So, it's my very great pleasure to introduce our next speaker, Dr. Alice Powell.

So, Alice is a dual-trained, I'm going to say neurologist and geriatrician.

She might say the other way around.

So, Alice, I've known now for a number of years. She was my registrar some years ago.

And she's now working both clinically here at Macquarie, but also at Royal North

Shore Hospital and is completing a PhD through the University of New South Wales.

Looking at maintaining high cognitive ability and mental and physical health with increasing age.

So thank you very much, Alice. Thank you.

So this was my brief for 20 minutes. So this is going to be a bit of a cook's

tour through age-related cognitive decline, dementia classification and diagnosis.

This is what I thought I'd cover. So what's kind of normal age-related cognitive

decline, some terminology and classification. a few different types of dementia

and then some diagnostic tests.

So I've got no disclosures. I don't know about everyone here,

but these are two of the most common questions I get in clinic.

So you think you've explained things properly, and then they'll say,

what's the difference between dementia and Alzheimer's? And you're like, okay, let's go back.

Or, you know, isn't this just normal for this person's age?

So we do know that there are changes in cognitive abilities with age,

and I'm particularly aware of

processing speed because this is one of the first things that goes down.

So your processing speed is highest in your 20s and you probably remember in

university that, you know, things were much quicker.

You'd sort of get through information quicker. You'd, you know,

comprehend things and then that will drop off from about the age of 25 and then

many other things will drop off from the 30s and 40s.

But this tends to be a gradual decline and the fluid abilities,

which is your processing speed, some executive functions, mental flexibility

tends to drop and then your crystallised abilities, which is general knowledge,

you know, autobiographical memory, those kinds of things up the top tend to

remain reasonably stable.

And then things like wisdom tend

to grow with age. So just good to have a general idea of what's going on.

So, while you will have changes in cognitive abilities with your age,

it's not normal for there to be a significant cognitive decline.

And when we say significant, that's usually looking at norms for age and people

who are dropping below those norms.

Age is the major risk factor for dementia, and your lifetime risk of anyone is about 24%.

The prevalence will just go up sort of incrementally with age and about 50%

of centenarians, so those 100 and above or near centenarians have dementia,

but it's not inevitable.

There was this really nice case study that I often bring out from the 90 plus

study, which is a study that recruits people from the age of 90 and they do

cognitive assessments and physical examinations every six months.

And then when they die, they donate

their brains for autopsy and they have neuropathological assessment.

So this particular man had at

least three different neuropathologies at an intermediate or higher stage.

He actually had multiple pathologies in his brain. But he was performing,

I think, in the top 85th percentile until the last six months of his life.

So just because you have pathology doesn't mean that you're actually going to

have significant cognitive decline.

And we know that a lot of the variability in people's trajectories of cognition

is actually not explained by how much pathology they have.

So pathology only explains 43% of variability. So, there are many other factors.

So, you know, people's level of education, how active they are,

their general health, those things are really important.

So, a bit of terminology. This is probably the first stage that we would be

interested in, which is called subjective cognitive decline,

which is when people are noticing something that's different and that's progressing over time.

And it's a bit more concerning if someone else is also noticing that.

So if they come with a partner or a family member and they've also noticed that

there are some memory problems, for example.

This is a little bit different from what we called worried well,

which is people who are worried about getting dementia or worried about declining,

but they don't actually observe a change in their cognition.

And we know that many neurodegenerative diseases, Alzheimer's being the classic

one, will be developing in the brain for decades.

So the initial signs are very subtle. So I think we should be picking up on

those sort of very early subtle signs.

Going on to mild cognitive impairment. So this is concern from the patient themselves

or someone who knows them well, or perhaps even, you know, yourselves who've

been seeing a patient for many, many years and you've noticed that something has changed.

And then they have to have objective impairment on cognitive testing and usually

that's about 1.5 standard deviations below where they should be sitting.

There should be a decline over time and the distinguishing factor between people

with mild cognitive impairment and dementia is they have general preservation

of functional abilities.

So the question I like to ask is if you went overseas and left this person by

themselves for a few weeks or a couple of months, would they be okay? Would they manage?

So, these people are independently functioning. There might be some minor changes

in their functional ability, but generally there's preserved independence.

And that can be quite challenging. So, I find that border zone between mild

cognitive impairment and dementia, sometimes it's a very gradual transition there.

And then when we're talking about dementia, these are people who do have cognitive

or behavioural symptoms, and they are really interfering with their function,

so work or usual activities.

And with these previous criteria, they required at least two of the various cognitive symptoms.

So very quick note on rapidly progressive dementia because this is quite important.

So most of the patients we see have had a decline over months to years.

When someone progresses from the initial symptoms to dementia,

so functional impairment within a year, that would be considered rapidly progressive dementia.

And that's very important to recognize because there may be something else going

on. So, do they have some autoimmune encephalopathy?

Do they have some other reversible cause for this?

Or tragically, in some cases, do they have a prion disease?

And sporadic CJD is actually the commonest cause of a clear,

rapidly progressive dementia.

Having said that, it's often a failure of history. So, or it's people not noticing things.

So, they might just say, oh, this has only been a few months.

But when you really dig into it, actually there have been changes for a longer period of time.

So we've already talked quite a bit about Alzheimer's disease,

but this is the commonest neurodegenerative condition.

Typically, people present with episodic memory impairment. So they have what

we call rapid forgetting.

So typically short-term memory to begin with, they'll be given some information

and then they'll very quickly forget it.

So these are the people who are asking the same question five minutes later

because they've forgotten that piece of information.

There's what we call a temporal gradient. So the memories that they've made

most recently are the ones that are lost first, and then the most distant memories are preserved.

So when you get into really advanced stages, people will remember their childhood,

and they'll be talking about their parents and those kinds of things,

because those memories are still preserved.

But they can have patchy loss of that more distant memory as well.

Word-finding difficulties are quite common, and it tends to be when you're assessing

people that they have a nominal aphasia, so naming problems.

Apraxia is something to look out for. It doesn't tend to be very prominent in typical Alzheimer's.

It won't be the sort of thing that you see in like a corticobasal syndrome,

but at least seeing a little bit can be a clue.

Visuospatial impairments and then the classic features on imaging are temporal

atrophy, parietal atrophy and hypometabolism and those regions on PETE.

Now, limbic-associated, I'm going to forget the acronym now.

Age-related TDP 43 encephalopathy, which I always forget the full name for it,

which is why later is a little bit easier.

This is a little bit more recently recognised, and we have clinical criteria

which were actually published this year.

This is a common Alzheimer's mimic and there are a couple of them.

So there's late, there's a couple of tauopathies, things like PART,

which is primary age-related tauopathy and agarophilic grain disease,

which can present very similarly and they can be difficult to distinguish clinically from Alzheimer's.

Typically, they're in older people. That's sort of the clue of late,

that tends to be people over the age of 80.

And usually it's very isolated memory impairment and usually for a couple of

years before you get any other impairments.

They have significant hippocampal atrophy on MRI and medial temporal low pipe metabolism on PET.

And while this is usually in people over the age of 80 and is very common,

so it's probably a third of people sort of into the 80s or more,

it can be seen in younger people and there is this cohort of potential early

late so even people over the age of 60 there are people who have some late pathology.

Those are the current criteria.

And when you have a combination of Alzheimer's and late, that progresses more

quickly than when you have one or the other, which would make sense.

I don't have time to go into, like, vast details of, you know,

every other type of dementia.

But the frontotemporal loba degeneration spectrum includes these three classic phenotypes.

So your behavioural variant from frontotemporal

dementia these are people who have quite pronounced behavioural

changes and they tend to lack insight so

they will usually come in they won't have initiated the consultation they'll

say oh there's nothing wrong but it will be their caregiver or their family

member who sort of gives you reams of paper and collateral history on what's

been going on And then two of the primary progressive aphasias,

so these are primary disorders of language, which then progress over time to

involve other cognitive disorders.

Domains. So, the semantic dementia and progressive non-fluent aphasia.

Logopenic primary progressive aphasia is an Alzheimer's subtype.

So, there are a couple of atypical Alzheimer's syndromes. So,

logopenic primary progressive aphasia, posterior cortical atrophy and frontal

variant Alzheimer's disease, which are much less common, but they're commoner in younger people.

So, the atypical presentations always commoner in younger people.

DLB, this is a dementia subtype which is quite under-recognized.

People always think about the classic phenotype of people who look like they

have Parkinson's, they have quite pronounced visual hallucinations,

but there are other features to this.

So they do tend to be forgetful, but it's not the same type of memory impairment

that you get with Alzheimer's.

Attentional lapses are common.

Visuospatial issues and executive dysfunction, often quite early.

And this variability and fluctuations. So, usually ask people,

are there times when you're really sharp and times that you find it a bit harder

to concentrate, that you're a little bit off air?

And if you're getting that sort of story, then you should be thinking about Lewy body.

Also quite commonly comorbid with Alzheimer's. So that makes it a bit more complicated.

The alpha-synucleinopathy symptoms are important.

So these are the symptoms that are common to Parkinson's disease,

dementia with Lewy bodies, and multiple system atrophy.

So anosmia, lack of sense of smell, sense of taste, constipation,

and REM sleep behaviour disorder.

So these are the people who are acting out their dreams, talking in their sleep.

So asking someone else if they're doing that.

They can have a very characteristic pattern on an FDG PET scan.

It tends to be this occipital posterior hypometabolism and the cingulate island sign.

So this means that the posterior cingulate is quite bright, but the surrounding area is down.

So posterior cingulate tends to be involved in Alzheimer's early, but not in Lewy body.

Vascular dementia is a big one. So, this is very common and it's very commonly

comorbid with neurodegenerative conditions.

It tends to act synergistically with other conditions. So, if you've got Alzheimer's

and you've also got quite a lot of vascular disease, that's going to progress more rapidly.

There are different presentations of this. So, it could be immediately after a stroke.

It could be a stepwise progression if someone's having little lacuna infarcts.

Or it could be this kind of slow gradual progression with subcortical ischemia

with lots of white matter hyperintensities.

Typical features tend to be slow processing speeds, attention and executive

deficits, and a retrieval pattern of memory impairment.

When I say retrieval, I mean more that people having difficulty retrieving the

memory, but when you give them a clue, then they'll be able to recognize it.

So, that helps with them remembering it, whereas Whereas people who have a rapid

forgetting pattern, you'll give them clues and it doesn't help. It's just gone.

So it's retrieving that's the issue.

And gait apraxia. So these are the people who take those really small steps.

The thing that we call Marsha Petipa.

That's a characteristic feature of significant cerebrovascular disease.

So, in terms of diagnostics, I'd always do these kind of basic panel of blood tests.

What you're really looking for there is anything that may be a secondary cause,

something that's reversible or something that may be contributing that you can optimise.

I put a little star next to the ECG because that's not diagnostic, but it's helpful.

So particularly if you think someone's on that border zone between mild cognitive

impairment and dementia, and you're thinking about trying a cholinesterase inhibitor,

or even if you're thinking about antidepressant or some sort of other symptomatic

medication, just to check that that's safe.

And then I've put a sleep study in brackets as well, because I wouldn't do a

sleep study on every person.

There is pretty good evidence that screening for

sleep apnea in people with cognitive impairment and then

treating it is not you know very helpful but

if someone's got symptoms of sleep apnea and you always ask about that then

you should check and the other reason why it's useful is you can look for what's

called REM sleep without atonia which is a confirmatory test for a REM sleep

behavior disorder so those people who are acting out their dreams they're not

paralyzed like they should be in REM sleep,

and that's a very big clue for an alpha synucleinopathy, so,

Parkinson's, Lewy body, multiple system atrophy.

So that will just give you a little bit more information in that case.

Not all the time, which is why I've sort of put it in brackets.

In terms of structural imaging, MRI is always better than CT.

If you can't get an MRI, by all means do a CT.

But I sort of think of a CT being a black and white TV and MRI being your high definition TV.

So you're getting a lot more detail with that.

We want to have a really good look at the brain structure. So that's the T1 sequences.

And it's helpful to have a coronal sequence to look at the hippocampi,

to look at the frontal lobes, temporal lobes.

Sagittal, so you can sort of look at the gradient from the front to the back.

And it's also very useful for looking at the parietal lobes.

And then the axial sequences are also good for the temporal lobes and the parietal lobes.

You can usually do a volumetric analysis once you've got the T1 and there's

various programs that you can use to do that.

And that'll give you a sort of quantification of volume loss.

The flare sequence is important looking for any vascular disease,

any inflammatory changes or tumors or any other pathology.

DWI-ADC is for stroke and that would be stroke that's occurred in the last two

weeks but then also looking for cortical ribboning in CJDF.

It's a rapidly progressive course and then the SWI and GRE we learned about

before is looking for microhemorrhages.

So two reasons for that. One of them is if they're a candidate for these new therapies.

The other one is if they have cerebral amyloid angiopathy, which is that amyloid

that deposits around the blood vessels, causes leakiness, bleeding,

swelling, which is quite strongly associated with Alzheimer's disease as well.

Uh, FTG PET, this is on Medicare, um, so we can get that covered.

Um, reasons for doing this.

One of them is that the atrophy on an MRI can lag behind the clinical syndrome.

So sometimes you'll see earlier abnormalities on an FTG PET,

but I'll just make the note that I've been burnt a couple of times in people

who've got early symptoms, um, and mild cognitive impairment,

that in that case, it can not be particularly helpful.

It can either be normal or it can be very nonspecific.

And then there's not really much you can do with that information.

You can get the raw images and the statistical analysis, and that's really the

best way of looking at it because that will be, you know, how much metabolism

is going on in that area compared with controls.

And usually under minus two would be significant, and then you can compare all

of the brain regions. So you get the kind of printout of the numbers as well as the visual read.

Used to be taught that it's helpful in anxious patients. I've sort of been a

little bit bent with this as well because, you know, people who are a bit depressed

as well, sometimes they can have a bit of reduction in metabolism in the frontal lobes.

And sometimes the scan is a little bit off. And then you're kind of making them

more anxious by doing that.

So it's helpful when it's completely normal. But if it's a little bit abnormal,

probably not very helpful. There are some very classic passions.

So the posterior cingulate hyperintensis, so that island sign in Lewy body disease,

posterior cortical atrophy, posterior hypometabolism, that condition is quite helpful.

And then it's part of the diagnostic criteria for behavioural variant frontotemporal

dementia, for example, the hypometabolism in the frontal and temporal lobes.

Note of caution with SPECT which used to

be done a lot it's not done very much anymore I've had

people come to me with a SPECT scan report that

says they have dementia um like very confidently so uh there's a lot of noise

with these scans there's a lot of interference and it can be very misleading

and it's not as accurate as an FTG PET so So, I generally avoid doing those scans.

That's the cingulate island sign, so you'll see that the posterior cingulate

is lighting up and then the back of the brain, those occipital lobes are quite low.

And we've talked a bit about biomarkers.

In terms of biomarkers that are available in clinical practice,

they're really just the ones for Alzheimer's disease at the moment,

but biomarkers are being developed in other dementia conditions.

So what we can test includes the amyloid and the tau, and then we can look at

that in terms of blood, cerebrospinal fluid, and brain imaging.

And then there are some non-specific biomarkers

which can still be helpful which include neurofilament

light and the other one is gfap but as far

as i know that's not sort of available clinically neurofilament

light is just a general marker of injury so that can be good in distinguishing

people who've got a psychiatric presentation from a neurodegenerative disease

because if it's completely normal that makes a neurodegenerative disease very

unlikely but it's very non-specific So it will be up in Parkinson's, Alzheimer's,

if someone's had a stroke, if they've got multiple sclerosis, basically anything.

It's sort of like the CRP of the central nervous system. It's one way of thinking of it.

So, in terms of what is available,

the biomarkers that have been studied the most in Alzheimer's are amyloid PET

and CSF, and both of them are around 90% accurate.

So, there are different traces, but Floor Beta Pen is the one that's being used

both at Macquarie Medical Imaging and Rural North Shore, and this picks up amyloid plaques.

So you should get whether it's

positive or negative so whether there's actually amyloid there

and a quantification as far

as i know here i think they're still using the b-a-p-l which is a grading of

how much amyloid there is and i think goes up to four but what's used a little

bit more in trials and what can be helpful to look at you know how much amyloid

someone has and then if they've managed to clear it with these new treatments,

is the centeloid.

And that's usually 0 to 100, but you might see in a report that someone's got

either lower than 0 or higher than 100. So these are just anchor points.

0 would be considered, you know, a healthy normal person who doesn't have amyloid.

That would be 0. But I've seen reports of someone who's, say,

got minus 11, so it can be lower. and then 100 is typically someone who's got

mild to moderate Alzheimer's.

And the MCI range is about kind of high 70s, 80s.

Uh we don't have access to

tau pet at the moment but i think it's not far

off um and you know it's being

used in research and i think that will be helpful in the csf we can look at

the amyloid beta 4042 the phosphorylated tau total tau and the ratios and if

you get the full um combination of abnormalities there, then that's very accurate too.

So, the earliest thing is the amyloid beta 42 will go down.

And then after that, you have elevations in phosphorylated tau and total tau

and abnormalities of the ratios.

The phosphorylated tau is specific to Alzheimer's.

The total tau is just a marker of neuronal damage.

So, again, if someone's had a traumatic brain injury or a stroke,

their total tau will be up.

And if their total tau is really high, we're talking sort of over 1,300,

you'll be thinking about Kreutzfeldt-Jakob because that's a really destructive

condition that's going on in the brain.

And then what's new really is the blood-based biomarkers.

This is kind of a whole talk in itself, so I won't go into it in too much detail

and I'm being told to hurry up.

But these are coming. I think HETAL 181 has just been approved.

PTAL 217 is being used in the research space and that one is a bit more sensitive and specific.

And these are going to be really more of a bit of a rule-out test.

There is some caution using them in people who have renal impairment.

They can be falsely elevated and in high BMI.

So my general takeaways would be significant cognitive decline is not part of

normal aging, but age still is the main risk factor for dementia.

Dementia diagnosis requires thorough history, cognitive testing and appropriate

investigations to confirm the diagnosis and exclude reversible contributors.

Diagnostic test accuracy is variable but

it's definitely improving and there's no one

single test that will tell you this person has dementia and what type but it's

an integration of all of your data points and longitudinal monitoring and as

we've heard an early and accurate diagnosis will allow people to plan ahead

and also for access to therapies and clinical trials.

Thank you.