cognition – Prof G's MS Blog Archive

#ThinkCognition: how precious is my brain?

Barts-MS rose-tinted-odometer: ★

As someone with MS do you worry about how you are going to cope with ageing and old age?

As MS shreds both your brain and cognitive reserve will MS bring forward and accelerate the ageing process and the time when you may develop neurodegenerative diseases such as Alzheimer’s disease? These are all hypotheses but are very relevant to people with MS (pwMS) and their families.

I recall how much stick I got from the MS community, including some very close colleagues when I tried to rebrand MS as a ‘preventable dementia’. The objective of the #ThinkCognition campaign was to make the MS community look beyond the blinkers of the EDSS and realise that MS was not only physical disabling but it was affecting cognition much earlier than people realised. For example, 40% of people already have significant cognitive impairment in at least two cognitive domains at the CIS (clinically-isolated syndrome) stage of their disease. If you go earlier to RIS (radiologically-isolated syndrome) or asymptomatic stage of the disease about a quarter of subjects have cognitive impairment. People with RIS and CIS are not aware of having cognitive impairment because the brain is able to compensate for the damage at an early stage.

In early MS cognitive impairment is more likely to cause cognitive fatigue and be associated with anxiety and depression than overt cognitive problems. The brain compensates for the damage by doing extra work, consuming more energy and getting tired more easily. Most people with MS realise they attention spans are often markedly reduced because of this phenomenon.

The reason why 50% of pwMS living in Europe are unemployed at an EDSS of 3.0 to 3.5 is not physical but cognitive disabilities. The #ThinkCognition campaign highlights the early hit the MS brain takes and makes the argument for effective early treatment to prevent dementia.

The problem with society’s view of dementia, i.e. of a little old lady with poor memory in a care home, is that it doesn’t easily translate to MS. What you have to remember is that dementia is a syndrome and MS is a well-known cause of dementia. The definition of dementia is that it is an acquired (not born with it), chronic (greater than 6 months), progressive condition (gets worse over time) that affects cognition in multiple domains (for example, problem-solving, processing speed, memory, speech, calculations, etc.) and impacts on the individuals occupational and social functioning. I would challenge anyone to say that worsening MS-related cognitive impairment fulfil this definition of dementia. The good news is that dementia associated with MS is preventable, i.e. if you treat MS early and effectively you will stop the end-organ damage and prevent the consequences of MS on longterm cognitive functioning.

Now the question about bringing forward ageing and the presentation of other neurodegenerative diseases is an open question. Below is a case report of an elderly woman with MS who presents with memory loss and a workup showed a pattern of cognitive decline that was more in keeping with Alzheimer’s disease than MS. She then goes onto to have diagnostic amyloid and is diagnosed as having Alzheimer’s disease. One could argue if she didn’t have MS this may have protected her from getting Alzheimer’s disease or at least delayed its onset by several years.

It is important to stress that the type of cognitive impairment associated with MS is very different to that of classic or amnestic Alzheimer’s disease and well-done neuropsychological tests should be able to differentiate the two conditions (see pilot study below). Saying that I have a handful of patients with ‘cognitive MS’ who have taken a massive hit on their ability to store and process short term memory because in their case MS has affected the temporal lobes and their connecting structures that are critical for memory.

Other issues that the #ThinkCognition campaign addresses are (1) the need to be able to identify relapses as being purely cognitive, (2) using cognitive impairment to say that patients with RIS have CIS or MS so they can be treated, (3) using a change in cognition to define worsening MS or progressive disease, (4) incorporating cognition into our treatment target in MS, (5) including cognitive screening or testing as part of the annual MS assessment and (6) including cognition in our longterm treatment goal of maximising brain health for the life of the pwMS.

I want to point out that none of the points I make in this post is necessarily accepted by the wider MS community and many of the points remain controversial, which is why I would encourage a debate around these issues. What I can tell you, however, if I had MS I would want my neurologist and MS team to treat me as if my brain was the most precious thing on planet earth; I would want them to protect my cognition and make it their number one objective. I suspect this is easier said than done.

Progressive brain volume loss or atrophy in a pwMS over 18 months

Jakimovski et al. Differential Diagnosis of Cognitive Decline in Elderly Individuals With Multiple Sclerosis. Cogn Behav Neurol. 2020 Dec;33(4):294-300.

Due to increasingly improved disability outcomes, and the resultant significantly improved life span, of the multiple sclerosis (MS) population, questions regarding cognitive aging and the prevalence of comorbid Alzheimer disease (AD) have emerged. We describe neuropsychological and MRI-based changes that occurred in an 84-year-old MS patient with comorbid amnestic mild cognitive impairment (a precursor to AD) and cerebrovascular pathology. The neuropsychological examination demonstrated impairment in cognitive processing speed as well as in verbal and visual memory-domains that are potentially affected by any, or all, of the three co-existing diseases. Amyloid-based PET imaging showed increased focal uptake within the gray matter of the occipital lobe. We highlight how these clinical and radiologic observations can inform future research that could elucidate interactions between MS, a probable AD diagnosis, and cerebrovascular pathology in elderly individuals with MS. A comprehensive neuropsychological examination of multiple cognitive domains of individuals with MS may aid in the differential diagnosis of late-in-life cognitive decline.

Roy et al. Preliminary investigation of cognitive function in aged multiple sclerosis patients: Challenges in detecting comorbid Alzheimer’s disease. Mult Scler Relat Disord. 2018 May;22:52-56.

Background: Cognitive impairment can be seen in patients of all ages with multiple sclerosis (MS). However, there is limited research on neurocognitive disorder in older adults with MS and how to detect Alzheimer’s disease (AD) or its prodromal stage, amnestic mild cognitive impairment (aMCI). Thus, the MS clinician is challenged to discriminate between signs of MS-related cognitive decline versus a secondary neurodegenerative process.

Objective: Compare cognition in older MS patients to patients with AD and aMCI.

Methods: We evaluated cognitively impaired and unimpaired MS patients, AD patients, aMCI patients, and healthy controls (HCs), all elderly (n = 20 per group). AD and aMCI diagnoses were derived by consensus conference independent of the MS research project. Neuropsychological measures assessed domains commonly affected in AD, including verbal memory and expressive language.

Results: Cognitively impaired and unimpaired MS groups did not differ on any measures sensitive to AD. Unimpaired MS patients were comparable to HCs. Impaired MS patients showed decreased semantic fluency, similar to aMCI patients. Lastly, while both AD and aMCI groups had deficient memory retention, there was no evidence of a retention deficit in either MS group.

Conclusion: Our findings suggest that the cognitive profiles of MS and AD are distinct. In contrast to AD, MS is not associated with impairment of memory consolidation. However, there may be overlap between cognitive deficits related to MS and aMCI. Thus, evidence of poor memory retention, in an older MS patient may merit comprehensive dementia evaluation. The study is preliminary and includes no AD biomarkers (e.g., amyloid imaging) to confirm or rule out AD pathology.

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CoI: multiple

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Glass-half-full

Barts-MS rose-tinted-odometer ★★★★★

I was attacked yesterday for painting a too bleak picture of MS outcomes and for not focusing on the fact that some pwMS actually age well and do well in the long-term. I apologise for being so negative, hence this post to address the data gap.

The best data we have on the longterm follow-up of pwMS in a ‘community-setting’ is the Gothenburg study. In Gothenburg, they were fortunate to have 50+ year systematic follow-up of an original cohort of pwMS, who were born between 1950 and 1964. Of the 202 patients with an initial relapsing-remitting course, the probability of non-progressive disease after 40 years was 22% and after 50 years it was 14%. So 1 in 7 patients with relapse-onset disease had not become secondary progressive after 50 years of follow-up. Importantly, these patients were functioning well socially. Nine of them had an EDSS of 0-2.5, and four patients had a score of 3 or 3.5, with most of their disability dating back to attacks from decades ago. These 1 in 7 patients have what I call ‘burnt-out’ MS.

Eight of these patients, who underwent a complete and detailed neuropsychological examination, showed some cognitive impairment concerning memory and executive function compared to an age and socially matched control group. This indicates that even in these ‘burnt-out ageing-well’ cohort that MS has clipped some of their cognition. i.e. they have some hidden disabilities.

At the last follow-up of this group of patients in 2009-10, when the group had reached the average age of the Swedish population life expectancy, only 13 patients remained alive and non-progressive. That is 6.5% were alive and well compared to an expected rate of 50% for the general population.

It is important to point out that as these patients are from a pre-DMT era these figures should be viewed as the worst-case-scenario. I would expect them to be much better than this now and, importantly, they will get better over time as we learn to diagnose and treat MS earlier and more effectively.

I like to think of MS outcomes as a bell-curve with a small proportion of people who can expect to age normally. But as we improve outcomes we shift the curve to the right with more and more pwMS having a good outcome.

I don’t like to think of myself as a glass-half-empty, hopefully, this bell curve will make you realise that I am a glass-half-full.

Bengt Skoog et al. A Representative Cohort of Patients With Non-Progressive Multiple Sclerosis at the Age of Normal Life Expectancy. Brain, 135 (Pt 3), 900-11 Mar 2012.

Multiple sclerosis may have a non-progressive symptomatology for decades; however, it is not clear whether the disease activity may abate completely. We identified a cohort of patients, resident in Gothenburg at the time of disease onset, between the years 1950-64 (n = 307). These geographical and temporal restrictions, along with favourable conditions for a ‘spider’ epidemiological study, were optimal for an unbiased selection; this 15-year incidence cohort was essentially followed prospectively for 37-59 years after onset. The shortest follow-up time for patients without primary or secondary progression was 45 years. For patients with an initial relapsing-remitting course and multiple sclerosis diagnosis according to the Poser criteria (n = 202), the probability of non-progressive disease after 40 years was 22% (standard error 3.0%), and after 50 years it was 14% (standard error 3.2%). For attack onset including patients with possible multiple sclerosis, the corresponding probabilities after 40 and 50 years were 35% (standard error 3.3%) and 28% (standard error 3.5%), respectively. At the last follow-up in 2009-10, when patients reached the average age of the Swedish population life expectancy, only 13 patients from the multiple sclerosis diagnosis cohort, according to the Poser criteria, remained alive and non-progressive. Their annualized attack frequency diminished with time from 0.29 to 0.015. These patients had been functioning well socially. Nine patients had an Expanded Disability Status Scale score of 0-2.5, and four patients had a score of 3 or 3.5, with deficits dating back to attacks decades ago. Eight patients participated in a complete neuropsychological examination, which showed a slight difference (P < 0.01) concerning verbal memory and executive function compared to an age and socially matched reference group, whereas results for five other cognitive domains were within the normal range. Magnetic resonance images fulfilled the Barkhof-Tintoré criteria for multiple sclerosis in 10 of 11 patients, with conspicuously few subcortical lesions relative to extensive periventricular lesions and lesions extending from the inferior midline aspect of the corpus callosum. Prediction of the non-progressive stage was possible with moderate hazard ratios and low sensitivity. Early features that predicted a non-progressive course were complete remission of the onset attack, low or moderate initial relapse frequency and-when the patients with possible multiple sclerosis were included-dominating afferent symptoms. The clinical disease activity had abated in these 13 patients, with the caveat that transition to secondary progression continued to occur after four decades, albeit with decreasing risk.

CoI: multiple

What is advanced MS?

Barts-MS rose-tinted-odometer – zero stars

Someone recently asked what is advanced MS? I suspect they have been getting frustrated with our use of this adjective without a clearer understanding of what it really means. To find out if you have advanced MS you need to put yourself through a battery of stress tests to find-out much reserve you have left to deal with MS and life in the future.

What is advanced MS is a very important topic and we at Barts-MS have tried not to define it using the EDSS as it entrenches the physically-disabling, particularly lower-limb function, worldview of MS.

Advanced MS is really when someone has lost reserve in a particular neuronal system and they are noticing worsening in that system that is impacting on their ability to function at a personal, social or occupational level and by inference is affecting their quality of life.

Using this definition someone can have advanced MS with very little physical disability. As you are aware the initial impact of MS may be cognitive, which is probably the main driver of the high early unemployment rates we see in MS.

A software engineer with MS who depends on her cognitive skills for writing code, concentrating for prolonged periods of time and multitasking may find it very difficult-staying at the top of her game. She will notice much earlier her progressive cognitive loss based on her performance or lack of performance in her work. In comparison, a professional athlete may not necessarily notice early cognitive impairment but will be more susceptible to the effects of MS on their coordination and endurance, for example, the marathon runner with a dropped foot.

These examples are the two extremes, but they illustrate why we need stress tests of the nervous system to be able to ascertain how much reserve there is which will give us some idea how advanced MS is in a particular domain. One thing that is not done very well in MS clinics is cognition. Most MS centres don’t have the resources to monitor cognition properly. This needs to change (#ThinkCognition).

In almost every MS clinic I do I see patients who complain of cognitive symptoms; increasing forgetfulness, difficulty multi-tasking, the inability to learn and use a new technology or cognitive fatigue.

One of my high functioning patients, who worked in a large City law firm, simply could not keep up and was forced to take early retirement because of her MS. She had been interferon-beta-1b for 12 years but had stopped treatment about 7 years ago when she had moved to London. Her MRI showed a highish lesion load and severe brain atrophy. She had had a few relapses on interferon-beta in the early years, but her neurologist decided to leave her on interferon-beta. Back then this was normal practice; we didn’t expect interferon-beta to render you relapse-free. Interferons were only meant to reduced attack rates by about a third and severe attacks, i.e. those requiring steroids and/or hospital admission, by about a half. The only alternative when this patient was having relapses on interferon-beta was glatiramer acetate; this was in the pre-natalizumab era.

Apart from her cognitive problems, this patient had mild unsteadiness of gait, but this had not affected her walking distance and she was still able to do yoga several times per week. To help with her unemployment insurance claim I requested a formal neuropsychological assessment and she was documented to have profound cognitive deficits across multiple domains. The conclusion based on these tests was that she would never be able to have meaningful employment again; at least not in the knowledge economy When I took a detailed history it was clear that she had had progressive cognitive impairment over at least 7-10 years. In other words, she had advanced (secondary progressive) MS manifesting as progressive dementia.

You must not underestimate the impact MS has on cognition. Cognitive problems can be there from the start; approximately a quarter of people with a radiologically isolated syndrome (RIS) or asymptomatic MS already have cognitive impairment. The proportion with cognitive impairment gets higher the longer you have the disease. What is driving cognitive impairment is almost certainly grey matter pathology, both in the cortex and deep grey matter, which is not detected with our current monitoring tools.

Until recently we the MS community used the Paced Auditory Serial Addition Test (PASAT) for monitoring cognition in clinical trials. The PASAT is a measure of cognitive function that assesses auditory information processing speed and flexibility, as well as calculation ability. The PASAT is presented using audiotape or disk to ensure standardization in the rate of stimulus presentation. Single digits are presented every 3 seconds and you have to add each new digit to the one immediately prior to it. Shorter inter-stimulus intervals, e.g., 2 seconds or less have also been used with the PASAT but tend to increase the difficulty of the task. The PASAT is very difficult and requires multitasking; it is a very good cognitive stress test.

One of the reasons we dropped the PASAT test is because of its learning effect, when you do the PASAT test your scores improve because of so-called ‘learning’ or ‘practice’ effects. In reality this is a general phenomenon of most neurological stress tests; our nervous systems are wired for learning.

In the FREEDOMS 1 and 2 pivotal phase 3 fingolimod trials, we showed that not being able to improve on the PASAT at baseline predicted a worse outcome. We hypothesised that pwMS who couldn’t learn, i.e. were unable to improve their PASAT scores at baseline, would do worse and this is exactly what we found and we noted it regardless of treatment allocation; i.e. whether you were on fingolimod or placebo.

Not surprisingly, the poor learners were older, had a higher disability score at baseline, smaller brains and higher lesions volumes on MRI; i.e. they had reduced cognitive reserve or resilience. In other words, they had more advanced MS. The depressing point about this analysis was that even the poor learners on fingolimod did badly; it was if they were already primed to do badly and that starting a DMT had a limited impact on the outcome. In reality, their MS disease activity in the past had primed their brains to continue to deteriorate despite being on a DMT; previous damage or smouldering MS was now driving their disease worsening. This is why the treatment response on DMTs drop off with ageing and disease duration. Please note this applies to all DMTs, including HSCT.

It is important to prevent the ravages of MS by treating as early and effectively as possible. Some pwMS are luckier than others; i.e. you may present very early in the course of your MS before too much end-organ damage has accrued. In others, the asymptomatic period of the disease may be longer, during which time you acquire a lot of end-organ damage. Regardless of what group you are in, you still need to seriously consider getting on top of your MS disease activity as soon as possible to prevent any further damage.

It is clear from several data sources that on average pwMS do best on DMTs that have the greatest impact on inflammatory activity (new MRI lesions and relapses) and those that reduce brain volume loss. In reality, these are the high and very high efficacy DMTs. This is why flipping the pyramid and going for the most effective DMTs first-line is a very appealing treatment strategy; particularly the DMTs that ‘normalise’ brain volume loss.

This post illustrates why we should be monitoring cognition in routine MS clinical practice. Although this topic gets discussed and debated all the time most neurologists don’t agree with doing routine cognitive testing, because of the lack of evidence in terms of treatments that impact on cognition. This, however, will change as data emerges that DMTs have positive effects on cognitive function, even in advanced MS. For example, siponimod has been shown to delay cognitive worsening compared to placebo in people with SPMS.

At Barts-MS we will continue to run our #ThinkCogniton campaign. By shifting the MS worldview from a physical one to a cognitive one we will hopefully get the MS community to manage MS more actively.

Maria Pia Sormani et al. Learning Ability Correlates With Brain Atrophy and Disability Progression in RRMS. J Neurol Neurosurg Psychiatry, 90 (1), 38-43 Jan 2019.

Objective: To assess the prognostic value of practice effect on Paced Auditory Serial Addition Test (PASAT) in multiple sclerosis.

Methods: We compared screening (day -14) and baseline (day 0) PASAT scores of 1009 patients from the FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial. We grouped patients into high and low learners if their PASAT score change was above or below the median change in their screening PASAT quartile group. We used Wilcoxon test to compare baseline disease characteristics between high and low learners, and multiple regression models to assess the respective impact of learning ability, baseline normalised brain volume and treatment on brain volume loss and 6-month confirmed disability progression over 2 years.

Results: The mean PASAT score at screening was 45.38, increasing on average by 3.18 from day -14 to day 0. High learners were younger (p=0.003), had lower Expanded Disability Status Scale score (p=0.031), higher brain volume (p<0.001) and lower T2 lesion volume (p=0.009) at baseline. Learning status was not significantly associated with disability progression (HR=0.953, p=0.779), when adjusting for baseline normalised brain volume, screening PASAT score and treatment arm. However, the effect of fingolimod on disability progression was more pronounced in high learners (HR=0.396, p<0.001) than in low learners (HR=0.798, p=0.351; p for interaction=0.05). Brain volume loss at month 24 tended to be higher in low learners (0.17%, p=0.058), after adjusting for the same covariates.

Conclusions: Short-term practice effects on PASAT are related to brain volume, disease severity and age and have clinically meaningful prognostic implications. High learners benefited more from fingolimod treatment.

CoI: multiple

Zombie

Are you an anticholinergic zombie?

A few months ago a 63-year-old MSer was admitted to hospital because of faecal impaction and overflow diarrhoea. She had had worsening constipation for years and was having intermittent diarrhoea due to liquification of stool from an overgrowth of bacteria in her colon, above a massive faecolith (a faecal rock). Her neurologist had her on a long-acting formulation of solifenacin for her neurogenic bladder and 50mg of amitriptyline to help her sleep at night. She had restless legs due to myelopathic pain and spasticity, which was helped by the amitriptyline. Could this be you? Or if you are an HCP do you recognise this patient?

Her daughter had noticed that she had become increasingly forgetful over the last few months and had missed appointments and had started to repeat herself during casual conversation; often asking the same question during a short conversation. She also could not recall the name of her granddaughter, which was out of character and quite worrying. Her family had started to worry about whether, or not, she was developing dementia.

During her admission to hospital, her solifenacin was replaced with mirabegron, a new class of drugs that work by stimulating the beta-3 receptor in the bladder wall, that is not associated with CNS side effects. Her amitriptyline was also stopped. Both of these were done to reduce the anticholinergic effects of these drugs on her bowels, which is constipation and on rare occasions faecal impaction. A day or two after these changes to her medication and the clear out of her bowels she woke up cognitively; she became animated and began to interact with her daughter and family members in a way that she had not done for years. She also stopped repeating herself. I identify this syndrome as the ‘Anticholinergic Zombie Syndrome’. Centrally acting anticholinergics have major cognitive side effects and in people with MS, who have reduced reserve, these can be severe.

I have been developing the argument over the last few months that we should approach the management of MS holistically using the marginal gains philosophy developed by Sir Dave Brailsford when he initially started to manage the Team GB cycling team.

“The whole principle came from the idea that if you broke down everything you could think of that goes into riding a bike, and then improved it by 1%, you will get a significant increase when you put them all together.” Dave Brailsford.

If you apply this to MS, i.e. break down everything we can think of that goes into improving MS outcomes, and then improving it by 1%, we will get a significant increase when we put them all together. This also means avoiding things that make MS worse.

One particular factor that we know makes MS worse is exposure to anticholinergics. We use this class of drug mainly for bladder dysfunction, i.e. to reduce bladder irritability. The older the bladder drug the more likely it is to cross the blood-brain barrier and affect cognition. Oxybutynin, for example, reduces IQ or cognition by a half a standard deviation or 7 points. This is enough to make someone with MS-related cognitive impairment demented.

However, many of the other drugs we prescribe to help MSers have anticholinergic effects off-target. These include the tricyclic antidepressants. As a class, these are used to help MSers with myelopathic pains and as sedatives. It is quite remarkable how often neurologists reach from the prescription pad to prescribe amitriptyline for their patients. I think it is time for us to step back from this practice. We now have other options.

The remarkable thing is that in the general population exposure to anticholinergics increases your risk of developing dementia. The most recent population case-control study confirming this has just been published in JAMA. I suspect the MS brain is more vulnerable to the effects of anticholinergics and hence we may have inadvertently been exacerbating MS dementia. It is time for us to rethink how we manage the MS bladder and other symptomatic problems and avoid drugs with anticholinergic effects?

Dare I suggest we should have zero-tolerance for anticholinergics and try and avoid them altogether?

Coupland et al Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study. JAMA Intern Med. Published online June 24, 2019. doi:10.1001/jamainternmed.2019.0677

Question: Is the risk of dementia among persons 55 years or older associated with the use of different types of anticholinergic medication?

Findings: In this nested case-control study of 58 769 patients with a diagnosis of dementia and 225 574 matched controls, there were statistically significant associations of dementia risk with exposure to anticholinergic antidepressants, antiparkinson drugs, antipsychotic drugs, bladder antimuscarinics, and antiepileptic drugs after adjusting for confounding variables.

Meaning: The associations observed for specific types of anticholinergic medication suggest that these drugs should be prescribed with caution in middle-aged and older adults.

Importance: Anticholinergic medicines have short-term cognitive adverse effects, but it is uncertain whether long-term use of these drugs is associated with an increased risk of dementia.

Objective: To assess associations between anticholinergic drug treatments and risk of dementia in persons 55 years or older.

Design, Setting, and Participants: This nested case-control study took place in general practices in England that contributed to the QResearch primary care database. The study evaluated whether exposure to anticholinergic drugs was associated with dementia risk in 58 769 patients with a diagnosis of dementia and 225 574 controls 55 years or older matched by age, sex, general practice, and calendar time. Information on prescriptions for 56 drugs with strong anticholinergic properties was used to calculate measures of cumulative anticholinergic drug exposure. Data were analyzed from May 2016 to June 2018.

Exposures: The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls (index date).

Main Outcomes and Measures Odds ratios (ORs) for dementia associated with cumulative exposure to anticholinergic drugs, adjusted for confounding variables.

Results: Of the entire study population (284 343 case patients and matched controls), 179 365 (63.1%) were women, and the mean (SD) age of the entire population was 82.2 (6.8) years. The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date. There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs. Results were similar when exposures were restricted to exposure windows of 3 to 13 years (AOR, 1.46; 95% CI, 1.41-1.52) and 5 to 20 years (AOR, 1.44; 95% CI, 1.32-1.57) before the index date for more than 1095 TSDDs. Associations were stronger in cases diagnosed before the age of 80 years. The population-attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3%.

Conclusions and Relevance: Exposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia. These findings highlight the importance of reducing exposure to anticholinergic drugs in middle-aged and older people.

CoI: multiple