Thank you for coming this evening and
I need to
show my
Disclosures for research funding we've had funding from our National Research Institute the Institute of Health Research from the NIH our cyber Society of Canada
physician Services Incorporated and Lawson Health Research our local Research Foundation
I've also been a consultant to the
pharmaceutical companies listed there in
designing clinical trials and
We've also our group has received over the last twenty five years funding from all of those companies as well as the ones
Listed on the right-hand side of the screen. So if I'm contaminated, I'm equally contaminated by all of them
There are no favorites there, but we do work for the pharma sponsored studies with pharmaceutical companies
that's
Necessary, but we also do a lot of investigator initiated studies observational studies as well funded by the other agencies that we work
with
So we're going to use the live polling tonight and we're going to use an application called
Meeting pulse. So this is a bit of an experiment. This is the first time we've done this and
so it's going to be a bit of a cognitive test for me and
my colleague Dana who's going to be helping with the
polling I will cue you when the poll is ready and hopefully for those of you who want to participate using your
phones or your
Devices to be able to participate you can do it and
What we'll do during the course of the evening is estimate where you are on the spectrum of cognitive decline
Identify what your risk factors might be for cognitive decline in the future
Project where you might be in the future in particular 20 years out
Reflect on what you're doing now to reduce your risk and improve your brain function
And then later on after we've discussed some of these strategies and risk factors
to consider what additional strategies that you're not doing now that you may want to add and
lastly to evaluate your interest in cognitive research
Some of you may recognize this as the Montreal Cognitive Assessment
so this is an instrument which was a Canadian devised instrument in Montreal and
has had a lot of traction around the world. It's a screening instrument and
It doesn't make a diagnosis of dementia
But it's very useful in a number of different settings family physicians family health teams
Primary care memory clinics our own aging brain and memory clinic
We use it on inpatient services on the consultation service and the hospitals on our rehabilitation units
And so this gives us a measure. It's just gives us a measure of where a person might be
From time to time particularly if they're having delirium or if they actually have a progressive disorder
such as dementia
So you can see there. There's some animals and
We get them to name the animals and that blank space we get draw a clock. There's a cube copy
There's the first part of what we call the trails B
Alternating from a number to a letter to a number
then there are five words across the bottom and
These are five words that we I would say in the clinic to the person that I'm testing
And then I'm going to ask them to say the words back to me. So the five words are face
velvet church daisy red
OK you've got the idea
Okay, so we do that twice and we're going to do it again. So I'm going to say the words again face
velvet church daisy red
Okay, that's really good so we're going to just reflect on those and and normally in the clinic
I would ask a people people to remember those words and then we would go on and do the other
Components of the test. There are eight different elements of this test. We would look at tests of attention
Tests of language abstraction we would ask some words about orientation. We would eventually come back to those five words again
words again. Now this is the spectrum of cognitive decline
that we use in the aging brain and memory clinic and so there are people who have
What we refer to as being being super normal
These are people over 80 who score the same as 20 year olds on memory tests on detailed memory tests
This is an uncommon group of older people
Then there are people in their 50s 60s 70s 80s who have what we regard as normal age associated loss
Memory and cognitive functions start to change in about the 40s in a very subtle way, but then continue after that
subjective and those people do on the when they do the minii mental state or in particular the
Montreal Cognitive Assessment when they do that particular test they score better than
or
24, 26 or better on the MOCA test now
There are certain caveats about using a cut point on a test. Now some people may do better on the test than
26 may score up to 30
It depends a bit on the educational level and some people may score below but as a general rule
26 is the cut cut point that we regard as normal but a person with a low level of education
May not do quite as well and the other caveat on the test
is that the first time that you do the test a
Person who's not familiar with it may not do very well. But on a second may do better
So there are some caveats about this test that we have to be cautious about how we interpret them
Certainly doing the test repeatedly over time can be a very valuable
exercise and important information on knowing whether a person is improving staying the same or getting worse now people who have
people who have subjective cognitive decline are people who say that there has been a change in their memory
Their memory has changed. Usually it's their memory. It can be language. It can be another cognitive function, but often it's memory and
memory, and the second thing that they've noticed is they're concerned about it
others
Around them may not be aware of it. But when they do the MOCA, they score 26 or better
people with mild cognitive impairment
are people who
clearly have changes in their memory or maybe language and
they
They will score less than 26 on the MOCA
Their activities of daily living the instrumental activities of daily living are entirely normal
They may be a bit less slower at doing things but their instrumental activities of daily living are entirely normal
So those things like grocery shopping cooking yard work housework
finances
To the extent that a person did those things
dementia on the other hand are people who have cognitive impairment and
on whatever measure you you tend to use to measure particularly the MOCA but other instruments we use as well and
Also, their instrumental activities of daily living one or more of those instrumental activities of daily living are significantly
Impaired now to make that judgment we have to talk to family members to get that information
we usually talk to family members separately to try and
Determine if they're instrumental activities of daily living has changed and when we see families over time
We will talk to them separately and see whether there's been any change
if there's been
Impairment on the instrumental activities of daily living now across the bottom you can see if we looked at people in Canada today
today, so these are people here 65 and over
8% have dementia
17% have mild a cognitive impairment and the other 75% would fall into a normal range. That's 85 and over
One-third have dementia one-third have mild cognitive impairment and one-third will be in the normal range
Prodromal dementia, is that phase between mild cognitive impairment and dementia - it's the prodrome before we get to dementia and then dementia can obviously progressed a mild
to dementia and then dementia con progress from moderate severe or advanced and as it progresses to the right there
there's increasing dependence in those instrumental activities of daily living and then eventually
self-care activities of daily living so dressing bathing eating
grooming those things may become impaired as
Well, there may be increasing behavioral changes and psychological symptoms that occur with dementia
Okay, so all together (audience) face, velvet, church, daisy, red
You're pretty good I don't think any of you need to be here, but we'll go on that's good
Okay, so now having reflected on the spectrum of cognitive decline
This is where we're going to start our first poll
And what we're going to ask you is to look at the spectrum of cognitive decline and determine where on that spectrum of cognitive decline
cognitive decline that you think you are
So are you 1 if you're super normal, 2 if you're normal, 3
Subjective cognitive decline, 4 mild cognitive impairment, 5 dementia. You can't be more than one option
So
Is anyone still putting trying to decide where they are
Okay, I think what we'll do is we're going to close the poll
That's very interesting. So most of you and the age consistent loss
And we have some people who are super normal
I was looking at the group before and I didn't think there was anyone here who was over the age of 80. So I
Didn't think that was going to be possible, but maybe there are
So that's excellent
Okay, so we need to look at risk factors for dementia
So age as you might have guessed is the most important risk factor
The next risk factor we need to consider is a genetic risk factor, the most common genetic risk factors
There are several but the most common one we talk about is the APOE e
gene and
APOE e comes in three aleos or
types if you like APOE e2, 3, APOE e4 and
You get one gene from each of your parents and if you happen to get one or two copies of APOE e4
You are at increased risk of developing Alzheimer's disease and I'll explain later
why that might be
Family history is tied into that. There may be other factors as well
Down Syndrome is also risk factor, and I'll also explain why that is later. Now there are some risk factors that we can change: inactivity
midlife obesity, high blood pressure, high cholesterol, diabetes, smoking
major depressive disorders, low level of education,
head injuries. So those are things that we can try and prevent or change
If we look at the cumulative risk
and we look just look at risk of age alone at age 60 the risk of
having dementia would be about one percent at age 90 that risk
could be as much as 64%
If we add one risk factor
There's a doubling of that risk factor and if we add two risk factors in addition to age
We're adding a further doubling of the risk factors
So now a person with two risk factors and at age eighty they would have a risk factor
They would have a risk of having dementia of about sixty four percent on chance
So given that
thinking about those risk factors, where do you think you might be? So we're going to open your apps again
so we're going to
look at the app again. Where on that spectrum of cognitive decline do you think you're going to be?
So there's some discussion some people are not sure where they're going to be
and
What you'll see here, that's interesting, but there has been a shift to the left. So people are thinking they're shifting
Shifting sorry to the right
moving in that direction of the spectrum of the cognitive line
So I think you've certainly got an idea of what the spectrum of cognitive decline means. And also what your particular risks might be
So now there are ways that we're going to try and reduce those risk factors. So there are six non drug
strategies to reduce the risk of cognitive decline
So regular aerobic and resistive weight exercises, adherents to a mediterranean-style diet
and I'm going to speak about each of those in more detail with looking at a little bit of the evidence a
mental stimulation so finding new and interesting ways to stimulate the brain to challenge the brain
Socialization to be socially engaged not to be isolated
Restorative sleep. So at least seven or eight hours of sleep, and it needs to be fitful sleep
And avoid things like sleep apnea
Reduction and cessation of alcohol certainly if a person already has some cognitive impairment
we strongly recommend that they reduce alcohol and even consider complete cessation and there are very very
available now non alcohol beers. I understand that there
Non-alcohol wines. Some people don't care for them, but they are worth at least looking at if you need to reduce
alcohol or even try and
stop altogether and in terms of
psychoactive drugs a common anticholinergic
drug that people do use we certainly see people in the clinic who take Gravol for sleep. Now Gravol is a strongly anticholinergic
agent it opposes acetylcholine in the brain and we see people who come in with cognitive impairment. They stop the
Gravol and within 2 or 3 months there's improved cognition
So it's something to think about in terms of looking carefully at the drugs
Recreational drugs we don't know what's going to happen with marijuana in the future. But that's something where there's obviously going to be some research
obviously going to be some research to look at that
Now exercise in cross-sectional studies, we know that this improves brain health it improves heart health
But if we look at longitudinal prospective studies, so these are longer studies in physical activity and prevention of
Alzheimer's Disease, so these are 9 large studies involving over
20,000 participants over the age of
65 who are free of dementia at the beginning of the study and there's a definite reduced risk of Alzheimer's disease and
For those of you who are statistically inclined this would be a fixed effects ratio of 0.61
We have studied exercise in many different ways
But one way I want to share with you tonight is the changes that you might see on a brain image such as an MRI
scan, we do a lot of MRI imaging here in London at the Robarts Research Institute, and at the
The Grosvenor site here we have
MRI scanners as well as part of some of the research studies that we do and with physical exercise
you see greater grey matter grey matter as the part of the brain that does the thinking in the brain and also there's a
larger size of the hippocampus the hippocampus is what we refer to as the memory department as
well physical activity in people who already have dementia. So they've already got cognitive impairment
there's 18 randomized controlled trials there and when you push those studies together and what's called a meta-analysis you get a puzzle
overall effect on cognitive function particularly with interventions that involve aerobic exercise and it doesn't matter so much the
the frequency. It's the fact that you're doing something whether it's a high or low frequency. It's beneficial
We try to get at least three times per week
Thirty minutes at a time as a minimum
Walking is a very good in this image
here is a person with dementia with their ca  regiver
walking and this is the sort of thing that we want to encourage people to be able to continue to be
exercising and to be stimulated and to socialize in this way
There is a video if you want to look more about some of the evidence in a very brief
Whiteboard presentation by Dr. Mike Evans from the health design lab this is
really useful to look at it's called twenty three and a half hours
He's talking about the twenty three and a half hours during the day
where we're doing everything else but exercise and then 30 minutes a day
doing exercise and he presents this in a very convincing way. So I'd encourage you to look at that
Diet is important the Mediterranean style diet
is a
Pyramid, we certainly want people eating a lot of vegetables and leafy greens
high colored fruits and
whole grains for carbohydrates
Dairy in moderation certainly olive oil and nuts
Some some high-fat dairy. Certainly the fish is an important component of the Mediterranean style diet
So tuna
Salmon sardines anchovies
Herring. Not everyone likes all of those things, but certainly most people will eat tuna and
salmon and sometimes that they don't even like that then eating fish would be as good as well. This is the Mediterranean- style diet
style diet. The analyses of 13 out of 18 longitudinal and prospective studies say these are not just crux
cross-sectional studies these the studies are the long periods of time where they're followed people and looked at what are the outcomes are so higher
outcomes, so a high adherence to a mediterranean-style diet
either slows the rate of cognitive decline or minimizes the conversion to Alzheimer's disease and
will improve cognitive function.
There are future studies that are still going on that we want to get an idea
where can we have the greatest impact on late life cognition does the diet have to change in midlife?
Does it have to change even earlier is it?
Sufficient to start eating a Mediterranean- style diet in later life
What are the important components that provide that neuroprotection? Fish is certainly felt to be an important factor.
There was a Swedish study in this analysis, which did not show an effect of the Mediterranean-style diet
However, what it did show was increased meat consumption
was associated with the increased risk of dementia and a lower brain volume, so the brain was not as large
So we see different effects from some of these different studies
This is the combination of looking at both diet and exercise so you can see across
the baseline here, this is over many years 12 years, this is done in New York and this is the probability of remaining
Alzheimer's disease free and I want to highlight just two groups
those with very high physical activity and the group that had very high diet score on the
Mediterranean diet
the the score used to score the Mediterranean-style diet and
then those with the low physical activity and those with a low diet score and so this group has
progressed some have progress to dementia maybe 20% but in this group almost half have progressed to dementia
So this is a longitudinal observation study looking at
exercise and diet and then breaking the groups up into these different combinations
Another multi-domain study, so this is going even further
this was a planned study the finger study in Finland two years people at risk over the age of 60 to
77 and for those in the intervention group, so they
were randomly assigned to the intervention group. They got instruction on nutrition
they were given a physical exercise program cognitive training and
they addressed their vascular risk factors and
they were compared to a control group who got health advice alone
If they had vascular risk factors. They were given education about that as well and the outcomes were improved
cognition and reduced risk of cognitive decline for the intervention group
So this is a study that's ongoing and there will be some further outcomes from this finger study
But this is a very important landmark study and what it's telling us here is that it's not just going to be a single intervention
That it may be in fact a combination of interventions that is going to be even more powerful than just doing exercise or diet
I mentioned earlier there was
Mental stimulation
socialization restorative sleep
B vitamins and people with mild cognitive impairment that they have high homocysteine levels in their blood
May be a benefit and for the chocolate lovers in the room
The good news dark chocolate is good (mild laughter)
We want to reduce as well other risk factors and this is risk factors of
other medical conditions which might call clinical strokes or
silent strokes so we know that strokes
conditions that affect brain function and certainly affect cognitive function and
You can have silent strokes people can not be even aware. So people are quite surprised when we show the MRI scans
we pull them up in the
clinic, we look at the image and they see holes in their brain and they said how is it possible that I've had strokes and
I didn't even know about it. These are silent strokes and they can occur particularly in people with these high risk/high
These vascular risk factors high blood pressure and these are some of the strategies to control the blood pressure
standing blood pressure using home blood pressure recordings controlling diabetes
with home
monitoring and
Hemoglobin a1c which is the blood test which has done every three months or so to see that the diabetes is well controlled
managing elevated cholesterol stopping smoking and addressing atrial fibrillation. For some people
Coated aspirin may be appropriate as well. So these
are the vascular risk factors that people need to address in addition
using the non drug approaches for reducing the risk of cognitive impairment
So we're going to come to our next poll. and this one gets a little more complex. You're actually allowed
so if you open up your apps again, you're allowed to make a choice of
several choices of these different interventions will show those interventions again in a minute
so
What do you what are you doing now to reduce your risk, so you may not be doing anything?
but some of you will be doing exercise Mediterranean-style diet
restorative sleep mental stimulation
socialization
alcohol reduction and if you have any of those vascular risk factors
You may be controlling those so you can put any of those options in there into your apps
So I think everyone's put those in and we'll see what people are doing to actually control the risk factors
so I'm glad virtually everyone is doing something and
You can see where it actually falls. This is what people are doing. So it looks like most people are exercising
That's good that the single most important thing you could be doing is
exercise mental stimulation and socialization
it also gets a lot of support along with the Mediterranean-style diet restorative sleep and
And control of vascular risk factors
So we'll go on and talk about some of the types of dementia Alzheimer's I've mentioned briefly
this is the most common form of dementia The second most common form of
dementia is vascular dementia due to those strokes or silent strokes or a combination of them and
vascular dementia and Alzheimer's disease particularly in the people in their 80s and 90s if they have vascular risk factors
Often may be combined. So people may have both types of dementia.
Some of you may have heard of Lewy Body dementia, which is a dementia that is often is overlaid on Alzheimer's disease
So it's part of that mixed dementia, so you can have Alzheimer's and vascular dementia as a mixed dementia
But you could have Lewy Body in there as well
Sometimes occasionally you have Lewy body parts often. It's characterized by visual hallucinations parkinsonism and
fluctuations in levels of consciousness
Restless legs can also be part of that picture
Frontotemporal dementia is much less common
and it occurs tends to occur in people at a younger age often between the ages of 50 and
70
If we look at Alzheimer's
disease Alzheimer described
plaques and tangles
Those are the things that you'll have heard about and he described that over 100 years ago and the plaques are those brown
patches on the right side of the screen and this is in the cytoplasm and this is
clusters of what
We now know to be amyloid protein and I'll talk a bit a bit more about amyloid protein
We all have amyloid protein in our brain. This is an abnormal
aggregation of amyloid protein which
clusters together as misfolded proteins and is deposited in the brain and people who have the APOE e4 gene
One or two copies are much more likely to have this amyloid protein
accumulate in their brain and part of the problem is they don't make more amyloid protein than anyone else
They just don't get rid of it as well as people
Exercise may moderate that there is some evidence that exercise might actually help reduce that accumulation
After amyloid starts to deposit in the brain over a number of years the next change that occurs is the
tangles the neurofibrillary tangles and this is caused by a different type of protein called tau protein t-a-u and
this protein is another misfolded protein and
It accumulates and it accumulates in the nerve cells
And you can see on the right there the nerve cells there look different from the ones on
the left which are normal and these are
altered and then
Eventually, these nerve cells die
Now there is a model to actually describe what we think is going on here and I'll try and work through this
This is timeline in years. Cognitively normal people with mild cognitive
people with dementia and this is the degree to which the biomarker that we're looking at
changes so amyloid protein I talked about and it's accumulating in the brain over a period of time over a number of years this time
time it may be out here to to this point here, maybe as long as 10 or 15 years
the amyloid protein is slowly accumulating in the brain and
What we see
is then subsequently the tau proteins are accumulating in the brain and
causing injury to the nerve cells and loss of function of the nerve cells as
This is happening
The structure of the brain is changing in a subtle way and we can measure that using MRI images
We can do MRI images at one point and then again in a year or two and we can measure
changes in the structures within the brain particularly in the
Hippocampus and we can look at the ventricular system where we can see that the shrinkage of the brain occurring
Normally at age 65 and beyond the brain shrinks at about half percent per year
But in people with Alzheimer's disease that may be shrinking as much as 3 to 6 percent per year
So it's a magnitude greater
The next change that we see after the structural change is the cognitive change
So this is where we start to see people
Having the mild cognitive impairment and that impairment on the MOCA the MOCA scores are starting to decline
significantly and then function is starting to decline and this is where we cross that
threshold to making that functional diagnosis of dementia and in this instance It would be dementia
due to Alzheimer's disease because of the accumulation of the amyloid protein and subsequently the tau protein
Now
Alzheimer described this on an autopsy. So fortunately for us we don't have to go that route and we can do
unless there's a family history that we want to pursue
Certainly, we strongly encourage families if they're interested in knowing what their their family member died of we can do
autopsy examination. But here we can actually in real life
determine if a person has
Amyloid in their brain. This is a normal PET scan. This is a Positron Emission Tomography scan
This is a normal scan
And this is one showing the amyloid accumulation in the brain and there's an obvious difference between these two scans
These are scans that are done at this site at St. Joseph's on our PET scanner here.
We have a pet MRI scanner and it's a combined pattern MRI scan
It's the only one in Canada and we have one of the newest cyclotrons here
and so we make this compound this tracer to be able to make this amyloid scan and
This is what a scan would look like if we were to look at a combined amyloid and tau PET scan
So this again is a Positron
Emission Tomography scan and
We've got four different people here
They're four separate people and the first three are all cognitively normal
And this person here has Alzheimer's disease
And so this person here has a little bit of amyloid accumulating in the brain
This is the A beta amyloid protein and this is the same person scanned at the same time with the tau
PET scan showing the distribution you can see the distributions are a bit different.
They don't follow - they're not following exactly in the same place and
This is a person who's got more amyloid and more tau and this is a person he's even got even more
amyloid and more tau and still they're cognitively intact and part of the reason for this is that this person may have resilience to actually
developing cognitive impairment part of it may be education. Maybe they're doing a lot of the right things
to actually prevent the development of dementia. eventually, however those
Those resilience may be overcome and a person may progress the mild cognitive impairment and dementia
you can see now in this case a person has a
lot of tau protein here destroying the nerve cells in the internal cortex. This is in the temporal lobe
There are other new developments that are happening in
PET imaging
here and
This is a new development using
18 FEPPA which is developed here by our neuro chemists at this site in front of temporal dementia and
My colleague over at Parkwood Hospital Elizabeth Finger is one of the cognitive
neurologists involved this research with her colleagues from this site and
this is a pet MRI scanner and
This looks at
activated microglia in people who have frontal temporal dementia and this is what the images look like. So this is you Udanna
Anazodo who is a PhD
Scientist working with Dr. Finger
and the rest of the scientists here and so you can see this is the MRI image
so if we look at the normal image here, this is
an image in this axis through the brain like this. This is the next one above it is one straight down through the brain and
then you can see in the image in the person with the frontal temporal dementia. The temporal lobes are severely diminished and
there's a lot of shrinkage here if you compare this brain here with this one here
you see there's a lot of shrinkage in the brain on the MRI and then if you look at the
FEPPA scan
You can see the activated microglia been identified and compared to the control images here and here
So this is a test that could be used for
diagnosis that could be used for following a person if we had a treatment for frontal
temporal dementia and there are treatments now being tested as part of randomized controlled trials that might
actually improve the situation for this person and you might want to have a PET image to
actually be able to follow that over time. There are some treatments for Alzheimer's disease
which have been proven through randomized control trials over time and I got to talk a little bit about them
And then also where we're going in the future with some
potentially disease modifying treatments. So this is time over years
so this is the course of typically of what we have the progression of Alzheimer's disease from
diagnosis through to a person being severely impaired. This is a
scale here called the mini mental state. It's different from the MOCA. It's also scored out of 30 as well
But it's the American scale. It's five cognitive domains. It's a shorter test
It's a bit easier, but it's used in widely in clinical trials
So a person here has mild cognitive impairment and they may progress
This is that steep portion where families said the person's getting worse over time
And this is progressing through to severe dementia. We have treatments which may four different drugs
so you may be familiar with some of them the cholinesterase inhibitors and the
NMA, the NMDA inhibitor. This is a
course that a person who responds to that treatment might follow
Not everyone will respond to that treatment. Maybe about 35% of people will have a modest response
They're not going back to normal, but there may be some improvement over six months or a year. They may look more like
themselves, they may have better memory may have a little bit a better of executive function ability to plan things
However, we would like something that actually alters the course of the disease and what we're looking for with the current
treatments are disease modifying treatments one that might actually alter that course
So if a person over time ended up here as opposed to here or here
This would be a better place to be this would be a person who's still in the community
They may not be driving, but they may not be in a nursing home
so the
disease modifying treatments if we had a clinical trial if we had a successful clinical trial the people in the treatment arm
would follow that line there and the people in the placebo arm would follow that line there
And so that's what we're certainly looking for in our treatment trials now
This is a very complex disease and I don't want to minimize the complexity of this disease some
pharmaceutical companies have even pulled out of the search for trying to find a cure for this disease
however,  there are strategies and immunotherapy is one that has been pursued at present
Immunotherapy has been used in cancer treatments. It's been used for  Rheumatology and various rheumatic diseases and
So it's been used in Alzheimer's disease now with immunotherapy
you might understand what active immunotherapy would be like so this would be someone who had a vaccine if you've got a
vaccine to a flu virus in the fall you would develop antibodies your body will produce antibodies to that vaccine that's active
Immunotherapy and the immunotherapy most of the treatment trials that were pursuing involves passive immunotherapy
So we're going to give people in the trial either
medication or the placebo and the medication would be an antibody to
amyloid we're going to try and remove that amyloid from the brain to stop it from accumulating in the brain
and stop it triggering more of that tau protein in the brain
There are also antibody treatments going after the tau protein to try and remove tau from the brain and this passive
Immunotherapy is provided either as an antibody intravenously or we can also give it
as an injection under the skin. So this now is using PET scans in clinical trials
So to get into a clinical trial now, you actually have to have a positive PET scan
So the PET scans that I may refer to earlier, these can't be ordered clinically. They cost about
$5,000 each they're available as part of a research protocol and to go into a
clinical trial a person has to have a positive PET scan because if you're going to try and remove amyloid from the brain you want
to know the amyloid is there and
so
So you see the sense in that so (laughter)
Some of the earlier trials when we didn't have amyloid PET scans and some of the reason they failed is
because in retrospect when we then looked at some of the ones who actually did have some PET scans later on in the trial
36% of the people in the treatment arm
didn't have amyloid in their brain so they couldn't possibly although they had a clinical entity that looked like
Alzheimer's Disease, they couldn't have positively
benefited from the treatment because they didn't have amyloid in their brain to remove it. So this is an advance
this is something that we've learned from some of those negative trials that we've had. So this is the images here
these are PET scans at baseline and one year. So, this is PET scans
at two different time points and
These are the people in the placebo arm so they're scans look similar
But these are people who are on this drug Aducanamab, which is probably one of the leading
drugs being developed in a phase one trial now
being tested in a phase three trial, so we're waiting for the results of that three milligrams six milligrams
10 milligrams per kilogram body weight is the dose given every
month over a period of a year and so you can see that the people that are on the treatment
there's less amyloid in their brain
and
So this is another one. This is a complex slide
I'm just going to explain it because this is the way they sort of analyze the data from the study
So this is time in weeks. So this is out to 54 weeks here and this is the change from baseline. So everyone starts
it's adjusted to starting at the same baseline and during the course of twenty six
weeks out to this point here. Some people are on the treatments. Some people are on the placebo
So if we look at the placebo arm
This is the placebo arm the gray arm here
And as we get up this scale, this is the baseline in terms of the clinical dementia rating scale
This is a measure of cognitive function and and functional ability
it's a combined score but it's a very robust measure that we use in clinical trials and we can see that the
score is actually increasing for the people on the placebo
But you can see with increasing doses of the medication that the score is actually coming down now
Why doesn't it start immediately because it's a disease modifying treatment
It takes a while to work so you can start to see that at this level
We're starting to see a decline in the score from this pointer at six months out to a year
This is very important finding because this is the first time in a phase one trial
we've actually seen an effect of the drug. We don't look for effect in phase one trials we look for
safety we look for safety. So they found it was safe
But as well, they saw that there was a dose effect, which is actually a very compelling finding for this particular compound
It's an exciting finding
We are doing other trials and we're moving from
the right where we were doing a lot of trial in mild to moderate dementia and the learnings we got from those trials was that this
is almost too late to be doing the trials and so a lot of the trials are moving into mild cognitive impairment
We have one particular project. It's a small project and it's a
study involving jazzercize postmenopausal women doing Jazzercise as an exercise intervention learning new
exercise and also
Socializing so they're getting the mental stimulation
Socialization and learning while they're doing the exercise and we're going to do we're doing imaging with this study
So this is something that we're excited to see the outcome of this particular project
These two trials here are on people who are normal
so these are people who have one or two one generation two is is just one copy of e4 and
Generation is two copies of e4. So people who are
sixty to seventy four
Who have one or two copies of
these genes can participate in these trials now people won't know that but they may have a strong family history and if they
have a strong family history of Alzheimer's Disease they if they're in that age group
they may want to inquire would it be worthwhile doing this trial
Because you would find out what your genotype is and then you would get a PET scan and if the PET scan was
positive you could participate in the trial you could be randomized to be in the treatment getting intravenous antibodies
every month for three years and then continued treatment as part of an open-label phase
of the trial so
We're going to come to another poll
This is the second last poll and
what we want to do is to reflect on
everything that you're doing now everything that you've learned to see if there's anything that you would like to add
to or improve to your current regimen
So you can choose here. So you want to open your apps and choose
are any of these things you want to add to your
Current regimen
So it's interesting
everyone feels that there's something else that they may want to do and again mediterranean-style diet,
restorative sleep, exercise
So that's, that's important
One of the last things I want to talk about is why would people even want to go into a
randomized control trial. You're randomised to be in the placebo arm
nothing
versus treatment and there are six different
reasons that we consider people may want to think about going into a randomized control trial the placebo effect -
it has a positive effect. People who are on a placebo think they may be on a placebo. It has a positive effect
During the course of the study you get close medical monitoring. You'll be seen
monthly by the coordinator and usually every three months by the
investigator or at any other time that there's any
blood work abnormalities that's sent to your family doctor
Even if it's nothing to do with the clinical trial your family doctor will get a report
you get some additional stimulation and interaction with another group of people you'll expand your circle the
people that participate in the trials develop a really important relationship with the coordinators. If over the course of the
trial we see that a person is progressing, they can be referred to the community resources
So rather than waiting for the time that it comes to follow - my clinic right now is two and a half years
I see people after the initial assessment two and a half years later. They can be sooner here seen sooner and
referred to those resources if they're not already in contact though
that might be the Alzheimer Society or day programs or respite for caregivers and then
continued access to the medications
So if you're in a clinical trial you have participate in the trial after the trial is completed at that three year point
there's an open-label phase where everyone 100% of people go on the trial. That's what we mean by an open-label
phase, so then you can get access to the medication
waiting to see if it's effective waiting to see the outcome of the trial
whereas people who have not participate in the trial can't get access to that
medication because it's not yet approved and then altruism is the most compelling reason for a lot of people
They say I am on medications now
I'm benefiting from someone else's altruism who went head of me and
proved that the treatments that I'm on are safe and they're effective for me to take
I have benefited from their altruism and here I can give back to
other people and someone else it may not be me may benefit it may be my friend it may be my neighbour
It could be a family member that would know so that would be an additional reason
so we'll come to the last question if
you were eligible to participate in a clinical trial or a research study
how likely would you be to participate and so you just choose one answer. I have to open up your app and
Okay, so
That's nice to hear. There's certainly response support
for people interested in research and we certainly would encourage you there's lots of
observational studies that we have even for people of normal older controls many of you here who fall in that normal category
can participate in normal
observational studies if you fall in that older age group, there's that
generation 1 and generation 2 study
So if you plan on getting old (laughter)
Be careful what you plan for (laughter)
There are six non-drug approaches
We've talked about tonight to reduce your risk
And then we're going to talk about the control of to prevent the five vascular risk factors. What are they?
blood pressure
diabetes
Cholesterol
Atrial fibrillation
Smoking
Good. So consider how you can support research for the future and and really understand how we can improve
our understanding of dementia, and try to strive and maintain your brain now
There's one thing that won't have been lost on some of you. There was a really important day on
Saturday
Does anyone remember what was important on Saturday?
It was the world chocolate day (laughter)
That's true
so
When you leave we have an in honour of world chocolate day belatedly. We you may help yourself to a chocolate
Dana has brought the chocolates. I can see there's some takers now the caution. This is dark chocolate
it has to be is at least 70% chocolate and anyone who has
Antibodies or allergies to chocolate I'd ask you to abstain
Might be okay, so I do need to
thank people who have helped me tonight. Now. This is my memory test
Matthew
Warren
Craig
Rene
Dana
who's helped here with this. Dana happens to be working at Parkwood Hospital
with an important project
but she also happens to be my daughter (laughter) so she
She keeps me in line and
The other poor person who also keeps me in line
more than Dana is my lovely spouse Nancy who's here in the front row. She's my queen
of the mediterranean-style diet (laughter)
We had mediterranean-style diet tonight I didn't even have to prompt her tonight you had that before we came so that was lovely so
These are my other colleagues that we work with Jenny Wells
Elizabeth Finger, Steven Pasternak research managers. There's a number there if you want to call and participate in research
all of our coordinators, our nurse practitioners
clinicians
research assistants our trainees
Dr. Jennifer Fogarty here is a neuropsychologist who does a
an important job in doing more detailed neuropsychological tests in people who we have had very difficult
time diagnosing dementia, so we need to do a deep dive and then our colleagues Joe Lindsey
Medical Informatics and our group across the
city at Frank Prado who leads the group here on neuroimaging the PET imaging, Dr
Manuel Montero Odasso and the group across at Mental Health with Amer Burhan and Rob Bartha is at the Robarts Research
Institute. So we are going to have questions and I should have said this earlier on there is the opportunity to
Open the app and ask
questions and you can put in the questions there and I'll be able to read some of them off the screen if you
like a question you can like it and that can actually
influence
It can influence
the
position of the ranking of the questions as well for those of you who have decided that
you would prefer to ask a question
put your hand up and call out the question and I'll
identify you and I may have to repeat the question this gentleman here. Would you like to ask a question?
(audience member)How do you interact with Robarts Research? (Dr. Borrie) How is our group's interaction with Robarts Research Institute?
It's an important way in which we interact with them and that's with their neuroimaging group. Dr
Rob Bartha who I met there and they are involved with the
MRI scanners, they have 2 3 Tesla MRI scanners
They also have the only 7 Tesla scanner in the country
And this is a very powerful MRI scanner. And this is one that people can come and have a
scan as part of research
study we have a young
MD PhD graduate study who's doing an MRI study with them. We also look at the effect of drugs and
measuring we've done studies which we've published looking at drugs before and after
Before they go on the drug and after they go on the drugs
particularly they Alzheimer drugs the ones that are and in practice now are standard practice
We've published all of that data, so they measure
different types of images in the brain
They can measure chemicals in the brain
They can measure up to 19 different chemicals in the brain using a particular approach called EMA spectroscopy
So there's a lot of very interesting data that we can get from MRI scans
They also are also providing all of the imaging for our observational studies
with the ADNI study, the Alzheimer Disease Neuroimaging Initiative, which is an international study between the US
and Canada and also the Canadian initiative which we in London
are taking the initiative on we've got sixteen hundred people from across Canada participating and
Our site here in London is the most active site in that and all of the neuroimaging for that study has done through Robarts
So thank you for that. So we'll look at some of the questions here
So what are some of the early signs of dementia that I might be able to detect in a friend or a family member?
So this is a very important question to ask and it's an important question to be insightful about
So when we talked about subjective cognitive decline
the person who has subjective decline only they may know that they actually are
experiencing their symptoms particularly if they're in the workforce
They may be aware that they're not quite as sharp as they used to be. They may have definitely putting their finger on it
They may have difficulty remembering certain procedures that they do
They may have difficulty with certain applications on a computer
No one else would necessarily be aware of that at home the family member the spouse may say we don't see any change
however
beyond subjective cognitive decline as that progresses and so firstly if a person says I have concerns about my
memory and it's changing
it's very important that that's taken seriously too often in the past and some some people some family members or
even family physicians may say don't worry, dear
You're just getting old and that's not an acceptable explanation. It does need to be taken seriously
so you need to make the observations and record it and if you start to see changes in memory, so
conversations being repeated so if you have a conversation with someone and then they
discuss the conversation again, you say well, we just talked about that yesterday
so or we talked about that last week and they've forgotten that conversation the frequency with which or the the interval of
memory loss
decreases, so sometimes they'll get to a point where in a telephone conversation
you may actually have them repeating the same information twice in the same telephone conversation. That's a very
important concern. So I've highlighted memory there as one early sign
There are other signs and with the Alzheimer Society you can go into their website and they have all of the different signs
Early signs that you can look at so that's a resource you can look at. The other thing to look at is language
So not everything it changes is is memory it can be language
So people's language can change the way in which they use words. They may have word-finding difficulties
They may say nonsense words
or they may rhyme a word or they may substitute a word or they may say
You know that thing and they wait for you to fill in and say sometimes if you're an impatient person you'll fill in it
without even knowing you're doing it and then someone else and the family or say you're speaking for them
you know you're filling in for them and so will will become evident other early changes with frontal temporal
dementia a common feature of that disease might be a changes in behavior. So abnormal behaviors, so
disinhibited behaviors inappropriate comments in certain social settings inappropriate sexually inappropriate
comments. Behaviors that are not socially acceptable or there may be apathy. There may be loss of engagement in a
particular environment. Family come to visit and they're not even engaged with those family members
Now in some families that may be normal, (laughter) but
this is where there's a change in behavior we're looking
All families by the way are dysfunctional so (laughter)
Okay, so the question about family history
how strong so if you have one parent and
the problem began in their late 80s, you can anticipate that they might have problems in the 80s just from
80s or 90s are people who have problems in their 80s and 90s you might expect that
it's when family members have problems beginning in their 50s or in their 60s much earlier and
particularly, if they don't have some of those other risk factors like the vascular risk factors, so they haven't had strokes.
They don't have diabetes, they don't have high blood pressure
They haven't had elevated cholesterol
so if there are no vascular risk factors - one family member a parent would be
important if that parent had siblings that increases the risk
So it becomes an integral and and then you can go back through your family histories
We don't have the large generations that we used to have but you used to be able to go back
Sometimes we go back and you can see aunts and then you can see cousins and with some of these
diseases particularly in the frontal temporal dementia
you can see family histories, which go out and to other other generations
So I think you need to have a strong ended suspicion if it's occurring at a younger age
And if there's not another obvious course one thing we talked about head injury, so people who have had recurrent head
injuries, we're hearing more about this traumatic
encephalopathy chronic and traumatic encephalopathy
People with sports injuries that is a head injury as a concern. The other thing that we
haven't heard about and hasn't turned up is there's the question there of the
association with head injury. So I mentioned there the chronic brain encephalopathy
This is the people who have had recurrent head injuries. So if you take a soccer team, and that's particularly
Topical this week
You see those people out there heading the balls. The people that had the balls frequently have a higher likelihood of
developing dementia later in life. So this is recurrent head injuries to the ball
We know that we certainly see that in football players and in hockey players who have had head injuries
So it's a bad thing
to actually have head injury and if a young person has had injuries and had one or two head injuries
You need to seriously have the conversation with them
Do they really want to continue that sport do they is it really important that they continue to do that?
Because further head injuries the next time they had a head injury often
It's only a fairly minor head injury but they get major symptoms and then eventually you will start to see the cognitive declines
so I think there is a very definite connection with head injury the other one that
That I think is not spoken about is abuse different types of abuse
Childhood abuse sexual abuse this is something that were only just starting to become aware of but people who have
been abused as children, they have smaller hippocampi
Smaller memory departments than people who haven't been suffered from duress and this is on MRI images
So we need to pay more attention to that often with abuse, people don't talk about it
Sometimes we don't even hear about abuse until they come to the clinic and they're starting to develop dementia
And they're starting to become a bit
Disinhibited and they're now willing to talk about the thing that they could never talk about in their 40s and 50s
They've never revealed it. I've had a spouse in a clinic revealed to me that she was abused
before her marriage by another family member and never discussed this with her husband, and that was a very
poignant moment for her we discussed it eventually with her
She wanted to discuss it with her husband, but sometimes this won't even come out until later on
There are some other questions here
Okay, so best practices for mental stimulation
I think this is something this is an evolving field
There are some interesting researchers that are looking at this and I think one can look at the Finger
Study look at the different types of the mental stimulation
Watching television is not considered being a mental stimulation. It's not an excuse to sit there for Saturday afternoon
It new and interesting so Sylvie Belleville who is one of our
researchers as part of the Canadian collaboration on neurodegeneration and aging
is looking at different types of mental stimulation and she's looking at studies where she has people randomized to either
learning another language
They can't speak it already but they learn Spanish or they will learn a musical instrument
They'll learn how to play the piano and so this is a type of mental stimulation that she's exploring. There's another
Nicole Anderson is also participating in that she's at the Baycrest. She's another one of the 400 odd
They're not odd, but they're 400 plus
researchers across the country who are looking at dementia research
But she is at the Baycrest Centre and she's looking at mental stimulation as an intervention
So they're actually evaluating this - how much mental stimulation what type of mental stimulation
are some of the questions that we actually have to try and sort out how long
Some of the mental stimulation is through computer games
Computer tests up to now
they haven't really been shown that they're
good at improving your mental function and other areas they make you better at doing those particular tests
But it doesn't help you with other activities, but I think this is a new and innovative area that we're continuing to explore
So I think read the literature and see what starts to come out
The important thing is it shouldn't be
frustrating and it should be new and innovating because what you're trying to do is to get nerve cells that are not talking to
each other and if you think about the billions of nerve cells that you still have in your brain
and if you look at one
nerve cell on that nerve cell there will be up to two thousand synapses
What you're trying to do is to get some of those nerve cells to build new connections new
synapses and a new and interesting way to build in some of the resilience
So this is building on neuroplasticity
and even as we get older we can continue to do that
We certainly see that in the rehabilitation in people that come to rehab at Parkwood say people have had stroke and they
rehabilitate. Part of this is building on that neuroplasticity and this is what we believe is important in
people who have neurodegenerative diseases to try and alter the course of the disease
It said here is it possible to reduce amyloid and tau in the brain without using medications?
It's conceivable and I think
One of the things that we want to be able to do is now that we have neuro imaging and PET scans I think there
will be research they will look and try and answer some of these questions
so the PET amyloid imaging we've only had since
2004 the tau imaging we've only had since
2014 and we don't know yet, which is more important
Is it more important to reduce the amount of amyloid or is it more important to reduce?
That tau protein neuro degeneration that's occurring and killing the nerve cells
So would a strategy like exercise actually reduce those things
so if you had a long to Journal study and could do PET scans at the beginning and
At the end and have two groups compared those who do exercise on a regular basis
They and the other group that do stretching and toning
Is there a difference in the amount of amyloid that accumulates in the brain over a year or two years?
Is there a difference in the Tau accumulation?
These are some of the questions that we could ask so I think we could certainly explore. What is the role of exercise?
what are the
What is the role of other non drug approaches?
So we do have some those would be just an example of some of the tools that we could have
Is there research exploring the relationship between dementia and a client plant based vegan diet
This certainly would be research there
I can't -- we're not involved with it right now
But I think these are important questions to be asking one thing we need to be doing is moving towards plant-based diets
I think that's what the Mediterranean style diet and other diets I've chosen to present
Mediterranean style diet information here, but there are other diets been explored
They don't have the numbers yet, but we do need to be moving towards
Plant-based diets not just because of dementia we need to do that for the survival of our planet
We have to move away from meat as a source of protein and engage other
vegetable sources of proteins so I think
these are things that will be being explored but I can't speak specifically to that
So excessive alcohol intake
What role does it have in the development of dementia? So
one of the questions you have to ask yourself as what is excessive alcohol intake?
Excessive alcohol intake is someone who drinks more than their doctor (laughter)
Now I don't drink too much my daughter can they vouch for that?
But I think you're not usually going to ask your doctor how much they drink but I think there are important studies alcohol
Even you know that mediterranean-style diet there used to be a bottle of wine on that slide and I we've taken it out
Because we know now that a hundred grams of alcohol per week is about the most that anyone should be drinking
So that's only about six drinks a week yet
the recommendations in the States right now is twice that amount as an allowable amount but six drinks a week would be the
maximum that a person should be drinking standard drinks a week. Above that, there's increased dose of this - there's increased
death is much more likely if there's a higher occurrence of death or higher probability of death, but
Alcohol-related dementia is something that is grossly underestimated
I think that's something that we really don't have a really good handle on and
when we see people in the clinic who are doing any amount of drinking and they have cognitive impairment we say there's
a choice here. You've had a good trot (laughter)
You have been drinking for a while and
This is a trade-off between maintaining your brain
maintaining your independence,  maintaining your opportunity to be engaged in the community or
progressive dementia and ending up in a long-term
long-term care home or worse and and most people
are persuaded by that because they want to hold on to their independence. That's what they're really striving for and
they will listen to that and
Most of them will say, you know, I don't really enjoy it
It's just a habit my wife and I sit down and we have a drink together and it's something we've always done
it doesn't have to be alcohol and
in this hot weather
Drinking a non alcohol beer is nice
Why do you suspect there is an increased
Concentration of microglia? So this is an important question
I'm not involved with this research directly
But we do know that within dementia there are inflammatory
processes, whether it's with Alzheimer's disease or whether it's in frontal temporal dementia and what these tests
The FEPPA is actually getting in the activation of microglia
It's part of the underlying disease process. Why that inflammatory process is occurring, we don't entirely know
But I think it's important that we can actually measure it. There were some longitudinal studies of
anti-inflammatory medications looking at
people who are on
anti-inflammatory medications for rheumatoid arthritis and people who are on long-term
anti-inflammatory medications like the nonsteroidal antiinflammatories
they had less risk of developing dementia less risk of Alzheimer's disease, so
inflammation is part of this
so when I have talked to you about amyloid and tau protein this is not the whole answer and this in a sense is a
simplified way of looking at this. It is a very complex disease. There are inflammatory processes going on
There's a lot there that we still need to understand and each time
we do these clinical trials, even if it's a negative trial the analysis of that data helps us better understand. What is the underlying model?
So I'll do one more question maybe here for this (audience member) You mentioned earlier Downs Syndrome.
(Dr. Borrie) Thank you for that question, yes, so Down Syndrome, so what is it
Why do people with Down syndrome have risk of Alzheimer's disease?
Now, they're different from older individuals who accumulate amyloid in their brain because they can't get rid of it
but people with Down Syndrome have a trisomy on
Chromosome 21. So on chromosome 21 instead of having two short arms
They have three short arms. And on that short arm on chromosome 21 is the amyloid precursor protein
The amyloid precursor protein is encoded on that
short arm so instead of having two copies. they've got 50% more so they make more amyloid. So this is a model of
dementia and Alzheimer's disease so we know the connection here is with amyloid. These people make too much amyloid protein
So one could say if there was a way of removing amyloid from the brain
reducing or somehow inhibiting the expression of that
amyloid at a genetic level that might reduce the likelihood of them developing
Alzheimer's disease in their 40s or their 50s or the 60s because that's when it happens
They start to develop cognitive impairment and you can't test them
Some of them you can certainly we've had people who with Down Syndrome have come to the clinic and they can do well
cognitively on say a mini-mental state exam some of them haven't developed as well
intellectually, and so we use functional scales
But the routines that they used to be able to do the things that they were doing and they're in their workshops
These routines are starting to be abandoned and there'll be behavioral changes coming up and this is how their
dementia expresses, so thank you for coming back to that question. Okay. I'm going to stop it now
please remember to take your
Chocolate at the home. Otherwise, I'm going to be forced to eat it
and I know I have a couple of people to help me. Thanks very much. (applause)
