Brain Scans Link Physical Changes to Cognitive Risks for Common Over the Counter Drugs

Older adults might want to avoid a using class of drugs commonly used in over-the-counter products such as nighttime cold medicines due to their links to cognitive impairment, a research team led by scientists at Indiana University School of Medicine has recommended.

Using brain imaging techniques, the researchers found lower metabolism and reduced brain sizes among study participants taking the drugs known to have an anticholinergic effect, meaning they block acetylcholine, a nervous system neurotransmitter.

Previous research found a link between between the anticholinergic drugs and cognitive impairment and increased risk of dementia. The new paper published in the journal JAMA Neurology, is believed to be the first to study the potential underlying biology of those clinical links using neuroimaging measurements of brain metabolism and atrophy.

“These findings provide us with a much better understanding of how this class of drugs may act upon the brain in ways that might raise the risk of cognitive impairment and dementia,” said Shannon Risacher, Ph.D., assistant professor of radiology and imaging sciences, first author of the paper, “Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults.”

“Given all the research evidence, physicians might want to consider alternatives to anticholinergic medications if available when working with their older patients,” Dr. Risacher said.

Drugs with anticholinergic effects are sold over the counter and by prescription as sleep aids and for many chronic diseases including hypertension, cardiovascular disease, and chronic obstructive pulmonary disease.

A list of anticholinergic drugs and their potential impact is at http://www.agingbraincare.org/uploads/products/ACB_scale_-_legal_size.pdf.

Scientists have linked anticholinergic drugs cognitive problems among older adults for at least 10 years. A 2013 study by scientists at the IU Center for Aging Research and the Regenstrief Institute found that drugs with a strong anticholinergic effect cause cognitive problems when taken continuously for as few as 60 days. Drugs with a weaker effect could cause impairment within 90 days.

The current research project involved 451 participants, 60 of whom were taking at least one medication with medium or high anticholinergic activity. The participants were drawn from a national Alzheimer’s research project — the Alzheimer’s Disease Neuroimaging Initiative — and the Indiana Memory and Aging Study.

To identify possible physical and physiological changes that could be associated with the reported effects, researchers assessed the results of memory and other cognitive tests, positron emission tests (PET) measuring brain metabolism, and magnetic resonance imaging (MRI) scans for brain structure.

Image shows a pill in a person's hand.
Previous research found a link between between the anticholinergic drugs and cognitive impairment and increased risk of dementia. Image is for illustrative purposes only.

The cognitive tests revealed that patients taking anticholinergic drugs performed worse than older adults not taking the drugs on short-term memory and some tests of executive function, which cover a range of activities such as verbal reasoning, planning, and problem solving.

Anticholinergic drug users also showed lower levels of glucose metabolism — a biomarker for brain activity — in both the overall brain and in the hippocampus, a region of the brain associated with memory and which has been identified as affected early by Alzheimer’s disease.

The researchers also found significant links between brain structure revealed by the MRI scans and anticholinergic drug use, with the participants using anticholinergic drugs having reduced brain volume and larger ventricles, the cavities inside the brain.

“These findings might give us clues to the biological basis for the cognitive problems associated with anticholinergic drugs, but additional studies are needed if we are to truly understand the mechanisms involved,” Dr. Risacher said.

About this neuroscience research

Additional investigators contributing to this research were Brenna C. McDonald, Eileen F. Tallman, John D. West, Martin R. Farlow, Fredrick W. Unverzagt, and Sujuan Gao, IU School of Medicine; Malaz Boustani, IU School of Medicine, Regenstrief Institute and Eskenazi Health; Paul K. Crane, University of Washington; Ronald C. Petersen and Clifford R. Jack Jr., Mayo Clinic; William J. Jagust, University of California-Berkeley; Paul S. Aisen, University of Southern California, San Diego; Michael W. Weiner, University of California-San Francisco; Andrew J. Saykin, IU School of Medicine for the Alzheimer’s Disease Neuroimaging Initiative.

Funding: Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012).

ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through contributions from the following: Alzheimer’s Association; 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 & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., 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 is providing funds to support ADNI clinical sites in Canada.

Private sector contributions are facilitated by the Foundation for the National Institutes of Health. 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. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. ADNI was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation.

Additional support for analyses in this study was provided by the following sources: NIA R01 AG19771, P30 AG10133, 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.

Source: Eric Schoch – Indiana University
Image Source: The image is in the public domain.
Original Research: Abstract for “Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults” by Shannon L. Risacher, PhD; Brenna C. McDonald, PsyD, MBA; Eileen F. Tallman, BS; John D. West, MS; Martin R. Farlow, MD; Fredrick W. Unverzagt, PhD; Sujuan Gao, PhD; Malaz Boustani, MD, MPH; Paul K. Crane, MD, MPH; Ronald C. Petersen, MD, PhD; Clifford R. Jack Jr, MD; William J. Jagust, MD; Paul S. Aisen, MD; Michael W. Weiner, MD; and Andrew J. Saykin, PsyD; for the Alzheimer’s Disease Neuroimaging Initiative in JAMA Neurology. Published online April 18 2016 doi:10.1001/jamaneurol.2016.0580


Abstract

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

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.

“Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults” by Shannon L. Risacher, PhD; Brenna C. McDonald, PsyD, MBA; Eileen F. Tallman, BS; John D. West, MS; Martin R. Farlow, MD; Fredrick W. Unverzagt, PhD; Sujuan Gao, PhD; Malaz Boustani, MD, MPH; Paul K. Crane, MD, MPH; Ronald C. Petersen, MD, PhD; Clifford R. Jack Jr, MD; William J. Jagust, MD; Paul S. Aisen, MD; Michael W. Weiner, MD; and Andrew J. Saykin, PsyD; for the Alzheimer’s Disease Neuroimaging Initiative in JAMA Neurology. Published online April 18 2016 doi:10.1001/jamaneurol.2016.0580

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