Worsening cognition: ageing vs. smouldering MS
Worsening cognition: ageing vs. smouldering MS
Since having COVID-19 in 2021, my cognitive function has plummeted. Is there anything I can do about my cognition? My neurologist has told me this is what happens when you have MS and get old.

Case study

Prof G, I am 63 years of age and have had multiple sclerosis for 27 years. I have recently had to retire as a journalist because of cognitive impairment and fatigue. I do not have the mental energy and cognitive capabilities to perform my job. Since having COVID-19 in 2021, my cognitive function has plummeted. Using your online EDSS calculator, my EDSS is 5.0. I am still taking fingolimod, which seems to be working in that I have had no relapses, and my MRI has not shown any new lesions. I have been told that I do have some brain atrophy. Is there anything I can do about my cognition? My neurologist has told me this is what happens when you have MS and get old.

Prof G’s Opinion

How long is a piece of string?

How long is a piece of string? : r/technicallythetruth

This person describes what many of my patients complain about in clinic—worsening cognition despite being on an effective DMT and having no evident inflammatory disease activity or NEIDA. The cognitive impairment in this patient could be due to smouldering MS, superimposed ageing, long COVID or some other disease process. The knee-jerk reaction is to assume their progressive cognitive impairment is MS-related and to tell the patient there is nothing that can be done about their problem. It could be argued that this is a form of medical gaslighting and not how I would necessarily approach the problem. The following is my knee-jerk response to the query.

Rule 1: Don’t assume the cognitive impairment is MS-related 

This patient needs a full medical and neurological assessment, including a neuropsychological referral, to document the cognitive impairment and to define what domains are involved so that the patient can potentially be referred for cognitive rehabilitation. Many pwMS who complain of cognitive impairment are more likely to have depression and anxiety.  Treating depression and anxiety can help.

Rule 2: Don’t assume the cognitive impairment is age-related

I am aware that MS prematurely ages the brain and brings forward age-related cognitive decline. MS does this via several mechanisms. Firstly, by reducing neurological and brain reserve. Having fewer neurons, axons, and synapses reduces your biological resilience. In addition, ongoing smouldering MS-related inflammation will drive ageing mechanisms. Unfortunately, we have very little we can offer patients for age-related cognitive impairment outside of general brain health recommendations, which I have covered in an earlier MS-Selfie Newsletter (Brain Health: how important is it? 6th-Oct-2-22). 

This patient will need a brain health screen to see if anything can be modified, i.e. all the factors under the so-called non-MS targets below. Don’t underestimate the importance of every one of these factors in helping to improve your general and brain health. The big ones on the list are sleep, diet, exercise and comorbidities, including infections. This patient needs to be seen in the clinic to have a detailed medical history taken and a clinical examination.  In addition, they may need some regular blood tests done to exclude metabolic causes of cognitive decline, for example, hypo- or hyperthyroidism, vitamin B12 deficiency, diabetes, hypercalcaemia, etc…

Rule 3: Don’t assume because you haven’t had relapses and your last MRI is stable that, your MS is inactive.

This rule is very controversial but is supported by recent observations that clinical and MRI monitoring is very insensitive and does not pick up some ongoing inflammation. We are now offering patients like this patient a lumbar puncture to check to see if they have raised spinal fluid neurofilament levels that would indicate ongoing inflammation. We have shown that approximately 1 in 10 pwMS who are NEIDA have increased neurofilament levels that will guide DMT switching. In our centre, this patient would potentially be offered a switch to siponimod or recruitment into our add-on SIZOMUS trial to try and tackle smouldering MS. 

A spinal fluid analysis will also allow us to exclude an opportunistic infection that can occur on fingolimod, such as cryptococcal meningitis and to do a dementia screen on the fluid for Alzheimer’s disease. Yes, people with MS are also at risk of getting Alzheimer’s disease (AZD). The problem is very few neurologists think about co-morbid Alzheimer’s disease, mainly because we don’t have treatments for AZD. This will change in time as AZD DMTs emerge. 

This particular person thinks that COVID-19 accelerated their cognitive decline. This is possible for three reasons. Firstly, they may have long COVID or smouldering COVID-19. The latter is the prolonged shedding of SARS-CoV-2 in immunocompromised patients; in some patients, the shedding has been documented to occur over many months and rarely years. Smouldering COVID-19 is not a trivial medical problem and is likely to be the primary substrate for the emergence of new SARS-CoV-2 variants. As fingolimod is not that immunosuppressive, the chances of this person having smouldering COVID-19 is very small. Nevertheless, they should have a nasal and throat swab sent for SARS-CoV-2 PCR.

A second reason for this person having cognitive decline is long COVID. There is now mounting evidence that people with COVID-19 take a hit when it comes to the brain. There are several studies showing brain atrophy and/or cognitive deficits in people who have long COVID compared to controls. There are also pathological studies showing SARS-CoV-2 infection of the brain in people who have had COVID-19. However, before labelling this patient as having long-COVID-19-associated cognitive impairment, I would want to exclude other conditions referred to above. My problem with long COVID is that the definition of the condition and the diagnostic criteria for making the diagnosis are a bit vague and are also non-specific, so that long COVID is a bit of a dumping ground for clinicians. I am not saying that long COVID does not exist, but that a lot of people diagnosed with long COVID may have other causes for their symptoms. 

The third reason is the impact the COVID-19 pandemic has had on brain health in general. The paper below has just come out, showing how, in older people, the pandemic has affected cognitive function in general. The researchers think the main drivers are reduced exercise, increased alcohol consumption and social isolation. What this study shows us is how susceptible the brain is to minor insults and that we should take brain health more seriously in future.

I have been writing and talking about MS brain health for over a decade, and very few MS services include brain health screening and management in routine clinical practice. The problem is bandwidth. We have very little time to manage MS and its problems and even less time to cover brain health. I think we are missing a trick and that if we all adopted the marginal gains approach to managing MS, our patients would have better outcomes and better quality of life. 

I would like to know if you have had a brain health screening done and/or been advised in your regular MS follow-up assessment on optimising your brain health. Similarly, has the concept of prehabilitation been discussed with you (please see: Prehabilitation the ultimate in self-help, 5-Jul-2021). 

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Research paper

Corbett et al. Cognitive decline in older adults in the UK during and after the COVID-19 pandemic: a longitudinal analysis of PROTECT study data. Lancet Healthy Longev 2023; 4: e591–99.

Background: Although the long-term health effects of COVID-19 are increasingly recognised, the societal restrictions during the COVID-19 pandemic hold the potential for considerable detriment to cognitive and mental health, particularly because major dementia risk factors—such as those related to exercise and dietary habits—were affected during this period. We used longitudinal data from the PROTECT study to evaluate the effect of the pandemic on cognition in older adults in the UK. 

Methods: For this longitudinal analysis, we used computerised neuropsychology data from individuals aged 50 years and older participating in the PROTECT study in the UK. Data were collected from the same participants before the COVID-19 pandemic (March 1, 2019–Feb 29, 2020) and during its first (March 1, 2020–Feb 28, 2021) and second (March 1, 2021–Feb 28, 2022) years. We compared cognition across the three time periods using a linear mixed-effects model. Subgroup analyses were conducted in people with mild cognitive impairment and in people who reported a history of COVID-19, and an exploratory regression analysis identified factors associated with changes in cognitive trajectory. 

Findings: Pre-pandemic data were included for 3142 participants, of whom 1696 (54·0%) were women and 1446 (46·0%) were men, with a mean age of 67·5 years (SD 9·6, range 50–96). Significant worsening of executive function and working memory was observed in the first year of the pandemic across the whole cohort (effect size 0·15 [95% CI 0·12–0·17] for executive function and 0·51 [0·49–0·53] for working memory), in people with mild cognitive impairment (0·13 [0·07–0·20] and 0·40 [0·36–0·47]), and in people with a history of COVID-19 (0·24 [0·16–0·31] and 0·46 [0·39–0·53]). Worsening of working memory was sustained across the whole cohort in the second year of the pandemic (0·47; 0·44–0·49). Regression analysis indicated that cognitive decline was significantly associated with reduced exercise (p=0·0049; executive function) and increased alcohol use (p=0·049; working memory) across the whole cohort, as well as depression (p=0·011; working memory) in those with a history of COVID-19 and loneliness (p=0·0038; working memory) in those with mild cognitive impairment. In the second year of the pandemic, reduced exercise continued to affect executive function across the whole cohort, and associations were sustained between worsening working memory and increased alcohol use (p=0·0040), loneliness (p=0·042), and depression (p=0·014) in those with mild cognitive impairment, and reduced exercise (p=0·0029), loneliness (p=0·031) and depression (p=0·036) in those with a history of COVID-19. 

Interpretation: The COVID-19 pandemic resulted in a significant worsening of cognition in older adults, associated with changes in known dementia risk factors. The sustained decline in cognition highlights the need for public health interventions to mitigate the risk of dementia—particularly in people with mild cognitive impairment, in whom conversion to dementia within 5 years is a substantial risk. Long-term intervention for people with a history of COVID-19 should be considered to support cognitive health.


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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.



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