Abstract
Overactive bladder (OAB) is often treated with medications that block the cholinergic receptors in the bladder (known as anticholinergics). The effect of this medication class on cognition and risk of dementia has been increasingly studied over the past 40 years after initial studies suggested that the anticholinergic medication class could affect memory. Short-term randomized clinical trials demonstrated that the administration of the anticholinergic oxybutynin leads to impaired memory and attention, and large, population-based studies showed associations between several different anticholinergic medications and dementia. However, trials involving anticholinergics other than oxybutynin have not shown such substantial effects on short-term cognitive function. This discordance in results between short-term cognitive safety of OAB anticholinergics and the long-term increased dementia risk could be explained by the high proportion of patients using oxybutynin in the OAB subgroups of the dementia studies, or a study duration that was too short in the prospective clinical trials on cognition with other OAB anticholinergics. Notably, all studies must be interpreted in the context of potential confounding factors, such as when prodromal urinary symptoms associated with the early stages of dementia lead to an increase in OAB medication use, rather than the use of OAB medication causing dementia. In patients with potential risk factors for cognitive impairment, the cautious use of selected OAB anticholinergic agents with favourable physicochemical and pharmacokinetic properties and clinical trial evidence of cognitive safety might be appropriate.
Key points
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Short-term randomized clinical trials (most <4 weeks) have not shown substantial cognitive impairment with overactive bladder (OAB) anticholinergics other than oxybutynin.
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Very few long-term clinical studies (>3 months) on OAB anticholinergics exist, and those studies that are available have conflicting results and are limited by methodological issues.
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Large, observational studies of OAB anticholinergic use have shown that these medications are associated with an ~20% increased relative risk of dementia, but residual confounding and reverse causality cannot be ruled out.
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Alternative OAB treatments might be more appropriate for patients >65 years of age and those patients with underlying mild cognitive impairment (or conditions that put them at risk of it); if necessary, careful use of anticholinergics with favourable physicochemical, pharmacokinetic and pharmacodynamic properties and cognitive safety data could be considered.
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References
Milsom, I. et al. Global prevalence and economic burden of urgency urinary incontinence: a systematic review. Eur. Urol. 65, 79–95 (2014).
Abrams, P. et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol. Urodyn. 21, 167–178 (2002).
Heidler, S. et al. The natural history of lower urinary tract symptoms in females: analysis of a health screening project. Eur. Urol. 52, 1744–1750 (2007).
Peyronnet, B. et al. A comprehensive review of overactive bladder pathophysiology: on the way to tailored treatment. Eur. Urol. 75, 988–1000 (2019). An excellent article on OAB pathophysiology that includes a review of several potential mechanisms and phenotypes of OAB.
Gormley, E. A., Lightner, D. J., Faraday, M. & Vasavada, S. P. Diagnosis and treatment of overactive bladder (Non-Neurogenic) in adults: AUA/SUFU guideline amendment. J. Urol. 193, 1572–1580 (2015).
Nambiar, A. K. et al. EAU guidelines on assessment and nonsurgical management of urinary incontinence. Eur. Urol. 73, 596–609 (2018).
Hesch, K. Agents for treatment of overactive bladder: a therapeutic class review. Bayl. Univ. Med. Cent. Proc. 20, 307–314 (2017).
Maggiore, U. L. R. et al. Pharmacokinetics and toxicity of antimuscarinic drugs for overactive bladder treatment in females. Expert Opin. Drug Met. 8, 1387–1408 (2012).
Chapple, C. R. et al. The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur. Urol. 54, 543–562 (2008).
Maman, K. et al. Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison. Eur. Urol. 65, 755–765 (2014).
Visco, A. G. et al. Anticholinergic therapy vs. onabotulinumtoxina for urgency urinary incontinence. N. Engl. J. Med. 367, 1803–1813 (2012).
Yeowell, G. et al. Real-world persistence and adherence to oral antimuscarinics and mirabegron in patients with overactive bladder (OAB): a systematic literature review. BMJ Open 8, e021889 (2018).
Kessler, T. M. et al. Adverse event assessment of antimuscarinics for treating overactive bladder: a network meta-analytic approach. PLoS ONE 6, e16718 (2011).
Coupland, C. A. C. et al. Anticholinergic drug exposure and the risk of dementia: a nested case-control study. JAMA Intern. Med. 179, 1084–1093 (2019).
Richardson, K. et al. Anticholinergic drugs and risk of dementia: case-control study. BMJ 361, k1315 (2018). An often-quoted study that suggests a potential causal association between anticholinergics and the eventual diagnosis of dementia.
Kay, G. et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur. Urol. 50, 317–326 (2006). A prospective clinical study that demonstrated that short-term oxybutynin use is associated with 10 years of ageing of the brain.
Livingston, G. et al. Dementia prevention, intervention, and care. Lancet 390, 2673–2734 (2017).
Petersen, R. C. Clinical practice. Mild cognitive impairment. N. Engl. J. Med. 364, 2227–2234 (2011).
Decalf, V. H. et al. Older people’s preferences for side effects associated with antimuscarinic treatments of overactive bladder: a discrete-choice experiment. Drug Aging 34, 615–623 (2017).
Thomas, T. N. & Walters, M. D. AUGS consensus statement: association of anticholinergic medication use and cognition in women with overactive bladder. Female Pelvic Med. Reconstr. Surg. 23, 177–178 (2017).
Wagg, A., Dale, M., Tretter, R., Stow, B. & Compion, G. Randomised, multicentre, placebo-controlled, double-blind crossover study investigating the effect of solifenacin and oxybutynin in elderly people with mild cognitive impairment: the SENIOR study. Eur. Urol. 64, 74–81 (2013).
Lipton, R. B., Kolodner, K. & Wesnes, K. Assessment of cognitive function of the elderly population. J. Urol. 173, 493–498 (2005).
Kay, G. G. & Wesnes, K. A. Pharmacodynamic effects of darifenacin, a muscarinic M3 selective receptor antagonist for the treatment of overactive bladder, in healthy volunteers. BJU Int. 96, 1055–1062 (2005).
Wesnes, K. A., Edgar, C., Tretter, R. N. & Bolodeoku, J. Exploratory pilot study assessing the risk of cognitive impairment or sedation in the elderly following single doses of solifenacin 10 mg. Expert Opin. Drug Saf. 8, 615–626 (2009).
Kay, G. G. et al. Evaluation of cognitive function in healthy older subjects treated with fesoterodine. Postgrad. Med. 124, 7–15 (2015).
Geller, E. J. et al. Effect of trospium chloride on cognitive function in women aged 50 and older. Female Pelvic Med. Reconstr. Surg. 23, 118–123 (2017).
Kosilov, K. et al. Influence of the short-term intake of high doses of solifenacin and trospium on cognitive function and health-related quality of life in older women with urinary incontinence. Int. Neurourol. J. 22, 41–50 (2018).
Chiang, C.-H. et al. Lower urinary tract symptoms are associated with increased risk of dementia among the elderly: a nationwide study. BioMed. Res. Int. 2015, 187819 (2015).
Syndulko, K. et al. Decreased verbal memory associated with anticholinergic treatment in Parkinson’s disease patients. Int. J. Neurosci. 14, 61–66 (2009).
Marzoughi, S. et al. Tardive neurotoxicity of anticholinergic drugs: a review. J. Neurochem. https://doi.org/10.1111/jnc.15244 (2021).
Wess, J. Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications. Annu. Rev. Pharmacol. 44, 423–450 (2004).
Conn, P. J., Jones, C. K. & Lindsley, C. W. Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends Pharmacol. Sci. 30, 148–155 (2009).
Lebois, E. P., Thorn, C., Edgerton, J. R., Popiolek, M. & Xi, S. Muscarinic receptor subtype distribution in the central nervous system and relevance to aging and Alzheimer’s disease. Neuropharmacology 136, 362–373 (2018).
Lonsdale, J. et al. The genotype-tissue expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).
Levey, A., Kitt, C., Simonds, W., Price, D. & Brann, M. Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. J. Neurosci. 11, 3218–3226 (1991).
Flynn, D. D., Ferrari-DiLeo, G., Mash, D. C. & Levey, A. I. Differential regulation of molecular subtypes of muscarinic receptors in Alzheimer’s disease. J. Neurochem. 64, 1888–1891 (1995).
Hersch, S. M. & Levey, A. I. Diverse pre- and post-synaptic expression of m1–m4 muscarinic receptor proteins in neurons and afferents in the rat neostriatum. Life Sci. 56, 931–938 (1995).
Messer, W. S., Bohnett, M. & Stibbe, J. Evidence for a preferential involvement of M1 muscarinic receptors in representational memory. Neurosci. Lett. 116, 184–189 (1990).
Anagnostaras, S. G. et al. Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat. Neurosci. 6, 51–58 (2003).
Kay, G. G. et al. Antimuscarinic drugs for overactive bladder and their potential effects on cognitive function in older patients. J. Am. Geriatr. Soc. 53, 2195–2201 (2005).
Pomara, N., Willoughby, L. M., Wesnes, K. & Sidtis, J. J. Increased anticholinergic challenge-induced memory impairment associated with the APOE-ε4 allele in the elderly: a controlled pilot study. Neuropsychopharmacology 29, 403–409 (2004).
Blain, J.-F., Sullivan, P. M. & Poirier, J. A deficit in astroglial organization causes the impaired reactive sprouting in human apolipoprotein E4 targeted replacement mice. Neurobiol. Dis. 21, 505–514 (2006).
Weigand, A. J. et al. Association of anticholinergic medication and AD biomarkers with incidence of MCI among cognitively normal older adults. Neurology 95, e2295–e2304 (2020).
Jewart, R. D., Green, J., Lu, C., Cellar, J. & Tune, L. E. Cognitive, behavioral, and physiological changes in Alzheimer disease patients as a function of incontinence medications. Am. J. Geriatr. Psychiatry 13, 324–328 (2005).
Serlin, Y., Shelef, I., Knyazer, B. & Friedman, A. Anatomy and physiology of the blood–brain barrier. Semin. Cell Dev. Biol. 38, 2–6 (2015).
van de Haar, H. J. et al. Blood–brain barrier impairment in dementia: current and future in vivo assessments. Neurosci. Biobehav. Rev. 49, 71–81 (2015).
Callegari, E. et al. A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder. Br. J. Clin. Pharm. 72, 235–246 (2011).
Geldenhuys, W. J., Mohammad, A. S., Adkins, C. E. & Lockman, P. R. Molecular determinants of blood–brain barrier permeation. Ther. Deliv. 6, 961–971 (2015).
Waterbeemd, H. van de, Camenisch, G., Folkers, G., Chretien, J. R. & Raevsky, O. A. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J. Drug Target. 6, 151–165 (2009).
Roberts, L. M. et al. Subcellular localization of transporters along the rat blood–brain barrier and blood–cerebral-spinal fluid barrier by in vivo biotinylation. Neuroscience 155, 423–438 (2008).
Geyer, J., Gavrilova, O. & Petzinger, E. The role of p-glycoprotein in limiting brain penetration of the peripherally acting anticholinergic overactive bladder drug trospium chloride. Drug Metab. Dispos. 37, 1371–1374 (2009).
Chancellor, M. B. et al. Blood-brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder. Drug Aging 29, 259–273 (2012).
Jakobsen, S. M., Kersten, H. & Molden, E. Evaluation of brain anticholinergic activities of urinary spasmolytic drugs using a high-throughput radio receptor bioassay. J. Am. Geriatr. Soc. 59, 501–505 (2011).
Zinner, N. Darifenacin: a muscarinic M3-selective receptor antagonist for the treatment of overactive bladder. Expert Opin. Pharmacother. 8, 511–523 (2007).
Maruyama, S. et al. In vivo quantitative autoradiographic analysis of brain muscarinic receptor occupancy by antimuscarinic agents for overactive bladder treatment. J. Pharmacol. Exp. Ther. 325, 774–781 (2008).
Starr, J. M. et al. Increased blood–brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. J. Neurol. Neurosurg. Psychiatry 74, 70 (2003).
Pakulski, C., Drobnik, L. & Millo, B. Age and sex as factors modifying the function of the blood-cerebrospinal fluid barrier. Med. Sci. Monit. Int. Med. J. Exp. Clin. Res. 6, 314–318 (2000).
Coyne, K. S. et al. Comorbidities and personal burden of urgency urinary incontinence: a systematic review. Int. J. Clin. Pract. 67, 1015–1033 (2013).
Nishtala, P. S., Salahudeen, M. S. & Hilmer, S. N. Anticholinergics: theoretical and clinical overview. Expert Opin. Drug Saf. 15, 753–768 (2016).
Tan, M. P. et al. Use of medications with anticholinergic properties and the long-term risk of hospitalization for falls and fractures in the EPIC-norfolk longitudinal cohort study. Drug Aging 37, 105–114 (2020).
Kachru, N., Holmes, H. M., Johnson, M. L., Chen, H. & Aparasu, R. R. Risk of mortality associated with non-selective antimuscarinic medications in older adults with dementia: a retrospective study. J. Gen. Intern. Med. 35, 2084–2093 (2020).
Lisibach, A. et al. Quality of anticholinergic burden scales and their impact on clinical outcomes: a systematic review. Eur. J. Clin. Pharmacol. 77, 147–162 (2021).
Welsh, T. J., Wardt, V. van der, Ojo, G., Gordon, A. L. & Gladman, J. R. F. Anticholinergic drug burden tools/scales and adverse outcomes in different clinical settings: a systematic review of reviews. Drugs Aging 35, 523–538 (2018).
Turró-Garriga, O. et al. Measuring anticholinergic exposure in patients with dementia: a comparative study of nine anticholinergic risk scales. Int. J. Geriatr. Psychiatry 33, 710–717 (2018).
Chuang, Y.-F., Elango, P., Gonzalez, C. E. & Thambisetty, M. Midlife anticholinergic drug use, risk of Alzheimer’s disease, and brain atrophy in community-dwelling older adults. Alzheimers Dement. 3, 471–479 (2017).
Risacher, S. L. et al. Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults. JAMA Neurol. 73, 721–732 (2016). This study linked anticholinergic medication use to brain atrophy as measured on MRI, and worse cognitive function performance.
Perry, E. K., Kilford, L., Lees, A. J., Burn, D. J. & Perry, R. H. Increased Alzheimer pathology in Parkinson’s disease related to antimuscarinic drugs. Ann. Neurol. 54, 235–238 (2003).
Gray, S. L. et al. Exposure to strong anticholinergic medications and dementia-related neuropathology in a community-based autopsy cohort. J. Alzheimers Dis. 65, 607–616 (2018).
Richardson, K. et al. Neuropathological correlates of cumulative benzodiazepine and anticholinergic drug use. J. Alzheimers Dis. 74, 999–1009 (2020).
Chhatwal, J. P. et al. Anticholinergic amnesia is mediated by alterations in human network connectivity architecture. Cereb. Cortex 29, 3445–3456 (2018).
Ketai, L. H. et al. Mind-body (hypnotherapy) treatment of women with urgency urinary incontinence: changes in brain attentional networks. Am. J. Obstet. Gynecol. 224, 498.e1–498.e10 (2020).
Katz, I. R. et al. Identification of medications that cause cognitive impairment in older people: the case of oxybutynin chloride. J. Am. Geriatr. Soc. 46, 8–13 (1998).
Todorova, A., Vonderheid-Guth, B. & Dimpfel, W. Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous system. J. Clin. Pharmacol. 41, 636–644 (2001).
Lackner, T. E., Wyman, J. F., McCarthy, T. C., Monigold, M. & Davey, C. Randomized, placebo-controlled trial of the cognitive effect, safety, and tolerability of oral extended-release oxybutynin in cognitively impaired nursing home residents with urge urinary incontinence. J. Am. Geriatr. Soc. 56, 862–870 (2008).
Kay, G. G., Staskin, D. R., MacDiarmid, S., McIlwain, M. & Dahl, N. V. Cognitive effects of oxybutynin chloride topical gel in older healthy subjects. Clin. Drug Invest. 32, 707–714 (2012).
Diefenbach, K. et al. Effects on sleep of anticholinergics used for overactive bladder treatment in healthy volunteers aged ≥50 years. BJU Int. 95, 346–349 (2005).
Staskin, D. et al. Trospium chloride is undetectable in the older human central nervous system. J. Am. Geriatr. Soc. 58, 1618–1619 (2010).
Isik, A. T., Celik, T., Bozoglu, E. & Doruk, H. Trospium and cognition in patients with late onset Alzheimer disease. JNHA 13, 672 (2009).
Iyer, S. et al. Cognitive changes in women starting anticholinergic medications for overactive bladder: a prospective study. Int. Urogynecol. J. 31, 2653–2660 (2019).
Esin, E. et al. Influence of antimuscarinic therapy on cognitive functions and quality of life in geriatric patients treated for overactive bladder. Aging Ment. Health 19, 217–223 (2015).
Moga, D. C., Abner, E. L., Wu, Q. & Jicha, G. A. Bladder antimuscarinics and cognitive decline in elderly patients. Alzheimers Dement. 3, 139–148 (2017).
Roeck, E. E. D., Deyn, P. P. D., Dierckx, E. & Engelborghs, S. Brief cognitive screening instruments for early detection of Alzheimer’s disease: a systematic review. Alzheimers Res. Ther. 11, 21 (2019).
Pieper, N. T. et al. Anticholinergic drugs and incident dementia, mild cognitive impairment and cognitive decline: a meta-analysis. Age Ageing 49, 939–947 (2020).
Marcum, Z. A. et al. Anticholinergic medication use and falls in postmenopausal women: findings from the Women’s Health Initiative cohort study. BMC Geriatr. 16, 76 (2016).
Kachru, N., Carnahan, R. M., Johnson, M. L. & Aparasu, R. R. Potentially inappropriate anticholinergic medication use in community-dwelling older adults: a national cross-sectional study. Drug Aging 32, 379–389 (2015).
Grossi, C. M. et al. Increasing prevalence of anticholinergic medication use in older people in England over 20 years: cognitive function and ageing study I and II. BMC Geriatr. 20, 267 (2020).
Aldus, C. F. et al. Undiagnosed dementia in primary care: a record linkage study. Heal. Serv. Deliv. Res. 8, 1–108 (2020).
Gray, S. L. et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern. Med. 175, 401–407 (2015).
Grossi, C. M. et al. Anticholinergic and benzodiazepine medication use and risk of incident dementia: a UK cohort study. BMC Geriatr. 19, 276 (2019).
Fox, C. et al. Anticholinergic medication use and cognitive impairment in the older population: the Medical Research Council Cognitive Function and Ageing Study. J. Am. Geriatr. Soc. 59, 1477–1483 (2011).
Boustani, M., Campbell, N., Munger, S., Maidment, I. & Fox, C. Impact of anticholinergics on the aging brain: a review and practical application. Aging Heal. 4, 311–320 (2008).
Chew, M. L. et al. Anticholinergic activity of 107 medications commonly used by older adults. J. Am. Geriatr. Soc. 56, 1333–1341 (2008). An in vitro study that quantifies the actual anticholinergic effect of common medications based on clinically relevant doses, and their ability to penetrate the CNS.
Liu, Y.-P. et al. Are anticholinergic medications associated with increased risk of dementia and behavioral and psychological symptoms of dementia? A nationwide 15-year follow-up cohort study in Taiwan. Front. Pharmacol. 11, 30 (2020).
Bali, V. et al. Risk of dementia among elderly nursing home patients using paroxetine and other selective serotonin reuptake inhibitors. Psychiatr. Serv. 66, 1333–1340 (2015).
Heath, L. et al. Cumulative antidepressant use and risk of dementia in a prospective cohort study. J. Am. Geriatr. Soc. 66, 1948–1955 (2018).
Hafdi, M. et al. Association of benzodiazepine and anticholinergic drug usage with incident dementia: a prospective cohort study of community-dwelling older adults. J. Am. Med. Dir. Assoc. 21, 188–193.e3 (2019).
Hong, C.-T., Chan, L., Wu, D., Chen, W.-T. & Chien, L.-N. Antiparkinsonism anticholinergics increase dementia risk in patients with Parkinson’s disease. Parkinsonism Relat. Disord. 65, 224–229 (2019).
Wang, Y.-C. et al. Cumulative use of therapeutic bladder anticholinergics and the risk of dementia in patients with lower urinary tract symptoms: a nationwide 12-year cohort study. BMC Geriatr. 19, 380 (2019).
Yang, Y.-W., Liu, H.-H., Lin, T.-H., Chuang, H.-Y. & Hsieh, T. Association between different anticholinergic drugs and subsequent dementia risk in patients with diabetes mellitus. PLoS ONE 12, e0175335 (2017).
Barthold, D., Marcum, Z. A., Gray, S. L. & Zissimopoulos, J. Alzheimer’s disease and related dementias risk: comparing users of non-selective and M3-selective bladder antimuscarinic drugs. Pharmacoepidemiol. Drug Saf. 29, 1650–1658 (2020).
Welk, B. & McArthur, E. Increased risk of dementia among patients with overactive bladder treated with an anticholinergic medication compared to a beta-3 agonist: a population-based cohort study. BJU Int. 126, 183–190 (2020). A retrospective administrative data study that demonstrated an increased risk of dementia among new users of OAB anticholinergics compared with new users of β3 agonists.
Schuemie, M. J. et al. A plea to stop using the case-control design in retrospective database studies. Stat. Med. 38, 4199–4208 (2019).
Richardson, K. et al. History of benzodiazepine prescriptions and risk of dementia: possible bias due to prevalent users and covariate measurement timing in a nested case-control study. Am. J. Epidemiol. 188, 1228–1236 (2019).
Baumgart, M. et al. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alzheimers Dement. 11, 718–726 (2015).
Dallosso, H. M., McGrother, C. W., Matthews, R. J. & Donaldson, M. M. K. The association of diet and other lifestyle factors with overactive bladder and stress incontinence: a longitudinal study in women. BJU Int. 92, 69–77 (2003).
Plassman, B. L. et al. Incidence of dementia and cognitive impairment, not dementia in the United States. Ann. Neurol. 70, 418–426 (2011).
Barnish, M. S. & Turner, S. The value of pragmatic and observational studies in health care and public health. Pragmat. Obs. Res. 8, 49–55 (2017).
Araklitis, G. et al. Anticholinergic prescription: are healthcare professionals the real burden? Int. Urogynecol. J. 28, 1249–1256 (2017).
Averbeck, M. A., Altaweel, W., Manu-Marin, A. & Madersbacher, H. Management of LUTS in patients with dementia and associated disorders. Neurourol. Urodyn. 36, 245–252 (2017).
Caplan, E. O. et al. Impact of coexisting overactive bladder in medicare patients with dementia on clinical and economic outcomes. Am. J. Alzheimers Dis. Other Demen. 34, 492–499 (2019).
Mori, S., Kojima, M., Sakai, Y. & Nakajima, K. Bladder dysfunction in dementia patients showing urinary incontinence. Nihon Ronen Igakkai Zasshi 36, 489–494 (1999).
Gannon, M. et al. Noradrenergic dysfunction in Alzheimer’s disease. Front. Neurosci. 9, 220 (2015).
Griebling, T. L. et al. Effect of mirabegron on cognitive function in elderly patients with overactive bladder: MoCA results from a phase 4 randomized, placebo-controlled study (PILLAR). BMC Geriatr. 20, 109 (2020).
Sink, K. M. et al. Dual use of bladder anticholinergics and cholinesterase inhibitors: long-term functional and cognitive outcomes. J. Am. Geriatr. Soc. 56, 847–853 (2008).
Triantafylidis, L. K., Clemons, J. S., Peron, E. P., Roefaro, J. & Zimmerman, K. M. Brain over bladder: a systematic review of dual cholinesterase inhibitor and urinary anticholinergic use. Drugs Aging 35, 27–41 (2018).
NICE Guideline Urinary incontinence and pelvic organ prolapse in women: management (NICE, 2019).
Jessen, F. et al. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease. Alzheimers Dement. 10, 844–852 (2014).
Dewey, S. L. et al. Age-related decreases in muscarinic cholinergic receptor binding in the human brain measured with positron emission tomography (PET). J. Neurosci. Res. 27, 569–575 (1990).
Norbury, R. et al. In vivo imaging of muscarinic receptors in the aging female brain with (R,R)[123I]-I-QNB and single photon emission tomography. Exp. Gerontol. 40, 137–145 (2005).
High, R. A. et al. Protocol for a multicenter randomized, double blind, controlled pilot trial of higher neural function in overactive bladder patients after anticholinergic, beta-3 adrenergic agonist, or placebo. Contemp. Clin. Trials Commun. 19, 100621 (2020).
Richardson, K. et al. Use of medications with anticholinergic activity and self-reported injurious falls in older community-dwelling adults. J. Am. Geriatr. Soc. 63, 1561–1569 (2015).
Rahman, A. et al. Sex and gender driven modifiers of Alzheimer’s: the role for estrogenic control across age, race, medical, and lifestyle risks. Front. Aging Neurosci. 11, 315 (2019).
Sakakibara, R. et al. Is overactive bladder a brain disease? The pathophysiological role of cerebral white matter in the elderly. Int. J. Urol. 21, 33–38 (2014).
Sexton, C. C. et al. Persistence and adherence in the treatment of overactive bladder syndrome with anticholinergic therapy: a systematic review of the literature. Int. J. Clin. Pract. 65, 567–585 (2011).
Acknowledgements
J.N.P. is supported in part by funding from the United Kingdom’s Department of Health NIHR Biomedical Research Centres funding scheme. K.R. is supported by funding from the United Kingdom’s Alzheimer’s Society.
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B.W., K.R. and J.N.P. researched data for the article, made substantial contributions to discussion of its content, and wrote, edited and reviewed the article prior to submission.
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Glossary
- Protopathic bias
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Also known as reverse causality. When a medication is initiated to treat the initial symptoms of an undiagnosed disease.
- Mini-mental state examination
-
(MMSE). A standardized and widely used test of cognitive function for adults, which evaluates orientation, attention, memory, language and visual–spatial skills.
- Face–name association test
-
A cross-modal associative memory test, which uses 16 face–name pairs and 16 face–occupation pairs, and the person has to try to remember different pairs during both immediate and delayed (30 min later) tests.
- EEG frequency bands
-
Electroencephalogram (EEG) readings can be decomposed into different component frequencies (delta, theta, alpha, beta and gamma), which are associated with specific functional characteristics.
- Selective serotonin reuptake inhibitors
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(SSRIs). Medications that inhibit the reabsorption of serotonin into neurons, which can help with psychiatric problems such as depression and anxiety.
- Cholinesterase inhibitors
-
These medications prevent the breakdown of acetylcholine, and can improve intracellular communication and treat symptoms of dementia.
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Welk, B., Richardson, K. & Panicker, J.N. The cognitive effect of anticholinergics for patients with overactive bladder. Nat Rev Urol 18, 686–700 (2021). https://doi.org/10.1038/s41585-021-00504-x
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DOI: https://doi.org/10.1038/s41585-021-00504-x
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