It’s now been discovered that our clever brain has more than one way of learning. For the last twenty or thirty years our understanding of the way our brain works to learn or store memories has been that it involves a particular receptor called the NMDA receptor found at the terminal end of brain cell dendrites. This receptor is particularly active in the area of our brain called the hippocampus, which is the area that specialises in helping us to learn and encode memories.

The way it works is that when this particular receptor is activated it allows calcium to enter that brain cell, which then triggers further molecular reactions which results in our brain being able to process, store and then retrieve that information.
Last week Bryce Vissel from the Sydney Garvan Institute of Medial Research was talking on ABC radio discussing the results of the study he had been involved in, that has now been published in the 29th September edition of PLoS One.

Bryce Vissel and other researchers from Australia and the United States had been looking to artificially replicate this NMDA mechanism to provide a way to circumvent the difficulties of memory loss associated with brain injury through stroke and disease. What they found coincidentally was that the brain actually already has a secondary pathway in place, which enables us to store new information. This has been termed “second learning” as this pathway uses a different receptor called AMPA but this is only activated if the information received relates to similar information that has been learnt before. The implication of this finding is that this natural second pathway, may allow us to circumvent the disease, or damaged NMDA receptors, which could prove useful to provide new and alternative ways of treatments for stroke and Alzheimer’s disease.

Among the questions now being raised from this finding, is to work out what allows or triggers this second mechanism to operate. Once that is understood the hope will be to be able to find ways to engage this pathway to take over the role of the NMDA mechanism that isn’t working through disease or injury.
The other potential implication of this finding is that having this second means of learning could have really important effects on how we approach teaching in the classroom in the future as well.

Ref: A Role for Calcium Permeable AMPA Receptors in Synaptic Plasticity and Learning.
Wiltgen BJ, Royle GA, Gray EE, Abdipranoto A, Thangthaeng N, et al. 2010 A Role for Calcium-Permeable AMPA Receptors in Synaptic Plasticity and Learning. PLoS ONE 5(9): e12818. doi:10.1371/journal.pone.0012818

During a chat with a group of ladies last week, we got onto the topic of of supplements, and which herbs and spices might be beneficial in promoting brain health. One lady advised me that every morning she pours a good dollop of flaxseed oil onto her breakfast cereal along with some L.S.A and psyllium. Plus a heaped teaspoon of turmeric.

Mmm, I remain to be convinced about the taste, although she reassured me she didn’t mind it. So, what is the deal with turmeric and why would she be adding it to her breakfast cereal?

Turmeric or Curcuma longa is an Indian spice and a member of the ginger family. It has a wonderful yellow hue that gives it’s colour to curry, mustard and piccalilli relish.

It was noted some years ago that the incidence of Alzheimer’s disease in India is about one tenth of Western societies. One study in rural North India reported an incidence of 0.62 % in those over the age of 55 years and 1.07% in those aged 65 and older. Compare that to 10% for 65 year olds in our society. There have been a number of reasons postulated as to why this should be. But one of the thoughts is that it is due to the curcumin found in turmeric and in India a huge amount of turmeric is consumed in curries on a daily basis.

The curcuminoids in the turmeric have been associated with a number of significant health benefits and a number of studies have been completed looking at how it may afford protection against neuro-degenerative disease.

Let’s have a look at some of the research.

In Alzheimer’s disease one of the hallmark findings, are of plaques in the brain made of a substance called beta amyloid. The body has it’s own defence system to try and get rid of this in the form of scavenging cells called macrophages. These travel around the brain trying to remove any amyloid it finds. One study looked at the effect of treating these macrophages with curcumin and found that the macrophages were then better able to gobble up the beta amyloid with an improvement rate of 50%.

Curcumin has potent anti-inflammatory and anti oxidant effects. It is thought that inflammation plays a role in the development of Alzheimer’s. This led to studies to see whether anti-inflammatory drugs, and or curcumin through it’s anti-inflammatory effect could be useful in treating beta amyloid build up. One study conducted at UCLA looked at the anti inflammatory effect of curcumin vs ibuprofen (a commonly used anti-inflammatory drug). Using rats with beta amyloid in their brains, both curcumin and the ibuprofen were shown to provide equivalent protection from the inflammatory damage caused by the beta amyloid. The curcumin reduced the number of plaques in the rat brains by up to 80% at low dose and the rats given the curcumin performed better on spatial memory tests compared to the control group. Curcumin can cross the blood brain barrier and binds to amyloid protein fragments, which can then no longer clump together to form plaques.
However follow up clinical trials in patients with Alzheimer’s disease who were prescribed anti-inflammatory drugs such as Ibuprofen unfortunately only produced limited or negative results. Likewise the ADAPT cognitive function tests using Naprosyn similarly showed no benefit in improving cognitive function in older adults. There remains the possibility that the NSAID’s could be useful if taken in the years prior to any cognitive decline. This has yet to be shown.

Curcumin and Vitamin D

Moving back to curcumin and its possible role with Vitamin D. In 2009 UCLA researchers discovered that Vitamin D together with curcumin might help to stimulate the immune system to clear the brain of amyloid beta.
A small study was undertaken with 9 patients with Alzheimer’s disease, 3 healthy controls and one subject with mild cognitive impairment. Blood samples were collected and a type of white cell, monocytes (which can transform into macrophages) were isolated and then incubated with amyloid beta, Vitamin D3 and either natural or synthetic curcumin.
The synthetic curcumin was devised as naturally occurring curcumin was found to be less readily absorbed and so is less potent.

The researchers found that the curcuminoids enhanced the surface binding of amyloid beta to macrophages and that Vitamin D also strongly stimulated the uptake and absorption of amyloid beta by the macrophages in the majority of patients.

A previous study by the same team had demonstrated that MGAT 111 and TLR-3 genes are the genes associated with the immune system’s ability to ingest amyloid beta. Dr Milan Fiala found that there were two types of Alzheimer’s patients: type one who did respond positively to curcuminoids and type two who did not. He noted that as the curcumin and Vitamin D work differently in the immune system, it might be that either a combination of the two or each used alone, might be more effective depending on the individual. He suggests larger and more studies using Vitamin D and curcumin are necessary to see if this would be the case.

How does the curcumin exert its effect?

Dr A Ramamoorthy at the university of Michigan has shown that the curcumin inserts itself into cell membranes, changing the physical properties of the membrane rather than interacting directly with the membrane proteins.
He is is now working on looking at determining the relative potency of a variety of curcuminoids derivatives which could potentially lead to new compounds being formulated as treatments. He is also investigating the effects on how curcumin exerts its effects on the formation of amyloid.

So if eating curry with turmeric may assist in keeping our minds sharp as we age, how much should we be eating? According to Dr Sally Frautschy, Associate Professor of UCLA (who eats curry four times a week), one tablespoon or 200mg per day.

But I think I still prefer to eat my turmeric in curry rather than on my breakfast cereal though.

What about you? How do you take your turmeric?

There has been an exponential increase in the number of people around the world who are obese and or have diabetes, both significant risk factors for dementia.

For many of us the battle of the bulge is seemingly the result of consuming too much fat, being too sedentary, or just simply eating too much.
As we get older our metabolic rate declines, so while we still experience hunger and enjoy our food, we need to reduce our total food intake to keep our weight in the normal range.

We know too that being overweight or obese puts us more at risk of other chronic illness and disease. We increase our risk of cardiovascular disease, stroke, diabetes and cancer.
But there is something else we need to be aware of as well.

Being overweight or obese doubles our risk of developing dementia or Alzheimer’s disease.
It is associated with having a smaller brain volume.

Having a smaller brain through obesity affects our brain function in specific areas:

In the hippocampus, the area specialised for learning and memory.
In the frontal lobes, our executive suite, concerned with planning, organisation and paying attention.
In the anterior cingulate gyrus, an area involved in decision-making, empathy and emotion.
In the thalamus, an area associated with coordinating other brain areas.

But it is the belly fat that puts us most at risk.
Having a big tummy with stick legs and arms actually puts you at greater risk than someone who is more generally rounded. The implication here, is that you don’t have to be particularly overweight to be at increased risk, if all the extra is sitting around your middle.

A study published last month showed this link. Over 700 subjects from the Framingham Heart Study were recuited. The mean age of the group was 60 years and 70% were women. Dr. S Seshadri and colleagues looked at the association of Body Mass Index (BMI), waist circumference, waist to hip ratio, CT measured abdominal fat and MRI brain scans looking at total brain volume and other variables, as well as the number of brain infarcts (mini areas of stroke) present. The results showed a strong correlation between central obesity (ie the fat in your abdomen) and the risk of dementia and Alzheimer’s disease.

Being obese in middle age, having an elevated systolic blood pressure (that’s the top reading of your blood pressure) and a high total cholesterol each are significant risk factors and individually double your relative risk of dementia. Put them together and you can end up with x6 the risk.

A meta-analysis of 10 international studies covering a 10 year period confirmed these findings, revealing that obesity increases the relative risk of dementia for men and women overall by an average of 42% compared to people of normal weight.

However after the age of 65years it appears that the trend is reversed. Annette Fitzpatrick from the University of Seattle reported the results of a study she undertook where she had around 300 people as subjects who did not have dementia. They had their weight at age 50 recorded and then repeated height and weight at age 65yrs to calculate the BMI’s at the different ages.

Over the 5-year follow up, those people classified as obese (BMI >30) were more likely to have developed dementia.
However the older subjects ie 65 years plus, who were underweight (BMI <20)

also

had an increased risk of dementia and the older subjects appeared to have gained a protective effect in later life.

So there appears to be an obesity paradox. There is a change in the predictive ability of BMI with dementia risk with age.

Why should this be?

The answer is yet to be revealed. There has been the suggestion that the onset of weight loss in older life may precede the onset of dementia. Studies have shown that women in particular will show weight loss about 10 years before the first signs of dementia become apparent.

However it is still the case that reducing obesity in midlife (especially central obesity) is crucial to reduce an individual’s overall risk of developing dementia or Alzheimer’s.

So meanwhile there is a big job ahead of us, to reduce obesity in those Western societies where being overweight has become the norm. The risk if we don’t, is that we will see increased mortality at an earlier age from cardiovascular disease and stroke and the added burden of the increased number of people developing dementia and Alzheimer’s disease.

Now I do enjoy a nice glass of red wine occasionally and there is a lot of noise in the media about red wine being good for us.

Why? Because red wine contains resveratrol, an antioxidant with supposedly lots of health benefits such as protecting us from cancer, cardiovascular disease and perhaps cognitive decline.

Look in the health food shops selling memory enhancing supplements and many include resveratrol. You can even buy resveratrol in capsule form.

So should be we be taking these supplements or drinking more red wine?

Let’s have a look at what some of the research is saying about all this.

First off, resveratrol is not only found in red wine. It’s also found in a number of other plants and foods such as blueberries, mulberries, peanuts even eucalypt, lily and spruce. But it is grapes, which have drawn the most attention.
The grape vines contain resveratrol in the roots, stalks, seeds and especially the skin of the grape.
I think I’ll stick to the grapes and the skin.
In the fermentation process to make red wine, the skins which contain a lot of resveratrol are included. This is what differentiates it from white wine fermentation where only the crushed berry juice is used, not the skins.
Not all red wines are equal either. The highest concentrations of resveratrol are found in the Labrusca, Muscadine and Vitus Vinifera varieties.
Dr Richard Hoffman and Mr Johansson at the University of Hertfordshire, UK have been looking at a number of different red wines to determine which have the highest concentration of resveratrol. So that one day we will be able to select which wine we wish to purchase, based on it’s resveratrol content.

So how does resveratrol exert it’s health benefits in the brain?

Let’s look at a study on ischaemic stroke published in April 2010. Researchers from John Hopkins used resveratrol in mice studies and found that the resveratrol works to increase a neuro-protective enzyme (called haem oxygenase) Mice given resveratrol as supplements who then suffered an induced ischemic stroke, sustained less brain damage than those mice who had not received the supplement, because the resveratrol boosted the haem oxygenase levels.

Moving on to look at Alzheimer’s disease where having higher blood markers of inflammation is known to be associated with a higher risk of developing the disease. In the Framingham Heart Study, 691 healthy seniors (aged 79 years and older) had their levels of cytokines (markers of inflammation) measured in blood tests. Over the next 7 years, 44 of the participants developed Alzheimer’s disease.
The results showed that those with the highest levels of cytokine in their blood had twice the risk of developing Alzheimer’s disease.

So what’s the link to resveratrol and inflammation?

Resveratrol has been shown in mice studies to protect them from acute inflammation. Researchers in the Medicine Faculty in Glasgow demonstrated that resveratrol supplements helped to prevent the body from producing substances called sphingosine kinase and phospholipase D, which are involved in triggering the inflammatory response.

So how does resveratrol help to protect us from Alzheimer’s disease?

In Alzheimer’s disease, the main brain changes are massive brain cell loss and the appearance of neurofibrillary tangles and plaques of beta amyloid.
Ongoing studies indicate that resveratrol promotes the clearance of beta amyloid that has formed, by inducing the body’s proteasomes. The proteasomes are the body’s waste disposal units for getting rid of unneeded cellular proteins that can then be recycled. The mechanism for how resveratrol does this, as yet remains unknown.
All that is known is that in those people with Alzheimer’s disease, the natural activity of proteasomes is reduced.

Thus much of the story remains untold. As yet we don’t know which are the best red wines to be consuming, or the quantity to produce the beneficial effects. It may be that resveratrol itself is the messenger, a stimulator of other protective enzyme systems, rather than the major player in the process.

What we do know now is that resveratrol

• Increases a neuro protective enzyme called haem oxygenase that will help protect us to some extent, in the event of a stroke.
• Dampens down inflammation (a marker for increased risk of Alzheimer’s disease) in the body by reducing the amount of inflammatory enzymes that form.
• Promotes the body’s natural protein waste disposers, the proteasomes, which help clear the brain of beta amyloid deposits.

Until the remaining pieces of jigsaw are found to explain all of how resveratrol works, it would appear that continuing to enjoy a small amount of red wine is unlikely to be detrimental to our brain health and might even be doing us some good.

Mention Alzheimer’s’ Disease and most people will think of an older person with dementia.
But not everyone with dementia is over the age of 65.

There are a number of people diagnosed around the world every year with what is known as early onset Alzheimer’s disease. The majority of these people are in their mid forties and fifties.
In what many would consider their prime of life.
They account for 5-10% of all people diagnosed with Alzheimer’s disease.

But what if you were in your early thirties?

Could you possibly contemplate what it would be like to be told at the age of 31 or 32 that you had Alzheimer’s disease?

A couple of days ago I watched a short TV segment which told the story of two young women both in their early thirties who have early onset Alzheimer’s disease.
It was confronting viewing.

One young woman was diagnosed just after finding out she was pregnant with her first child. Now a young mother, she is incapable of caring for her new baby and has to be supervised 24/7. Her daughter will never know the once vibrant, energetic woman who is her mother. The young woman’s eyes have that vacant look, she has difficulty speaking, and her prognosis is bleak. Her husband appears to be coping (at least in front of the television cameras) but is clearly grieving. Her own mother, devastated by her daughter’s rapid deterioration, helps where she can, caring for her daughter and granddaughter.

The other young woman is scared, very scared. Not only for herself, as she witnessed her own mother die from the disease when she was in her thirties, but for her own daughters. She has three girls aged 15 months, 8 years and 9 years. Because this particular form of Alzheimer’s is autosomal dominant, her daughters have each got a 50% chance of inheriting the same condition.

These two women have a very rare form of Alzheimer’s disease triggered by a defective gene called presenilin 1. This is one of three genes that are linked to early onset familial Alzheimer’s disease. Presenilin 1 is the most common of the three.

This is different from the APOE gene that can increase your risk of developing Alzheimer’s disease in general. Having APOE does not guarantee that you will definitely develop Alzheimer’s. Though not having it doesn’t guarantee that you won’t either.

But the genetic link with Presenilin 1, Presenilin 2 and APP is far stronger and hence the risk of familial transmission is far greater. A prenatal test for early onset Alzheimer’s disease due to Presenilin 1 is apparently available.
Genetic counselling would be very important to have, before undergoing this test.

Professor Ralph Martins based in Perth, West Australia is one of the world’s top leaders in Alzheimer’s’ disease research. He has dedicated his life to this research and has spent 26 years in this field. He is currently involved in an international study, which is looking at sufferers of early onset Alzheimer’s disease such as the two young women on the TV program. Because this group experiences a much more aggressive form of the disease which progresses much faster, they may hold the key to assist researchers find out more about how and why the disease develops. Professor Martins hope is that by identifying markers, a simple blood test will be able to devised, which will allow people to know whether they have Alzheimer’s disease long before any symptoms develop.

If picked up early, then there will be greater chance for interventional treatments to be more effective in limiting the devastating effect of the disease. Perhaps one day it will also be possible to to prevent the progression of the disease.

The link for the TV segment is below.
Please watch it.

http://au.tv.yahoo.com/sunday-night/features/article/-/article/7147834/alzheimers-research/