Imaging Shows Basis for Anticholinergic Harm in Elderly

Megan Brooks

April 21, 2016

A neuroimaging study sheds light on how anticholinergic drugs act on the brain to increase risk for cognitive problems in the elderly.

Use of anticholinergic drugs (compared with nonuse) in cognitively normal older adults correlated with increased brain atrophy and hypometabolism, as well as poorer memory, executive function, and increased risk for cognitive decline, the researchers found.

"Previous studies have shown significant associations between the use of anticholinergic medications and poorer cognition, as well as an increased risk of dementia. Our study replicated the previous findings and further extended the work by looking at neuroimaging measures of brain structure and function," Shannon L. Risacher, PhD, Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, told Medscape Medical News.

"Ultimately, this study extends the previous literature by suggesting potential brain alterations that could be leading to the impairments in cognition that have been observed with anticholinergic medication use by us and other researchers," Dr Risacher said.

The findings support recommendations to avoid anticholinergic medications in the elderly when possible, she noted.

The study was published online April 18 in JAMA Neurology.

The findings are based on 402 older cognitively normal adults (mean age, 73 years) from the ongoing longitudinal Alzheimer Disease Neuroimaging Initiative (ADNI) and the Indiana Memory and Aging Study (IMAS).

As part of the studies, cognitive, neuroimaging, and other data are collected at regular intervals. Of the 402 patients, 52 were taking at least one medication with medium or high anticholinergic activity (the AC+ group) and 350 were not taking anticholinergic medications (the AC– group).

Compared with the AC– group, the AC+ group had lower average scores on Wechsler Memory Scale-Revised Logical Memory Immediate Recall (raw mean scores: 13.27 for AC+ vs 14.16 for AC–; P = .04) and performed more poorly on the Trail Making Test Part B (raw mean scores: 97.85 sec vs 82.61 sec; P = .04), the researchers found.

The AC+ patients also had a lower executive function composite score (raw mean scores: 0.58 vs 0.78 for AC– patients; P = .04).

A significant effect of AC drug use on brain structure was also observed, with AC+ participants showing reduced total cortical volume (P = .02) and temporal lobe cortical thickness (P = .02) and greater lateral ventricle (P = .01) and inferior lateral ventricle (P < .001) volumes relative to AC– participants.

After adjustment for account relevant covariates, there was a significant association between AC medication use and future progression to mild cognitive impairment (MCI) and/or Alzheimer's disease (hazard ratio, 2.47; P = .01), the researchers report.

The effects appeared to be additive, they note, in that increased burden of AC medications was associated with poorer executive function and increased brain atrophy. "These results suggest that medications with AC properties may be detrimental to brain structure and function, as well as cognition," the authors write.

Avoid or Monitor Closely

"Given the literature on impaired cognition with these medications, as well as our current findings," said Dr Risacher, "patients taking anticholinergic medications should talk to their doctors about all prescription and over-the-counter anticholinergic medications they are taking to see whether continuing these medication is prudent given the risk/benefit ratio and/or if alternative treatments are available."

"However, for some medications, good alternatives may not be available (antimuscarinic bladder control medications, for example). For these medications, we would suggest that doctors closely monitor these medications and their effects and use the lowest dose that is effective in their patients. Finally, doctors should always consider the cognitive effects of all medications in older adults, as this group is at the highest risk for cognitive problems and dementia," Dr Risacher advised.

Cyrus Raji, MD, PhD, University of California, Los Angeles, who reviewed the study for Medscape Medical News, said the findings "make sense. There is a list of medications that should be avoided in the elderly and a lot of the medications on that list are anticholinergic medications."

"This new paper shows why those medicines should be avoided in the elderly, which is because they have effects on the brain that are negative, in terms of reduced brain volume. That is a very sensible correlate for why we try not to prescribe these medicines in the elderly. It is standard of care to avoid anticholinergic medicines in the elderly, and we now see why that is the case," Dr Raji noted.

Dr Risacher said her group plans to do follow-up studies in additional study populations to replicate the neuroimaging findings.

"We would also like to look in older adults who already have cognitive problems (such as those with MCI) to determine whether these medications exacerbate their cognitive problems and/or associated brain changes. Finally, we would like to look at other measures of brain activation, blood flow, and brain structure to better understand the central brain effects associated with anticholinergic medication use," she said.

"Future studies in animal models might also be warranted to better understand any direct effects that these medications are having on the brain," Dr Risacher said.

The study was funded by ADNI and Department of Defense ADNI. Dr Risacher and Dr Raji have disclosed no relevant financial relationships.

JAMA Neurol. Published online April 18, 2016. Abstract

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