There’s something very interesting about a certain blood pressure pill and dementia

It can take many years and many millions of pounds sterling or dollars for new medications to come to market.

Not only do the drugs have to work, but they also have to do so with an acceptable range of potentially adverse effects.

Most feel it was a rash promise, with a massive political twang, to offer a cure for dementia by 2020. Certainly, it is hard to get very excited about this promotion of the pharmaceutical industry reported to have been ‘ailing’, while care in this jurisdiction due to swingeing cuts has been on its knees.

Losartan is a medication, routinely used in management of high blood pressure. It is “an angiotensin receptor blocker” (also called an angiotensin-II receptor antagonist (AIIRA)). The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. Recently, several local RASs in organs such as brain, heart, pancreas and adipose tissue have also been identified.

And the wide-ranging actions of such drugs have attracted much interest for much time (e.g. Goodfriend, Elliott and Catt, 1996).

Losartan works by blocking the effect of a chemical called angiotensin II which is made in your bloodstream. Angiotensin II causes your blood vessels to narrow and also leads to the production of another chemical called aldosterone, which increases the amount of fluid in your blood.

By preventing the action of angiotensin II, losartan reduces how much work your heart has to do and lowers your blood pressure. It also has a protective effect on your kidneys.

The Dementias and Neurodegenerative Diseases Research Network (DeNDRoN) has worked in partnership with researchers on eight of the 21 studies announced by the government to receive funding, including the RADAR clinical trial.

DeNDRoN will work with sites across the UK to actively recruit 230 participants for the RADAR clinical trial over the next two years. Those regions involved are Oxford, Leicester, Reading, Brighton, Exeter, as well as three sites in Scotland and one in Wales.

With generous funding of nearly £2 million by the Medical Research Council (MRC) and managed by the National Institute for Health Research, the double blinded placebo-controlled randomised trial, known as RADAR (Reducing pathology in Alzheimer’s Disease through Angiotensin taRgeting), will recruit approximately 230 participants from a number of sites across the UK over two years.

Among these locations will be the BRACE Centre at Frenchay Hospital in South Gloucestershire. This is a memory clinic under the direction of Dr Liz Coulthard, who is a co-investigator on the RADAR study but whose own research is also funded by BRACE.

Dr Liz Coulthard was one of the speakers at the brilliant event held yesterday by Alzheimers BRACE.

Amazing photo BRACE

The study uses brain imaging at CRICBristol and other locations around the country to measure if losartan can help improve people’s memory and quality of life.

This groundbreaking study was first reported in March 2013.

But there is something very curious about the chemical at the heart of all this, for reasons I should like to explain.

Angiotensin firstly is known to be a mediator of inflammation.

This could be relevant to dementias such as Alzheimer’s disease in a number of ways. An excellent review (Benigni, Cassis and  Remuzzi, 2010) looked at how studies in the last few years have however documented new roles for this molecule as a pro-inflammatory molecule and more recently as a possible pro-fibrotic agent that contributes to progressive deterioration of organ function in disease.

Binding of Ang II to its receptors (in particular AT(1)) mediates intracellular free radical generation that contributes to tissue damage by promoting mitochondrial dysfunction. Blocking Ang II signalling protects against neurodegenerative processes and promotes longevity in rodents.

In a separate strand of policy, a link has been made between obesity and dementia.

Some scientists have found evidence that being obese in middle age raises your risk of developing dementia later in life, with the latest study suggesting that people as young as 30 who are obese may be at greater risk..

Intriguingly, according to Clare Wotton and Prof Michael Goldacre, obesity is associated with a risk of dementia in a way that appears to vary with age. Investigation of the mechanisms mediating this association might give insights into the biology of both conditions (Wotton and Goldacre, 2014).

This is not where the story ends – but actually gets a bit complicated.

As reviewed recently (Kalupahana and Moustaid-Moussa, 2012), Evidence from clinical trials suggests that in addition to anti-hypertensive effects, pharmacological inhibition of RAS also provides protection against the development of type-2 diabetes.

Moreover, animal models with targeted inactivation of RAS genes exhibit improved insulin sensitivity and are protected from high-fat diet-induced obesity and insulin resistance.

And there has been scrutiny of the remarkable suggestion that being diabetic might possibly increase your risk of dementia.

It is thought that a third of Alzheimer’s disease, the most common form of dementia worldwide, can be explained by modifiable risk factors (Norton et al., 2014), so the argument of the effect of the environment can be overplayed.

To give an example, researchers in Italy enrolled 120 outpatients, 54 males and 66 females, aged 75–89 years (mean age: 81.3 years) with mild to moderate essential hypertension.

Using simple bedside tests of memory, the authors of that study data suggested that in very elderly hypertensive patients, chronic AT1 receptor blockade by losartan could improve cognitive function, in particular immediate and delayed memory (Fogari et al., 2003).

And evidence from the part of the brain known to be a key player in memory, the hippocampus, suggests there may be something genuine going on here.

Inhibition of central angiotensin II enhances memory function and reduces damage in rat hippocampus (Bild et al., 2013).

It will now be very interesting to see if, given the relatively safe side effect profile of losartan, whether losartan can actually prevent the onset of Alzheimer’s disease, or slow its rate of progression.

Certainly, losartan’s mechanism of action here is odd.

But it is also extremely interesting.




Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med. 2010 Jul;2(7):247-57. doi: 10.1002/emmm.201000080.

Bild W, Hritcu L, Stefanescu C, Ciobica A. Inhibition of central angiotensin II enhances memory function and reduces oxidative stress status in rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jun 3;43:79-88. doi: 10.1016/j.pnpbp.2012.12.009. Epub 2012 Dec 20.

Fogari R, Mugellini A, Zoppi A, Derosa G, Pasotti C, Fogari E, Preti P. Influence of losartan and atenolol on memory function in very elderly hypertensive patients. J Hum Hypertens. 2003 Nov;17(11):781-5.

Goodfriend TL Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med. 1996 Jun 20;334(25):1649-54.

Kalupahana NS, Moustaid-Moussa N. The renin-angiotensin system: a link between obesity, inflammation and insulin resistance. Obes Rev. 2012 Feb;13(2):136-49. doi: 10.1111/j.1467-789X.2011.00942.x. Epub 2011 Oct 31.

Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 2014 Aug;13(8):788-94. doi: 10.1016/S1474-4422(14)70136-X.

Wotton CJ, Goldacre MJ. Age at obesity and association with subsequent dementia: record linkage study. Postgrad Med J. 2014 Oct;90(1068):547-51. doi: 10.1136/postgradmedj-2014-132571. Epub 2014 Aug 20.



The health checks for future risk of dementia themselves may not be in good health

Earlier this year, the influential Alzheimer’s Disease International charity published its World Dementia Report 2014.

Dementia and Risk Reduction: An analysis of protective and modifiable factors critically examines the evidence for the existence of modifiable risk factors for dementia.

It focused on sets of potential modifiable risk factors in four key domains: developmental, psychological and psychosocial, lifestyle and cardiovascular conditions. The report makes recommendations to drive public health campaigns and disease prevention strategies.

Indeed, in that report the authors stated, “There is no evidence strong enough at this  time to claim that lifestyle changes will prevent  dementia on an individual basis.”

The report is littered all the way through it with qualifications on how, whilst a current focus on modifiable risk factors is justified by their potential to be targeted for prevention, “non-modifiable risk factors (eminently age, gender and genetic factors) are also very important.”

The full name of the Alzheimer’s Disease International, as its CEO Marc Wortmann (@marcwort) is keen to point out, is  “Alzheimer’s Disease and Associated Disorders”.

This is clearly relevant as there are about a hundred different types of dementia, of which the dementia of the Alzheimer type happens to be the most prevalent. The media – and certain members of the medical profession – regularly like to conflate all dementias with Alzheimer’s disease, a phenomenon known as “Alzheimerisation”.

But it is hoped that accurate communication of risk of the dementias may play an important rôle in prevention, and in combatting stigma and discrimination. The big unresolved question is, of course, is how this emphasis exactly will help nearly a million currently living in the UK with dementia.

It is not thought that the prevalence of dementia in England is static. It is thought that it is falling.

As argued in a paper in the Lancet(Neurology), from the Medical Research Council Cognitive Function and Ageing Collaboration at the  MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge University, “This study provides compelling evidence of a reduction in the prevalence of dementia in the older population over two decades.” (1)

Indeed, the authors of that study indeed signpost what could be driving that reduction in their introduction.

“By contrast, factors that might decrease prevalence include successful primary prevention of heart disease, accounting for half the substantial decrease in vascular mortality, and increased early life education, which is associated with reduced risk of dementia.”

Prevention of dementia is likely to be big business.

In discussing recent data,  Geeert Jan Biessels from the Department of Neurology, Utrecht, Netherlands mooted how identification of ‘at risk’ individuals could take place (2):

“Apart from timing of interventions, a question is whether prevention programmes should be population wide or target specific high-risk subgroups, as is now common in the prevention of cardiovascular disease. To target individuals at increased risk of Alzheimer’s disease, these individuals would need to be identified at a very early stage, well before the disease process commences.”

The NHS Health Check was launched in 2009 to assess and treat patients aged 40 to 74 for their risk of developing heart problems, diabetes, high blood pressure and kidney disease.


In July 2014, Prof Clare Gerada was reported as voicing serious concerns.

Gerada “backed the calls to end the routine checks, claiming they ‘devalued medicine’ and led to patients being needlessly worried as family doctors waste time on people who are not sick.”

‘You always find something that you can’t explain and then you do more tests,’ she said. ‘We’re constantly having to explain to patients that actually there’s nothing wrong.’

The Blackfriars Consensus Statement calls for new national focus to reduce risk of developing dementia.

Action to tackle smoking, drinking, sedentary behaviour and poor diet could reduce the risk of dementia in later life alongside other conditions such as heart disease, stroke and many cancers, according to the UK Health Forum and Public Health England in a joint consensus statement published on 20 May 2014.

The Blackfriars Consensus Statement argued that the scientific evidence on dementia risk reduction is evolving rapidly and is now sufficient to justify action to incorporate dementia risk reduction into health policies and to raise wider awareness about which factors can reduce the risk of developing dementia.

The Statement makes reference to a “precautionary principle”, which “requires that, even for those risk factors for which the evidence is less robust, we should recommend actions that could reasonably be presumed to reduce the risk of some types of dementia at least …”

This precautionary principle maximally allows for mission creep, of course, as rent seekers wish to establish new financial markets under the guise of prevention of medical disease.

According to one newspaper report today, “Middle-aged people will be screened by GPs for their risk of dementia and told how their “brain age” compares to their biological age, under new plans to “scare” people into adopting healthier lifestyles. It means a man of 40 could be told that he has the brain of a 60-year-old, and a significantly greater chance of diseases like Alzheimer’s, based on his weight, exercise habits, cholesterol levels and alcohol intake.”

The origins for this policy can be found in the computation of the ‘lifetime risk score’ for cardiovascular disease. Back in July 2013, there was a furore about the possibility of an army of patients being put on statin drugs to lower their risk from certain forms of cholesterol as a result of ‘JB3 guidance’. ‘Bad’ forms of cholesterol can cause heart attacks or stroke. The precise history of how the ‘Joint British Groups’ arrived at this is complicated, however.


But an influential article in the Heart journal from Joep Perk, Ian Graham, Guy De Backer from Sweden, Ireland and Belgium was pretty damning about this (3).

“Their ambition is to provide health workers, especially general practitioners, with answers to three key questions: Why should I start advising CVD risk reduction? When should I start? And what should I do?”

“However relevant these questions are, it should be noted that the proposed model has to our knowledge not been tested on a large scale. This remains the major shortcoming of all three sets of guidelines: in comparison with new drugs or technical equipment where extensive documentation is needed for approval, the methods for risk assessment or calculators remain remarkably poorly tested.

“On the one hand wide application in clinical practice is advocated, while on the other hand little is yet known about feasibility, acceptance rate in a busy general practice, the understanding of the patient, or even the effect on individual behaviour. This is clearly an important challenge for future studies.”

So even if dementia is amenable to modifiable risk factors, how much of it exactly is amenable?

Sam Norton, Fiona E Matthews, Deborah E Barnes, Kristine Yaff and Carol Brayne in the Lancet Neurology earlier this year argued, on the basis of their data, “After accounting for non-independence between risk factors, around a third of Alzheimer’s diseases cases worldwide might be attributable to potentially modifiable risk factors. Alzheimer’s disease incidence might be reduced through improved access to education and use of effective methods targeted at reducing the prevalence of vascular risk factors (eg, physical inactivity, smoking, midlife hypertension, midlife obesity, and diabetes) and depression.” (4)

But even this estimate there might be inaccurate. To give them credit, the authors themselves conceded, “A strength of the single risk factor approach is that it highlights the potential for individual risk factors, but a major limitation is that the estimated combined population-attributable risk makes the untenable assumption of independence of the risk factors.”

I don’t blame Dr Charles Alessi for wanting to ‘make a difference’. Prevention is a core strand of dementia policy globally.

As Alessi himself writes, “I am excited by the opportunity we have to make a difference to people’s lives and I am determined that we will seize the moment and really capture the emerging evidence that dementia is not an inevitable part of ageing and in some cases can be prevented or its progression delayed. My role as lead for the prevention of dementia is to make this a reality for all of us.”

But the reputation of and trust in the medical profession are both vital.

It is essential that any policy of ‘risk calculators’ in England is rolled out by members of the medical profession with the utmost integrity and probity, especially since the plan is to pay GPs for every diagnosis of dementia made.



(1) Matthews FE, Arthur A, Barnes LE, Bond J, Jagger C, Robinson L, Brayne C; Medical Research Council Cognitive Function and Ageing Collaboration. A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II. Lancet. 2013 Oct 26;382(9902):1405-12. doi: 10.1016/S0140-6736(13)61570-6. Epub 2013 Jul 17.

(2) Biessels GJ. Capitalising on modifiable risk factors for Alzheimer’s disease. Lancet Neurol. 2014 Aug;13(8):752-3. doi: 10.1016/S1474-4422(14)70154-1.

(3)  Perk J, Graham I, De Backer G. Prevention of cardiovascular disease: new guidelines, new tools, but challenges remain. Heart. 2014 May;100(9):675-7. doi: 10.1136/heartjnl-2014-305650. Epub 2014 Mar 25.

(4)Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data.Lancet Neurol. 2014 Aug;13(8):788-94. doi: 10.1016/S1474-4422(14)70136-X.




Sophisticated brain imaging and changes in eating behaviours in dementias

Food is a relatively undeveloped research subject in health and social welfare, particularly with respect to older people (Mennell et al. 1992), but some inroads have been made into understanding the specific neural substrates underlying abnormal eating behaviours for persons living with dementia.

It is probably fair to say that the dementia syndromes in which eating behaviours have been investigated the most include the dementia of Alzheimer type (at first signposted by problems in attention and new learning and memory, “DAT”), the behavioural variant frontotemporal dementia (at first signposted by problems in personality and behaviour, “bvFTD”), and temporal variants frontotemporal dementia (including problems in semantic knowledge, semantic dementia or “SD”).

First of all, it is important to appreciate that eating abnormalities are more likely in certain types of dementia more than others. For example, the frequencies of symptoms in all five domains, except swallowing problems, might be higher in the behavioural variant of frontotemporal dementia than in DAT (Ikeda et al., 2002); conversely, changes in food preference and eating habits were greater in SD than in DAT.

In semantic dementia, these authors found that the developmental pattern was very clear: a change in food preference developed initially, followed by appetite increase and altered eating habits, other oral behaviours, and finally swallowing problems. In bvFTD, the first symptom was altered eating habits or appetite increase. In Alzheimer’s disease, the pattern was not clear although swallowing problems developed in relatively early stages

Understanding which parts of the brain go wrong in producing these symptoms has turned out to be productive. Turning to the neuroanatomical implications of their findings, Ikeda and colleagues (Ikeda et al., 2002) have proposed that the changes in eating behaviours reflect the involvement of a common network in both variants of frontotemporal dementia—namely, the ventral (orbitobasal) frontal lobe, the temporal pole, and the amygdala (e.g. Cummings and Duchen, 1981).

The ventromedial frontal lobe is affected from an early stage in patients with bv-FTD and SD, ether by direct pathological involvement, or indirectly through damage to the temporal pole and amygdala, which are heavily interconnected with the ventromedial frontal lobe (Mummery et al., 2000).

The Kluver-Bucy syndrome has been known about by neurologists for some time, for its distinct cluster of symptoms. Bilateral degeneration of the amygdaloid nuclear complex in monkeys, and surgical removal of the temporal lobes in man, result in the Kluver–Bucy syndrome which is characterised by hyperorality, overeating, and the eating of quasi-food items (Bucy and Kluver, 1955; quoted in Ikeda et al., 2002).

The methodology of voxel-based morphometry has revolutionised our understanding of eating abnormalities in dementia. The aim of VBM is to identify differences in the local composition of brain tissue, while discounting large scale differences in gross anatomy and position.

This is achieved by spatially normalising all the structural images to the same stereotactic space, segmenting the normalised images into gray and white matter, smoothing the gray and white matter images and finally performing a statistical analysis to localize significant differences between two or more experimental groups.

vbm brain

The study by Howard Rosen and colleagues examined neuroanatomical correlates of behavioural abnormalities, as measured by the famous rating scale known as the ‘Neuropsychiatric Inventory’, in 148 patients with dementia using a brain imaging technique called voxel-based morphometry (Rosen et al., 2005). According to the authors, eating

behaviours did not uniquely associate with any specific brain region. The authors instead emphasized that eating behaviours in FTD are indeed complex and varied, and include carbohydrate craving, overeating with weight gain, obsessions for particular foods and occasionally oral exploration of nonfood objects, which may not always coexist in an individual patient (Miller et al., 1995).

Marked disturbances in eating behaviour, such as overeating and preference for sweet foods, are also commonly reported in bvFTD. And there has been for some time this might have something to do with a small area of the brainstem known as the “hypothalamus”.

The hypothalamus plays a critical role in feeding regulation, yet the relation between pathology in this region and eating behaviour in FTD is unknown.

The study by Piquet and colleagues (Piquet et al., 2011) identified significant atrophy of the hypothalamus in persons with bvFTD. Indeed, persons with prominent eating disturbance exhibited significant atrophy of the posterior hypothalamus. Features of eating disturbance, such as increased appetite, preference for sweet foods, and an increased tendency to eat the same foods, were present only in the bvFTD group, but were not observed in the healthy controls.

Taste and flavour are intimately enmeshed with one another. Deficits of flavour processing may be clinically important in FTD.

To examine flavour processing in FTD, Omar and colleagues (2012) studied flavour identification prospectively in 25 patients with FTD (12 with bvFTD, eight with semantic variant primary progressive aphasia (svPPA), five with non-fluent variant primary progressive aphasia (nfvPPA)) and 17 healthy control subjects, using a new test based on cross-modal matching of flavours to words and pictures (Omar et al., 2012).

Brain MRI volumes from the patient cohort were analysed using voxel-based morphometry to identify regional grey matter associations of flavour identification. Relative to the healthy control group, the bvFTD and svPPA subgroups showed significant deficits of flavour identification, and all three FTD subgroups showed deficits of odour identification.

Flavour identification performance in the combined FTD cohort was significantly associated with changes in distinct regions of the brain: grey matter volume in the left entorhinal cortex, hippocampus, parahippocampal gyrus and temporal pole. This profile, in fact, comprises brain substrates in the anteromedial temporal lobe which have been previously implicated in the associative processing of chemosensory stimuli (e.g. Gorno-Tempin et al., 2004).

Furthermore, in an interesting voxel-based morphometric study by Whitwell and colleagues, the authors found distinct neuroanatomical signatures of different abnormalities of eating behaviour (pathological sweet tooth and increased food consumption or hyperphagia) in individuals with frontotemporal lobar degeneration (FTD) (Whitwell et al., 2007).

In that study, sixteen male patients with FTD were assessed clinically.Volumetric brain magnetic resonance imaging was performed in all patients and in a group of nine healthy age-matched male controls and grey matter changes were assessed using an optimised VBM protocol.

Compared with healthy controls, the FTD group had a typical pattern of extensive bilateral grey matter loss predominantly involving the frontal and temporal lobes. Within the FTD group, grey matter changes associated with different abnormal behaviours were assessed. The development of pathological sweet tooth was associated with grey matter loss in a distributed brain network including bilateral posterolateral orbitofrontal cortex (Brodmann areas 12/47) and right anterior insula. Hyperphagia was associated with more focal grey matter loss in anterolateral orbitofrontal cortex bilaterally (Brodmann area 11).

Carers’ reports of changes in eating behaviour show that various forms of increased eating are commonly found at some stage in the course of dementia (Morris et al., 1989).

According to Keene and Hope (1998), Both studies showed that hyperphagia is a stable condition, generally occurring as a single episode. Duration of hyperphagia varied, ranging from 4 months to over 3 years in a few subjects. This is likely to be an underestimate as the end of the hyperphagia was often masked by the preventive measures taken by the carer.

Hyperphagia and associated eating changes occur frequently in DAT, and lead to considerable morbidity. However, the neurochemical basis for these neuropsychiatric behaviours is at present unclear. Medications known as selective serotonin reuptake inhibitors (SSRIs) have shown efficacy in the treatment of bulimia nervosa and binge eating disorders (Milano et al., 2005), as well as suppressing rebound hyperphagia in rats (Inoue et al., 1997).

Tsang and colleagues (2009) measured serotonin transporters, 5-HT1A, 5-HT2A, and 5-HT4 receptors using radioligand binding assays in the post-mortem temporal cortex of a cohort of controls and DAT patients longitudinally assessed for hyperphagia (Tsang et al., 2009). We found significant decreases in 5-HT4 receptor densities in the hyperphagic, but not normophagic, DAT group.

serotonin pathways

Intriguingly, Peter Nestor has described a virtual resolution of severe food and alcohol bingeing in anFTD patient using low-dose topiramate (Nestor, 2012). The prompt relapse on withdrawal and subsequent remission with reinstatement perhaps suggests that the improvement was causal and not coincidental to this behaviour abating as part of the natural evolution of the illness.

It will be interesting to work out whether the effect of topiramate is a primary one on eating behaviour, or part of a wider effect of topiramate on impulse control possibly involving serotonin somewhere (Pompanin et al., 2014).

It is clear that recent technological advances in neuroimaging have been able to shed much light on changes in eating behaviours in persons with dementia from different clinical diagnostic groups. In time, this might lead to suitable medications which might change these behaviours which can become difficult for some.




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Nestor, P.J. (2012) Reversal of abnormal eating and drinking behaviour in a frontotemporal lobar degeneration patient using low-dose topiramate, J Neurol Neurosurg Psychiatry, 83(3), pp. 349-50.

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