Losartan to slow the progression of mild-to-moderate Alzheimer’s disease through angiotensin targeting: the RADAR RCT

Alzheimer’s disease is a disorder of memory in older individuals. High blood pressure in mid-life increases the risk of developing Alzheimer’s disease. We and others have found that a biochemical pathway in the brain, which also influences blood pressure, may be more relevant in Alzheimer’s disease than changes to blood pressure. This pathway, the renin–angiotensin system, includes a small molecule called angiotensin II that is raised in brain tissue from people with Alzheimer’s disease. As well as raising blood pressure, angiotensin II influences inflammation and chemical stress in brain cells and stops the release of chemicals involved in memory. Angiotensin II also enhances the production of key proteins (amyloid-β and tau) that damage brain tissue in Alzheimer’s disease.

All of these damaging characteristics point to angiotensin II being a detrimental factor in Alzheimer’s disease.

We conducted a multicentre randomised clinical trial to test whether or not losartan, the first drug developed to reduce the function of angiotensin II, could slow the progression of Alzheimer’s disease compared with placebo. We believed that reducing angiotensin II function would slow brain cell damage, brain shrinkage and memory problems in Alzheimer’s disease while improving brain blood flow. We recruited 211 participants and their study partners through 23 centres across Great Britain and Northern Ireland. We used brain imaging techniques, 12 months apart, to measure changes in brain volume and, in a subset of people, levels of brain-related vascular damage and brain blood flow as indicators of disease. We also used established questionnaires to assess memory and thinking, quality of life and activities of daily living to explore if losartan brought any benefits. Unfortunately, we found no evidence that 12 months’ treatment with losartan slowed the progression of Alzheimer’s disease according to our main study measures. Although losartan was unsuccessful in this study design, other study designs testing related drugs may still be successful.

Read the full article: Published 2021, NIHR Journals Library
https://doi.org/10.3310/eme08190

The Free-Cog study: A novel hybrid scale for the assessment of cognitive and executive function in dementia

What was this research about and why was it important?

An estimated 1 in 14 people over the age of 65 living in the UK have dementia. Although we are yet to find a cure, early diagnosis and interventions can allow patients to live independently for longer. Therefore, early and efficient diagnosis is one of the most important tools in a clinician’s arsenal. However, diagnosis can be complicated by the fact that that many types of dementia exist and, the specific pattern of damage within a person’s brain will affect how individual symptoms present. Therefore, any test needs to be able to detect and pinpoint a range of symptoms. Being familiar with a range of clinical tests used to diagnose dementia, Professor Alistair Burns and his team noticed a problem with these existing tools. Not only were the majority subject to copyright, thus requiring payment for use, no single test combined measures of cognition (memory, visual and spatial function, language and fluency) with measures of executive function (social functioning, travel, self-care and safety in the home). It was this observation that sparked the idea for Free-Cog; a free-to-use assessment tool which combined tests of cognition and executive function into one global test, designed to be suitable for use in a busy clinical environment.

What did our patients say about taking part?

Patients and members of the public were involved in developing this project at a very early stage. Professor Burn’s team worked with The Alzheimer’s Society’s Research Network to ensure that the format and wording of the test questions were tailored to patient’s needs. This involvement appeared to be beneficial, since many patients who were involved in trialing out the Free-Cog assessment commented that they liked its ‘conversational style’ and that they felt more relaxed and confident taking this test than some other more commonly use assessments. “It didn’t feel like an examination, it felt more like a TV quiz and was much better than the other assessment”, “My father seemed more visibly relaxed completing the Free-Cog study then the previous assessment”

What did the study find?

In total, 956 participants from across the UK took part in trialing the Free-Cog assessment. Many Greater Manchester patients fed back to our research nurses saying they found the experience interesting and enjoyable. The study showed that Free-Cog was similar to existing, routinely used, tests in its ability to differentiate between patients with Mild Cognitive Impairment (MCI) and Dementia and between healthy patients with no cognitive diagnosis and those with MCI. Despite some limitations, including a lack of specificity inherent in being a global scale and minimal written instructions, designed to make it easier for busy clinicians but which may be less acceptable for inexperienced staff; the Free-Cog assessment performed well and may have a number of benefits over current routinely used tests.

How will it improve services in the future?

This tool is free to use, measures both cognitive and executive functioning and is less likely to be perceived as a ‘test’ by patients meaning overall performance may be less impacted by patient anxiety. Combine these benefits with the finding that its performance is on par with other more commonly used tests and that it has a telephone consultation version (Tele Free-Cog) which also discriminates between patient groups, this makes Free-Cog a particularly powerful tool which may also adapt well to non-face-to-face setting. The Free-Cog will remain freely available in perpetuity. It is available to anyone interested in trialling it, translating it or validating it.

Read the full article: Published 2021, International Journal of Geriatric Psychiatry
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984170/

Use of the Long-Term Conditions Questionnaire (LTCQ) for monitoring health-related quality of life in people affected by cognitive impairment including dementia: pilot study in UK memory clinic services

Diagnosis of dementia and mild cognitive impairment (MCI) is improving, but people affected by cognitive impairment need ongoing support to maintain a good quality of life. Current health and social care policy states that improved quality of life should be an outcome of effective services following diagnosis, but this is currently not being measured. The Long-Term Condition Questionnaire (LTCQ) is a patient-reported measure of ‘living well with long-term health conditions’ that could be used to monitor how well people are supported following a diagnosis of cognitive impairment. The purpose of this study was to test the use of LTCQ in English memory clinic settings. For the first phase of research, 12 people affected by cognitive impairment completed LTCQ during interviews and gave feedback about their experiences. A modified version of LTCQ was then completed through a survey taken by 105 people with a new diagnosis of MCI or dementia. Survey results showed that LTCQ scores were worse for patients with multiple long-term conditions (including MCI/dementia) and for patients who required more help in completing the survey. But most patients were able to respond to LTCQ questions themselves, to directly report their quality of life. Sixty-one patients completed LTCQ again four months later, and changes in LTCQ scores reflected whether patients’ health had gotten better or worse since diagnosis. We concluded that LTCQ could potentially be used to monitor quality of life following a diagnosis of cognitive impairment and should be tested further among larger numbers of patients.

Read the full article: Published 2021, Quality of Life Research
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178132/

Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer’s disease: the MADE Phase II, three-arm RCT

Alzheimer’s disease affects about 700,000 people in the UK and, although there are drug treatments that can modestly improve some of the symptoms, we do not yet have any treatments that slow down the progression of dementia.

Minocycline is an antibiotic that has been shown to protect brain cells in a number of experimental and animal models of Alzheimer’s disease. Minocycline is cheap and well tolerated. If it could significantly slow down the course of Alzheimer’s disease, it could quickly be made available to large numbers of people with Alzheimer’s disease worldwide. Although minocycline is probably one of the best current candidates for Alzheimer’s disease modification, the current evidence can only suggest a potential benefit.

A clinical trial was conducted to determine definitively whether or not minocycline is effective in slowing the decline in Alzheimer’s disease. Long-term treatment effects of minocycline were investigated, with two doses of minocycline, on decline in cognitive function, including memory, attention and language, and ability to carry out essential functions of daily living, such as getting dressed, grooming and eating.

Unfortunately, the study found that minocycline treatment did not have any measurable effect in slowing down the progression of Alzheimer’s disease. Participants who took minocycline showed exactly the same worsening of their cognitive functioning and activities of daily living as those who were allocated to placebo treatment. The trial also established that minocycline at the high dose is poorly tolerated in patients with Alzheimer’s disease, whereas the low dose of minocycline is well tolerated, with participants being no more likely to withdraw from trial medication than those taking placebo.

One limitation of the study is that biomarkers were not used to confirm Alzheimer’s disease diagnosis, as tests for biomarkers are not routinely available within the NHS. Compliance with medication was also worse than expected, with few patients in the high-dose arm completing 2 years’ treatment and only moderate compliance in the low-dose and placebo treatment arms. It was difficult to obtain outcome assessments that resulted in unequal numbers of completed assessments across treatment arms, which could have biased the study’s results. Having said that, additional analyses investigating potential bias have, reassuringly, shown the same pattern of results.

Although disappointing, these results are important because they will guide further research into the search for a treatment. There is currently much interest in treating inflammatory changes in the brain in Alzheimer’s disease and, as minocycline is a potent anti-inflammatory drug, the study’s results will show researchers which pathways they should focus on.

Read the full article: Published 2020, NIHR Journals Library
https://doi.org/10.3310/eme07020

Use and costs of services and unpaid care for people with mild-to-moderate dementia: baseline results from the IDEAL cohort study

This study uses data from the IDEAL programme, which is a large research project that aims to find out what helps people to ‘live well’ with dementia. Over 1,500 people with mild-to-moderate dementia (MMSE>14) and their carers were interviewed as part of the programme. The interviews included questions on people’s use of health and social services, out-of-pocket payments for equipment and travel to appointments and unpaid care provided by family and friends.
The average total costs of health and social care, out-of-pocket payments and unpaid care were estimated at £4,008 per person with dementia over a 3 month period, equivalent to over £16,000 a year. The estimated cost for the use of health and social care services over 3 months was £1,004. Most people used few health services other than GP services and hospital outpatient care, and use of social care services such as home care was low. As we are following this group of people over time, we will be able to see if the use of social care increases as the condition progresses.

The findings show that unpaid carers of people with dementia are disproportionately shouldering the costs of care – covering 75% of the total costs (£2,928 over a 3 month period and £11,712 a year) and giving upwards of 470 hours of their time over a three month period to care for people with dementia, equivalent to an average of 36 hours a week.

Most of the people with dementia (87%) received help on a regular basis from friends or relatives. For nearly a third (30%), this included assistance with personal care.

Relationship to carer, living alone, socio-economic group and income were all related to the likelihood of receiving social care. People living alone were nearly twice as likely as those living with others to use social care services.

Two thirds of the people with dementia surveyed in IDEAL used aids and adaptations, most commonly mobility aids; 13% used pendant alarms and 12% calendar clocks.

Those with Parkinson’s disease dementia had almost double the average care costs compared to other dementias (£8,609 over a 3 month period and £34,436 a year). Estimated primary and community health care, social care and medication costs were highest for this group compared to those for people with other types of dementia. Total costs for women were lower than for men.

Read the full article: Published 2022, IOS (not open access?)
https://content.iospress.com/articles/journal-of-alzheimers-disease/jad215117

Quality of life and well-being of carers of people with dementia: are there differences between working and nonworking carers? Results from the IDEAL program

Do caregivers of people with dementia who were also in regular employment (paid or voluntary) feel they have better quality of life and well-being compared to nonworking caregivers? We asked 1239 spouse, relative and friend carers who took part in the IDEAL programme to self-rate their quality of life and well-being, and to comment on other factors like their caregiving experience and social support. Our carers ranged in age from 26-96 years of age. Whatever their age, their gender, or their relationship to the care recipient (spouse, relative, friend), working carers reported higher quality of life score than carers who were not working. This may reflect the benefit of the sense of independence that supported work opportunities gives to carers. Whether they were working or not working, carers who had a good self-esteem and had found ways to reduce their stress levels felt better about their quality of life and well-being. Carers who had good social support, and who felt positive about the care they were providing and their own competence in providing good care reported higher quality of life and well-being scores. This is one of the biggest surveys comparing working and nonworking carers in the UK. It has revealed the value of supported work opportunities for people caring for people with dementia. It has also provided a clear message on how we can support and improve the health and well-being of the hundreds of thousands of people providing informal care for their relatives, by helping them to keep connected, to value themselves, their own skills and the huge importance of that caring role.

Read the full article: Published 2021, Sussex Research Online
http://sro.sussex.ac.uk/id/eprint/90458

Deconditioning in people living with dementia during the COVID-19 pandemic: findings from the Promoting Activity, Independence and Stability in Early Dementia (PrAISED) process evaluation

Restrictions introduced in response to the COVID-19 pandemic led to an increased risk of deconditioning in the general population; a loss of function in movement, mental status or the ability to accomplish daily activities. This study aimed to identify the causes and effects of COVID-19 related deconditioning specifically in people living with dementia. Interviews were conducted remotely with 24 participants living with dementia, 19 carers and 15 therapists 2 months after the first national lockdown in March 2020 and again 2 months later. The content of these interviews was analysed and a self-reinforcing pattern was common. The lockdown made the person apathetic, demotivated, socially disengaged and frailer which reduced activity levels and this then reinforced the effects of deconditioning over time. This deconditioning occurs in the general population yet we also found that this was exacerbated by having dementia and that there were particular contributing factors specific to dementia. Such as the cognitive demand required by them to remember and maintain social distancing rules and then the negative effects of further restrictions imposed by their carers to reduce their breaches in following restrictions. Without external support, most participants lacked the motivation and cognitive abilities to keep active, however those that received remote support from therapists via video were able to better combat deconditioning. This study highlights the increased risk that people with dementia have to deconditioning and the importance of support and potential that tele-rehabilitation has as an effective strategy to reduce it.

Read the full article: Published 2020, medRxiv
https://www.medrxiv.org/content/10.1101/2020.11.16.20231100v1.full-text