintraub, S , Bonakdarpour, B , Grafman, J & Alzheimer's Disease Neuroimaging Initiative 2016, 'Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults', JAMA Neurology, vol. 73, no. 6, pp. 721-732. https://doi.org/10.1001/jamaneurol.2016.0580

TY - JOUR

T1 - Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults

AU - Risacher, Shannon L.

AU - McDonald, Brenna C.

AU - Tallman, Eileen F.

AU - West, John D.

AU - Farlow, Martin R.

AU - Unverzagt, Fredrick W.

AU - Gao, Sujuan

AU - Boustani, Malaz

AU - Crane, Paul K.

AU - Petersen, Ronald C.

AU - Jack, Clifford R.

AU - Jagust, William J.

AU - Aisen, Paul S.

AU - Weiner, Michael W.

AU - Saykin, Andrew J.

AU - Trojanowki, John Q.

AU - Toga, Arthur W.

AU - Beckett, Laurel

AU - Green, Robert C.

AU - Morris, John

AU - Shaw, Leslie M.

AU - Khachaturian, Zaven

AU - Sorensen, Greg

AU - Carrillo, Maria

AU - Kuller, Lew

AU - Raichle, Marc

AU - Paul, Steven

AU - Davies, Peter

AU - Fillit, Howard

AU - Hefti, Franz

AU - Holtzman, Davie

AU - Mesulam, Marek Marsel

AU - Potter, William

AU - Snyder, Peter J.

AU - Schwartz, Adam

AU - Montine, Tom

AU - Thomas, Ronald G.

AU - Donohue, Michael

AU - Walter, Sarah

AU - Gessert, Devon

AU - Sather, Tamie

AU - Jiminez, Gus

AU - Balasubramanian, Archana B.

AU - Mason, Jennifer

AU - Sim, Iris

AU - Harvey, Danielle

AU - Bernstein, Matthew

AU - Weintraub, Sandra

AU - Bonakdarpour, Borna

AU - Grafman, Jordan

AU - Alzheimer's Disease Neuroimaging Initiative

PY - 2016/6

Y1 - 2016/6

N2 - 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 onWeschler 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.

AB - 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 onWeschler 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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Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults

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