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You can also sign up for a free trial of our premium membership to get access to

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hundreds of case-based micro-learning courses across all key RADIOLOGIES

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subspecialties. Today we are honored to welcome Dr.

0:37

Susie Bash for a lecture on critical updates in the dynamic landscape of

0:41

Alzheimer's disease and dementia imaging. Dr.

0:43

Bash is a neuroradiologist and medical director at RadNet. Prior to this,

0:47

she was on the faculty at U C L A as an assistant professor of neuroradiology

0:51

after completing a two year neuroradiology fellowship and residency.

0:54

Also at U C L A. Dr.

0:56

B'S passion and interest lie in artificial intelligence applications in advanced

1:00

neuroimaging, which add patient-centric value and quality.

1:04

She's a recurring guest on tv, radio, and podcasts,

1:07

and is actively involved in AI clinical trials, peer-reviewed publications,

1:11

and AI related educational talks and webinars. Dr.

1:14

Bash serves on the medical advisory board of several AI companies and also

1:18

serves on the editorial board in the AI section for applied radiology,

1:21

and is a frequent contributing author to this journal.

1:24

At the end of the lecture, please join Dr.

1:26

Bash in a q and a session where she will address questions you may have on

1:29

today's topic.

1:30

Please remember to use a q and a feature to submit your questions so we can get

1:33

to as many as we can before our time is up. With that,

1:37

we're ready to begin today's lecture. Dr. Bash, please take it from here.

1:42

Hi, my name is Suzy Bash. I'm a neuroradiologist at RadNet.

1:45

Thank you so much for joining us.

1:47

Today we're gonna talk about critical updates in the dynamic landscape of

1:50

Alzheimer's disease and dementia imaging. These are some disclosures.

1:57

So first we'll focus on, uh, sort of an introduction to dementia.

2:00

Then we'll talk about dementia imaging,

2:03

then disease modifying therapy and regulatory updates.

2:06

And then we'll move into aria,

2:08

which stands for amyloid related Imaging abnormalities,

2:11

and we'll actually do some aria training with clinical cases so that after this

2:15

webinar, you'll feel comfortable reading aria cases. Um,

2:18

and then we'll talk a little bit about the future of dementia and, uh,

2:21

and then get into some dementia clinical cases.

2:25

So there are a lot of different kinds of dementia. Um, uh, Alzheimer's disease,

2:29

vascular dementia, dementia with Lewy bodies, frontotemporal dementia,

2:33

logopenic progressive aphasia, traumatic brain injury,

2:37

cerebral amyloid angiopathy,

2:39

and c a a related inflammation as well as normal pressure hydrocephalus.

2:44

Uh, we won't have time to talk about all these today,

2:46

but we're gonna primarily focus on Alzheimer's disease.

2:49

And the reason we talk so much about Alzheimer's disease is it makes up the

2:53

majority of the causes of dementia with over 60% by

2:59

autopsy.

3:00

So there are 6.7 million Americans that are suffering from Alzheimer's disease.

3:05

Um, it's a, a big population issue costing our nation, uh,

3:09

355 billion in 2021,

3:12

and that will rise into the trillions of very, uh, shortly.

3:16

One in three seniors will die of dementia,

3:19

so that kills even more than breast cancer and prostate cancer combined.

3:23

Death from heart disease is down 7% since the year 2000,

3:27

but death from Alzheimer's disease is up 145%. Um,

3:32

and this is something that, you know, really progresses as you get older.

3:36

So it doubles in frequency every five years after the age of 60.

3:41

Now, uh, Alzheimer's disease has two major, uh, hallmarks, beta amyloid plaque,

3:46

which is extracellular and can be directly imaged with amyloid pet and

3:51

neurofibrillary tangles, which is intracellular tau,

3:54

most notably in the hippo camp eye. And that can be imaged with Tau pet. Now,

3:58

amyloid, uh,

3:59

PET study can be positive at the preclinical stage of Alzheimer's disease.

4:03

In fact, up to 20 years before the patient's symptomatic, um,

4:07

amyloid plaque by deposition and disease,

4:09

you'll tend to see a lot of it with Alzheimer's disease.

4:12

You can see some with dementia with Lewy bodies,

4:15

but you shouldn't expect to see any amyloid deposition in frontotemporal

4:18

dementia. This is an Alzheimer's, uh,

4:21

cell here with a plaque burden and neurofibrillary tangles compared to a healthy

4:25

looking cell. This is a positive amyloid pet here,

4:28

and this is a positive tau pet beta amyloid one 40 and

4:33

1 42 peptides are produced from amyloid precursor protein.

4:38

The beta amyloid 42 is the main peptide associated with Alzheimer's

4:43

disease,

4:43

and beta amyloid 40 is the main peptide associated with cerebral amyloid

4:47

angiopathy.

4:48

These beta amyloid peptides are transported across the blood-brain barrier

4:53

and then degraded by specific proteins and enzymes such as apo,

4:57

lipoprotein E and mm M P ss. The, uh,

5:01

accumulation of these amyloid fibers in the walls of small to medium

5:06

size are arterial blood vessels and capillaries in the cortex really

5:11

are thought to result from a disturbance of any of these time points,

5:14

either from increased production, impaired transport,

5:18

or impaired degradation of the beta amyloid peptides.

5:21

So this a barren pathway really helps explain cerebral amyloid angiopathy,

5:25

which is known to cause spontaneous int hemorrhages cognitive decline and

5:30

transient focal neurologic events in addition to, um, uh,

5:34

Alzheimer's disease.

5:36

Now we're now starting to realize the importance of the glymphatic system and

5:40

the role it plays in the clearance of beta amyloid plaques and other toxins.

5:43

So the glymphatic system denotes perivascular pathways whereby

5:48

C S F enters the brain parenchyma via the para arterial space,

5:53

and then mixes with interstitial fluid.

5:56

This drives clearance of interstitial metabolic solutes and waste,

6:00

such as beta amyloid plaque,

6:02

which then exit the brain via the para venous pathway, uh,

6:06

to drain into the lymphatic system. Now, uh,

6:09

these astrocytic aquaporin four water channels in both the arteries and the

6:13

veins play an important role in reducing the resistance of C ss F

6:18

to movement between the paravascular spaces and the interstitium. Um,

6:23

now unfortunately, as we age,

6:24

this glymphatic convective drainage pathway and the clearance of waste products

6:29

such as beta amyloid plaque will slow down.

6:32

So reduced waste clearance has not just been associated with Alzheimer's

6:36

disease, but also with traumatic brain injury, hemorrhage, hypertension,

6:40

strokes, and microvascular ischemic disease. Interestingly, uh, when we sleep,

6:45

these interstitial spaces increase in size, allowing more effective,

6:50

uh, clearance of the beta amyloid plaque. So good sleep patterns, uh,

6:54

actually are thought to play a protective role in Alzheimer's disease.

6:58

Tau is a protein that helps form and strengthen microtubules,

7:02

which transport nutrients along the axon. Now, in the disease brain,

7:06

there's an imbalance of protein kinases and phosphatases,

7:10

which cause tau to become abnormally hyper phospholate resulting in the

7:14

disassembly of these microtubules and this impairs cellular signaling.

7:19

So free ttt molecules then aggregate into insoluble paired helical

7:24

filaments, um, and straight filaments as well,

7:27

which accumulate in cells as neurofibrillary tangles in Alzheimer's disease and

7:32

other tauopathies. So, uh, tauopathies would include Alzheimer's disease,

7:36

behavioral variant, frontotemporal dementia, uh,

7:39

chronic traumatic encephalopathy downs, progressive supernuclear palsy,

7:43

and corticobasal degeneration.

7:46

There are two main types of Alzheimer's disease, uh, early onset,

7:50

which is familiar, that's less than 5%, much more rare and late onset,

7:54

which is sporadic,

7:55

and that's 95% Non-modifiable risk factors include

8:00

age, gender, as, so it's more common in women,

8:03

probably 'cause women live longer. And also genetics. Uh,

8:06

a p o e four is the most common genetic risk factor associated with Alzheimer's

8:10

disease. Now, modifiable risk factors include hypertension, diabetes, smoking,

8:15

excessive alcohol use, obesity, poor diet and poor exercise,

8:20

lack of cognitive engagement and social isolation, depression,

8:25

traumatic brain injury, and then as we mentioned before, um,

8:28

sleep deprivation due to the glymphatic system.

8:31

So APO lipoproteins play a role in lipid and cholesterol homeostasis in the

8:35

blood. There are three a p OE gene alleles, uh, E two, E three,

8:39

and E four of which E three is by far the most common, uh,

8:42

greater than 50% of the population has this. APOE four, however,

8:46

is the strongest genetic risk factor for Alzheimer's disease because it's

8:51

involved in impaired clearance of that beta amyloid plaque.

8:54

So 25% of the population carries one a o e four allele,

8:59

and so they're called heterozygous and they carry a three times risk of

9:02

Alzheimer's disease,

9:04

but two to 3% of the population carries two a o e four allele.

9:07

So they're homozygous and have a 12 times risk of developing Alzheimer's

9:12

disease. Now, a o E four is a risk factor, not just for Alzheimer's,

9:16

but also for cerebral amyloid angiopathy ca a, a related inflammation, uh,

9:21

dementia with Lewy body tauopathy,

9:23

microvascular ischemic disease and vascular dementia, multiple sclerosis,

9:27

poor outcome following traumatic brain injury, and also, uh, aria. Now,

9:32

when it comes to dementia imaging,

9:34

typically a patient will present with memory loss and undergo cognitive testing

9:37

often by the neurologist.

9:39

And then an M R I is typically ordered in part to rule out other pathology that

9:43

could be causing the memory loss. So, for example, uh,

9:46

posterior cerebral artery strokes can often infarct the hippocampus and result

9:51

in some memory loss. Uh,

9:53

so can heavy bourbons of microvascular ischemic disease. Um,

9:56

sometimes quantitative volumetric imaging is done. We actually do this, uh,

9:59

pretty routinely in my clinical practice.

10:01

We've been doing it for about 17 years now.

10:04

We find this very helpful in the evaluation of dementia. Uh,

10:07

and then if there remains clinical ambiguity, sometimes a PET study is ordered.

10:12

F D G PET is by far the most common PET study ordered,

10:14

and this is reimbursable by C M s. Amyloid PET is, uh,

10:18

hopefully right on the brink of being reimbursed right now,

10:21

which we'll talk about in a minute. Um, and then Tau pet,

10:24

which was so far not reimbursable,

10:26

but can be used in the evaluation of dementia. This is a positive F D G pet.

10:31

This is the PET Mr. Fusion, and these are both PET CT fusion images,

10:34

and you see cortical hypometabolism in the bilateral, um, temporal lobes here.

10:40

And, uh, this patient, uh, had Alzheimer's disease.

10:43

This was statistically significant when I ran it through the MIM neuro analysis

10:46

software. Now, this is amyloid pet, just for example here.

10:50

This is a negative amyloid where you see a tree and branch type pattern and no

10:53

binding of the amyloid tracer to the cortex as opposed to a positive pet where

10:58

we have diffuse binding of the tracer throughout the cortex.

11:01

This is color fusion right here.

11:03

I wanna take a volumetric imaging identifies and labels anatomic structures in

11:07

the vein,

11:07

and then quantifies the volume of those brain structures and compares that to an

11:11

age and gender match normative database.

11:14

And this provides volumetric tracking to assess for rate of change over time.

11:17

There are different companies that perform quantitative volumetric imaging.

11:20

That was one here is another.

11:23

This is another one here and another here. And then finally,

11:27

this is one that's in development. And there's different reports, uh,

11:30

that these companies produce, um, that, but basically the, the, they, uh,

11:35

track different pertinent areas of the brain and compare that to a large

11:39

normative database.

11:40

Anything in the pink zone here would be more than two standard deviations

11:44

outside of the mean. So you get an idea of what is, uh,

11:48

important and statistically significant for that patient's age.

11:51

This is a triage brain atrophy report, which is, again, uh,

11:54

broken down by areas of the brain. This is another, uh,

11:58

report from a different company, uh, that's also tracking the volumes over time,

12:02

uh, and comparing to a normative database.

12:05

And this is what another report looks like here. Now, uh, with,

12:09

when it comes to pet imaging, again, we tend to use amyloid. Uh,

12:13

tau can be used and F D G pet. Um, and this is,

12:17

these is what these studies look like in the normal scenario.

12:19

And here's abnormal. This is a positive amyloid pet, a positive tau pet,

12:24

and this is a positive F D G pet. This patient happens to have, uh,

12:27

Alzheimer's disease. Now, uh,

12:30

f d g pet patterns would look different across different diseases.

12:34

Alzheimer's would be temporal parietal, and, um,

12:37

posterior seeing that gyrus frontotemporal would, as it sounds,

12:40

tend to be frontal lobes and temporal lobes. Dementia with Lewy bodies can, uh,

12:44

look a lot like Alzheimer's disease or sort of a diffuse pattern,

12:48

but will often involve the occipital lobes as well. Now,

12:53

a tau pet,

12:54

unlike amyloid pet Tau pet accurately predicts the location of future atrophy.

12:58

So here is an, uh, amyloid pet where we have diffuse binding,

13:01

but this is a tau pet, uh, where tau accumulates in the areas that, uh,

13:06

have atrophy first. So tau. So this is, uh, tau here, and this is atrophy.

13:11

So tau is actually a better predictor of the timing of imminent cognitive

13:14

decline. Now, uh,

13:16

I'd like to talk about where these important regulatory updates.

13:19

This is a very exciting time, uh, for dementia. Uh,

13:22

following the FDA's decision on July 6th, 2023 to grant traditional

13:27

approval of embi, the, uh, generic name is Lecan.

13:31

C M s then immediately affirm that they will cover this medication broadly.

13:35

So this is a very pivotal step that really is allowing, uh,

13:39

means for drug access to the millions of Americans that are suffering from

13:44

Alzheimer's disease.

13:45

And the only criteria for c M S coverage is you have to have Medicare,

13:48

you have to have mild cognitive impairment or mild Alzheimer's disease,

13:52

which must be documented, uh, as evidence of amyloid plaque. And then,

13:57

uh, you, you also have to join a registry, which your neurologist will, um,

14:00

help take care of for you. It's on the C M SS website,

14:03

and it's a very simple registry for your neurologist to sign you up in. Uh,

14:07

individuals with original Medicare will pay the standard 20% co-insurance of

14:12

Medicare approved amount of embi once they meet their part B deductible.

14:16

But Medicare will cover the other 80% and actually the largest health system in

14:20

the United States. The va, uh,

14:22

started covering this drug even before C M S C M S was waiting for the F D a,

14:27

uh, traditional approval before they decided to make the decision to cover.

14:30

So that is very exciting. Now, there are, uh, different disease modifying, uh,

14:35

drugs that you have heard about so far. Uh, AADA Helm is really, um,

14:40

uh, really a historical at this point because, uh,

14:43

umab and Lecan have really outperformed, uh, at a helm.

14:47

But these are all IgG monoclonal antibodies. Um,

14:51

helm had received, uh, accelerated approval on June, 2021.

14:55

Umab has not yet, uh, uh, achieved, uh, uh, approval yet,

14:59

and Kinumab has re received accelerated in January, 2023.

15:03

Aducanumab never received, uh, traditional f D A approval. UMAB hasn't yet,

15:08

but will file soon for this. And, uh, Lecan received this, uh,

15:12

just on July 6th, 2023.

15:14

So this is the first disease modifying drug to have traditional approval. Now,

15:19

all three of these drugs did a great job at their secondary endpoints,

15:22

which is to clear beta amyloid plaque from the brain.

15:25

But when it comes to the primary endpoint,

15:27

which is slowing the rate of cognitive decline, um, ad helm did not do as well.

15:32

So only in one trial they had 23% improvement, but not in the other trial.

15:37

Umab actually had 35% slowing in cognitive decline. Uh,

15:41

their results of their trial were just recently released in July, 2023,

15:45

and Lecan had 27% slowing of cognitive decline. Um,

15:50

now the price tag for Lecan is big at 26.5 K, but you have to realize,

15:55

you know, also that this is a, uh, a lethal disease. Um,

15:59

and to be able to give time back to our loved ones, uh,

16:03

by slowing their rate of cognitive decline is a big deal. And again,

16:06

c M s is now covering, uh, as is the va,

16:10

and then private insurers tend to follow.

16:12

So in the CLARITY ad phase three trial,

16:14

which was published in the New England Journal of Medicine on January 5th, 2023,

16:19

kinumab met the primary efficacy endpoint by slowing the rate of cognitive

16:22

decline by 27% over an 18 month period, um,

16:26

based on the clinical dementia rating sum of boxes.

16:30

Now in the Trailblazer ALS two, phase three trial,

16:32

which was published in JAMA on, uh, July 17th, 2023. So just published,

16:38

umab met the primary efficacy endpoint by slowing the rate of cognitive decline

16:41

by 35% at 18 months. Additionally, nearly half.

16:45

So 47% of the UMAB participants had no disease progression at one

16:50

year, uh, with the C D R SB rating scale. So that is a really big deal.

16:55

Um, patients with less advanced disease.

16:57

So patients that had lower medium tau burden outperformed those with more

17:02

advanced disease that had higher tau burden.

17:04

And that is just confirming that the earlier the treatment is initiated,

17:07

the higher the clinical benefit, uh, which is why the, um,

17:11

the labels are suggesting this at the early stages of disease. So again,

17:16

it's important to note kinumabs the only one that's approved by traditional

17:20

approval, um, to treat this early Alzheimer's disease.

17:23

And approximately 1.5 million Americans will be candidate for on-label therapy

17:28

with lecan. So again, 6.7 million Americans have it,

17:31

but when you just look at the early stage disease,

17:34

we're probably talking about 1.5 million. Now,

17:38

numerous other trials are also ongoing, including disease prevention trials,

17:41

such as the dominantly inherited Alzheimer's network trials.

17:45

And then there are several trials that include pharmacologic targeting and

17:48

monitoring of other disease biomarkers for Alzheimer's,

17:51

such as neurofibrillary tangles, which can be imaged again with Tau pet. Now,

17:55

the National Institute of uh,

17:57

aging is currently funding more than 450 active clinical dementia trials.

18:02

So there is a lot of activity in this space. Uh,

18:05

this is looking at the primary endpoint for the CLARITY trial.

18:09

And here you can see lecan here slowing the rate of cognitive decline compared

18:14

to the, uh, placebo. And then if we look at the secondary endpoint,

18:17

which is clearance of the beta amyloid plaque, there's just no comparison.

18:20

Here's placebo here. No change at slight increase in plaque.

18:23

Whereas look at how well kinumab is doing in dropping the amount of, uh,

18:29

amyloid plaque in the brain. So again, here's placebo on an amyloid pet.

18:32

It looks the same a year later,

18:34

but the treated limb is really doing a good job of clearing that plaque. Now,

18:39

the efficacy of clearing the beta amyloid plaque is dose dependent.

18:42

The higher you go up in dose, the better job it does. Here's 10 mgs per kg,

18:46

and this is the, uh, it's, uh,

18:47

you can see that much more plaque is cleared at the higher dose.

18:51

But the problem is, is, uh, like most medications, you know,

18:54

there can be side effects. So with, uh,

18:57

disease modifying therapy in Alzheimer's disease with using monoclonal

19:00

antibodies, the uh, side effect is aria. Um, ARIA e,

19:05

uh, stands for edema or SoCal effusion that can develop. So here's, uh,

19:10

edema that's developed, and here's a SoCal effusion. And Aria,

19:14

h h stands for hemorrhage, um, uh,

19:16

represents micro hemorrhages that can occur in the brain.

19:19

So you see these tiny little dots on G R E or superficial cirrhosis.

19:25

Now, SoCal effusions, uh,

19:27

with aria are thought to represent a leakage of proteinaceous fluid from the

19:31

meningeal vessels.

19:32

And the Aria E edema is thought to represent leakage of proteinaceous fluid into

19:37

that parenchymal interstitial compartment. Um,

19:40

if we look here across the disease modifying therapies,

19:44

you can see that the incidence of ARIA is much higher with a helm. Uh,

19:48

with embi, it's the lowest, it's 21% overall. Um,

19:52

you can see that the Aria E is about half of that for donan. Um,

19:57

and the symptomatic aria, which is the one that we really care about, again,

20:01

much higher for Aada helm, um, with Umab at 6%,

20:05

and then less than 3% for, uh, kinumab. So about half that of umab,

20:10

um, symptoms of ARIA can be varied, but it's often can be headache confusion,

20:14

dizziness, nausea, vomiting or visual disturbance.

20:17

And the risk factors include that initial treatment period.

20:20

So when you first go on treatment, at first three or four months,

20:23

you're at higher risk for developing aria. Also,

20:26

the higher doses are associated with an increased incidence of aria.

20:29

And if you are an A P O E four carrier, uh,

20:32

you have an in in increased incidence. And so, um,

20:35

the label like umab label actually recommends that you get tested for a O E

20:40

four, um, just so you can go over your risk, uh,

20:43

with your neurologist and have a decent idea of what your risk of developing

20:47

ARIA is. Um, so right now,

20:50

patients are paying out of pocket for that genetic test. And, you know,

20:52

maybe in the future that will be covered,

20:54

but that's why not everyone is getting it. But it is useful if you do get it.

20:58

Um, other risk factors for Aria would be cerebral amyloid angiopathy.

21:02

And then if you are on anticoagulation, um,

21:06

you are also at a greater risk of, uh, bleeding. Uh,

21:10

aria e and a p o e four carriers, uh,

21:12

occurs in 5% of heterogeneous carriers and 50% of

21:17

homozygous carriers. Again, why it's useful to get the test, um,

21:21

prior to starting medication. But again, the good news is that symptomatic aria,

21:25

which is what we really care about, is in less than 3%.

21:28

And the Aria e nearly always resolves within one year. In fact,

21:32

typically within, uh, four months, but, but usually always within a year. So,

21:36

uh, again, 97% are asymptomatic. Here's a look at Aria E, um,

21:41

temporal change over time. So this was, uh, the initial, uh,

21:45

development of r a e. It, it sort of got worse,

21:48

and then it started getting better and by 300 days had resolved.

21:52

Here's another case. Here's the baseline. M R I, uh, this is post dosing.

21:56

The patient developed r a e, but on the post dosing follow-up,

21:59

which is typically the follow-ups are typically done at one month,

22:02

it had completely resolved and the patient could resume treatment.

22:06

Here's another patient. Here's their baseline. They developed, uh,

22:09

aria E post dosing. It got a little worse at the one month stage,

22:12

and then by the two months it had gotten better. But, uh,

22:16

this is the G R E here. Uh, you notice here at the post dosing,

22:19

they developed some aria h uh, just two micro hemorrhages, just very mild.

22:23

That got a little worse over time and was even, uh,

22:26

worse again at that second follow-up, um, uh, study.

22:30

So let's talk about how you, uh, grade aria. Um,

22:34

there's mild, moderate, and severe, and there's specific criteria for this.

22:38

So Aria e grading is all about the size. Um,

22:42

pay close attention to this slide because we're gonna go through some, um,

22:45

cases, and I'd like you to be able to choose what you think the grading is.

22:49

So mild if for Aria E is five centimeters and monofocal moderate is,

22:54

uh, uh, less than five centimeters and multifocal,

22:58

or between five and 10 centimeters, and that can be either mono or multifocal,

23:02

then severe is greater than 10 centimeters, and again,

23:06

can be mono or multifocal. So once you get into multifocal,

23:10

you are by definition, moderate or severe in degree. Now,

23:13

aria h unlike r a e, is all about the count. So it's not about the size,

23:18

it's about the count. So micro hemorrhages,

23:20

if you have less than or equal to four, you're considered mild aria age. Uh,

23:24

if you have between five and nine your moderate,

23:26

and if you have more than 10 or equal to 10, you're severe. Now,

23:30

superficial cirrhosis would be, uh, a mild is one focal area,

23:35

uh, moderate is two, and severe is greater than two.

23:38

So you need to follow along the soci and, uh, see if it's all one, um,

23:43

area of involvement. Um, now let's talk about there,

23:46

let's look at some clinical cases where we can go over grading. Uh,

23:50

so what I'd like you to do is, uh, as you're looking at this, uh,

23:54

think in your mind what you think the grade is.

23:57

So here's baseline and here's post dosing.

23:59

We see one area here of Aria E development.

24:02

It looks like it is less than five centimeters in size. So this is mild,

24:07

it's monofocal, and it's less than five centimeters. Here's another case.

24:11

You have three areas of involvement while post dosing. Uh,

24:16

so that would put you into the moderate category because it's multifocal.

24:21

Uh, here's a patient at baseline, and here's post dosing. And you see here,

24:26

there's extensive involvement. In fact, you might be wondering,

24:29

do they have a big stroke, which is why D W I is a required sequence for, um,

24:33

ARIA screening. And no, this is not a stroke.

24:35

This is just shine through artifact. So this is a severe grading here.

24:40

Uh, here's another patient. Here's the baseline, and here's post dosing.

24:44

We see a little, uh,

24:46

area here of a SoCal effusion and another little area here.

24:51

So this is moderate because, uh, it's multi, uh, uh, focal.

24:55

And so we're in the moderate category. It can't be mild.

24:58

Here's another patient here. And we see, um,

25:01

multiple SoCal effusion here on both sides of the brain.

25:05

So this is going to be a severe Aria E case. Um, and here is,

25:10

again, baseline. Here's post dosing. We have this area of, uh,

25:13

SoCal involvement. And this is actually a mild case because, uh,

25:19

it is only involving, uh, one area of the brain here at the end. It is, uh,

25:24

less than five centimeters in size.

25:26

Now here's another case here where it's a little bit larger.

25:29

It looks like it's probably just under 10 centimeters in size for SoCal uh,

25:33

effusion. So this is moderate in degree. Here is a baseline.

25:36

Here's post dosing on G R E, and we see, um, some micro hemorrhage here.

25:41

And here's baseline on the flare. And here's post dosing on the flare.

25:46

This is mild for Aria H because there's less than, um, five foci,

25:50

and it's also mild for, um, uh, aria E as well.

25:55

Now, uh, here's, uh, uh, a G R E here post dosing.

25:59

You see multiple little foci. If you count these, these are actually,

26:03

I don't know if you can see it, but there's actually, um, uh,

26:06

five little foci here. The number matters. And even though it's small,

26:09

you have to count the individual a little foci.

26:12

Here's on flare where we see one area.

26:15

So this would be moderate Aria H because we have five, uh, uh,

26:19

foci here and mild for Aria E 'cause we just have one small area.

26:24

Here's another patient baseline. And then the post dosing, g r e,

26:27

we clearly have, uh, over, uh, uh, you know, uh, 10, uh,

26:31

foci here. Um, and on the baseline flare, and then the post flare,

26:36

you see an extensive area involvement.

26:37

So this is severe Aria H and severe aria E. Uh, here's another, uh,

26:42

this was, was actually post dosing, and this is all on the same patient,

26:45

multiple little foci of micro hemorrhages. So that's severe aria age. Uh,

26:49

here's another case here. This is the baseline. Here's post dosing where we see,

26:54

uh, superficial cirrhosis here, and then we have, uh,

26:58

two foci of micro hemorrhages.

26:59

These are actually just vessels that's not hemorrhage.

27:02

And so how would you grade this? This is actually mild r a h,

27:06

which you might be surprised about, but it's because we have just, uh,

27:10

one focal area of, um, superficial cirrhosis. If you follow these down,

27:14

these are all, uh, contiguous soci,

27:16

and we just have two little dots of micro hemorrhage.

27:19

So we're mild in category for micro hemorrhage,

27:22

and we're mild in category for superficial cirrhosis.

27:25

So it doesn't upgrade our call. The call stays as mild. Uh,

27:28

here is the baseline here is post dosing. We have superficial cirrhosis here,

27:33

and a second area of superficial cirrhosis. Again,

27:36

it's important to make sure you know,

27:38

if you're in the sulcus or if you're in the brain parenchyma,

27:41

this was judged to be in the sulcus. Uh,

27:43

so it is moderate in degree because we have two areas of superficial

27:48

cirrhosis. By the way, if this had been in the brain parenchyma,

27:52

then we would've downgraded to a mild because, uh, we have would,

27:56

if we would've called it one micro hemorrhage and one area of superficial

27:59

cirrhosis. But because this was judged to be in the small sulcus,

28:03

here we are in the moderate, moderate category. Now, um,

28:07

here's a baseline here, uh, post dosing one in two months. Again,

28:10

you see it getting worse over time,

28:12

but let's try to work on what we would call the grading. Here's the flare.

28:16

Here's the G R e. Um, we see a two foci here. Um,

28:20

some more foci here, and even more foci here. So this is, um, uh,

28:25

severe aria E at this day here, and then resolved aria E, um,

28:29

for the aria H We're at mild for this one, severe for this one,

28:32

and severe for this one. Now,

28:36

let's talk about aria e mimics and pitfalls. Uh, this is very important to note,

28:41

um, in this patient. Uh, this was actually a suboptimal protocol where,

28:46

uh, we're really sort of getting some, uh,

28:48

artifact here in the posterior occipital lobes. Uh, when this was, uh,

28:53

the, we, they actually weren't sure about this, had the patient repeat, uh,

28:56

with optimal, um, protocol parameters. And this went away. So that was, uh,

29:01

just artifact. Now, here, this patient was scanned, uh, initially at baseline.

29:05

And this vendor, they came back and were scanned on a different vendor.

29:08

And now we see this. And the question is, is that development of R ARIA E? So,

29:13

uh, what,

29:13

what they actually did was put the patient back on this vendor scanner,

29:17

and it looked just like this. So this was just a artifact,

29:20

and it was not development of Aria e Here is a patient, here's the baseline.

29:25

And then you see here on the follow-up study,

29:27

you see all this sort of SoCal flare hyperintensity,

29:30

but it turned out the patient was on supplemental oxygen. Uh, the patient,

29:34

they then took the patient off supplemental oxygen, repeated the study,

29:37

and it looked exactly like the prior exam. So that was a fake out.

29:41

It wasn't really an ARIA E case. Um, now this is a patient here,

29:46

this is the baseline study, and then you see this very abnormal looking study.

29:50

Um, but they felt that the parameters might not have been optimal.

29:54

There was poor C SS F suppression.

29:55

They actually repeated it with optimal parameters, and it all went away.

30:00

So this actually turned out to be a fake out,

30:02

but that would be very hard to know that. Um,

30:05

but that's what it turned out to be in this case. Um,

30:08

another thing to be aware of on, um, is, you know, um,

30:11

meta metal artifacts. So this is the initial exam. And this exam,

30:15

the patient had their hearing aid in. This is the G R E, and this is the flare.

30:19

But on the flare, you can see there's all this abnormal signal intensity.

30:22

But when you look at the G R E,

30:23

you can clearly see its artifact from the hearing aid.

30:26

And then this was a patient that, uh, this was their post dosing.

30:30

They did develop a small area of re e, so mild r a e. And, uh,

30:34

the question is, uh, was this a e as well,

30:37

which is why it's always mandatory that we do d w i when we're doing therapeutic

30:41

imaging. 'cause this turned out to be an acute infarct. Then, you know,

30:45

the dosing, uh, was originally suspended, um,

30:48

but the r a e actually just went away.

30:51

And that little focus stayed because that's just temporal evolution of the, uh,

30:55

infarct. Now, when we talk about ra uh, h, these are some, um, uh,

31:00

pitfalls that you can see. This was the initial M R I, you see the small, uh,

31:04

micro hemorrhage. What happened to it and did it go away?

31:07

It turns out this is just a differences in slice sampling and a different

31:10

scanner, but that little focus is still there.

31:13

But you can see how in reverse order, you know, um,

31:16

you may think that a micro hemorrhage developed when it didn't. Um,

31:19

the other thing to be aware of is vessels.

31:22

And so you have to track up and down and make sure you're not looking at a

31:25

vessel. SS w i imaging is much higher sensitivity for both vessels and bleeds.

31:30

So it's a little bit harder, uh, like you're finding, uh,

31:33

wearers waldo in a sea of vessels. Um,

31:36

which is why SS w I was not utilized for the trial,

31:39

and also why it is not recommended for therapeutic screening. That's why we use,

31:43

uh, G R E and also to remain a consistent protocol.

31:47

But this just turned out to be a vessel here. Now, when vasal gangly, uh,

31:50

mineralization is symmetric, um, and trunky like this, it's very easy to see.

31:54

But when it's little punctate foci, it might be harder to tell. I, I would, uh,

31:59

you know, I would just assume that's mineralization. But you know, again,

32:02

it's something just to be aware of. And then also around the sinuses, um,

32:06

you can get, uh, dropout susceptibility artifact from the air.

32:10

And so you don't wanna overcall those as bleeds.

32:12

And particularly with the sometimes around the sinuses. Um, you, you know,

32:16

mastoid air cells here, um, you can get little punctate foci,

32:20

but those aren't bleeds there. And then, uh, the other thing to be aware of is,

32:25

uh, this particular patient, you see this, uh,

32:29

what appears is susceptibility artifact bilaterally in the occipital lobes,

32:33

but this was actually phase encoding artifact.

32:35

So you just look for the march across, um, the line in,

32:39

in the phase encoding direction, um,

32:41

to differentiate true hemorrhage from just artifact. Now,

32:45

when to suspend dose, uh,

32:48

so the criteria is different for aria E and Aria H.

32:51

But starting here with aria E, the main thing to remember for aria E is, uh,

32:56

moderate and severe. Um,

32:58

because whenever the degree of aria is moderate or severe,

33:02

the dose must be suspended. And also when the,

33:05

the clinical symptoms are moderate or severe, the dose must be suspended.

33:09

So anything in the moderate severe category, whether aria e or symptom, uh,

33:13

symptoms, you're gonna suspend the dose. If they just have mild symptoms,

33:17

you don't need to suspend the dose.

33:19

So this is very important for a neuroradiologist and,

33:22

and any radiologists that are reading these study to remember,

33:25

because it's up to you to convey back to the referring neurologist, uh,

33:29

what the degree of severity is and whether the dose must be suspended.

33:34

So please do not forget to call the neurologist.

33:36

If you see an aria category that would require a suspension of dose.

33:41

Now this is aria H here. If you're in the moderate or severe Aria H category,

33:46

you're gonna suspend the dose. Um, but unlike with Aria E,

33:49

any patients with Aria H that are symptomatic, you're gonna suspend the dose.

33:53

So all across here, if there's symptoms and you see any r a h, uh,

33:57

again, this is over baseline.

33:59

So let's say if they had on their baseline m r i five micro hemorrhages, uh,

34:03

after their next imaging study, once they're getting, uh, dosed,

34:07

if you see five, you're good. But if you see anything, a therapeutic, um,

34:10

you know, micro hemorrhages that has developed,

34:13

that's when you start your aria grading. Now,

34:15

what is the impact for imaging facilities? The primary, uh,

34:19

impact is gonna be increased. M R I scan volume. So, uh,

34:23

an m r I is required by label at baseline, and it should be recent. Um,

34:28

the old label said within one year,

34:30

but now the new label has been changed to say recent. I don't consider recent,

34:35

uh, a one year, obviously, so probably within a couple of months, um,

34:39

in some institutions are gonna sort of require it, but others, just if you,

34:42

you've got it within a couple of months, um, then you're good to go.

34:46

Then an MRI is required prior to the fifth dose, prior to the seventh dose,

34:50

and prior to the 14th dose. These are all at the high dose, um, categories,

34:54

which is 10 mgss per kg, um, administered by IV infusion every two weeks.

34:58

So MRIs must be acquired prior to these. These are scheduled MRIs.

35:03

The A U R guidelines also recommend, um, a, uh,

35:07

an M R I prior to the 26th dose. That's at 52 weeks.

35:11

So that's not on the KINUMAB label, but it is, uh, the recommended schedule.

35:15

So this is five MRIs here, and then plus additional MRIs,

35:19

non-scheduled MRIs whenever the patient develops a new neurologic symptoms.

35:23

So if you assume maybe the patient might have five headaches a year, you know,

35:28

the neurologist is probably gonna order an m r I each time and probably on an

35:32

urgent basis. So, you know, if you assume about 10 scans per year,

35:36

roughly, um,

35:38

and let's say there's 1500 treatment candidates in the United States,

35:42

we're looking at 15,000 new MRIs a year, um,

35:46

impacting imaging facilities in the US alone, uh, throughout our country.

35:50

So this is a very big number.

35:52

Imaging facilities really need to be prepared for the increased number of MRIs

35:57

that they're going to see. Now, another impact for imaging, uh,

36:00

facilities would be consistency,

36:02

and that is consistency in protocol field strength, and ideally with vendor.

36:07

Um, the protocol is very important. So the required sequences, uh,

36:11

as recommended by the, um, the AS S N R, uh,

36:15

Alzheimer's ARIA Study group is A G R E A flare. And A D W I,

36:20

I can tell you at our institution, we're just gonna do a routine brain. Um,

36:24

now some people may be doing an SS w i as part of their routine brain,

36:28

and some neurologists may always require an SS w i, again,

36:31

because the increased sensitivity. If that's the case,

36:34

please do A G R E in addition to that,

36:36

because when you're doing therapeutic screening,

36:39

you need to do the count off the G R E. So in your dictation,

36:43

you would report the number of micro hemorrhages you see on both the G R E and

36:46

the S W I.

36:47

But just put a note in there that you using the G R E for the re grading. Um,

36:51

and then field strength, um, you know,

36:54

ideally really should be done on a three T or 1.5 T. Um,

36:58

and preferably maintain the same field strength between each visit. And then,

37:02

you know, ideally, if you can stick with the same vendor, that would be, uh,

37:05

wonderful. But I know that that's not possible in a lot of cases. Uh,

37:09

at our imaging enterprise, uh, we, you know,

37:11

we are the largest outpatient freestanding I imaging enterprise in the

37:14

United States. We have 355 freestanding imaging centers that we read from.

37:18

So we, we have a big diverse, uh, fleet of scanners,

37:21

so we can't always maintain the same vendor. Now,

37:23

the other impact for imaging facilities would be an educational initiative for a

37:27

neuroradiologist, uh, for training for, uh, aria.

37:30

We're gonna do ARIA training here in this webinar. But, you know,

37:34

ALS imaging is a good website, uh, for additional information and educational,

37:38

uh, initiatives are also, uh,

37:40

ongoing through the A S N R and through R S N A and through, uh,

37:44

other educational webinars and things like that. Now,

37:47

another impact is quantitative volumetric imaging. We're already, um,

37:51

at least in my area, my clinical practice, I, my referrers order this, uh,

37:56

for almost every dementia patient, but in other areas,

37:58

it's not ordered as frequently. But this is a very useful, uh, AI tool.

38:03

It can allow you to track the hippocampal volumes,

38:06

and it can help with automated ARIA screening report,

38:09

and is also was used in some of the trials. Um,

38:12

the other implication for imaging facilities would be the beta amyloid

38:16

confirmation, which is required prior to treatment. Um, this,

38:19

it can be done through lp, which is covered right now, but, uh, again, uh,

38:23

amyloid PET would be a preferable way for patients to be screened for

38:28

a beta amyloid confirmation. And, you know,

38:31

we're hoping to see that that will be covered in the near future. Um,

38:35

and then privity ad and also, uh, quest has a new, uh, blood test as well.

38:39

These are both blood tests at this point. Um, uh,

38:42

there's still some variability in the reliability there. And, uh,

38:46

also no coverage as of yet for blood testing. Um, now, uh,

38:50

let's talk about ARIA reporting.

38:52

So Aria screening and follow-up can be reported manually. Um,

38:57

the neuroradiologist are, again, uh,

38:59

very important because it impact impacts the therapeutic decisions. Um,

39:04

it's, uh, in terms of the interest level, uh, for, uh, ARIA and Alzheimer's,

39:09

it's very interesting 'cause the ASS N r American Society of Neuroradiology has

39:13

an alls ARIA study group. Um,

39:14

there's about a thousand neuroradiologist that come a year.

39:17

There's actually 2,700 that are members of the AS N R,

39:19

but about a thousand make it to the meeting every year. And, you know,

39:22

they thought that there might be a small number who study we would sign up for

39:25

the study group. Well,

39:25

it turned out 800 neuroradiologists signed up for the study group. Um,

39:29

and then we sent out a poll to all 2,700 neuroradiologist that

39:34

are members of AS S N R and of the responding poll neuroradiologist.

39:39

It turned out that 63% of them were interested in using an automated

39:43

proprietary, uh, computer audit detection, uh, screening software,

39:48

AI software for RA detection, longitudinal follow-up and automated reporting.

39:52

So we will talk about that and look at that. Now,

39:55

automated RA reports are in active development right now, uh, from, uh,

39:59

some of the major vendors and pending f d a approval.

40:03

So this is kind of what it looks like.

40:05

This automated segmentation for quantitative M R I, this is, uh,

40:09

the white matter overlay, which would you use for Aria e screening, uh,

40:14

on the flare sequence. And the other input sequence would be G R E,

40:17

where you'll see automated, uh, detection of the foci of micro hemorrhage.

40:23

Um, so this is the G R E before you see these little, uh,

40:27

foci of micro hemorrhage. And they can be very small. And Adam,

40:30

I'm not sure if you can appreciate this, but there's actually two right here.

40:34

Um, and then there's a few more along here, one here and one here.

40:37

And this is what it looks like after the automated detection is applied. Um,

40:41

here's an Aria E case automated detection, uh, through quantitative, uh,

40:46

M R i, again, r a e and automated, uh, detection.

40:50

Here's an r a e with SoCal effusion case that is color coded after it goes

40:54

through the Q M I software. This was originally, um, so again, uh,

40:59

it's very useful for, uh, detection of, uh,

41:02

r a e and r Aria h Uh, there are different screening reports, uh,

41:06

that can be, um, generated. This happens to be one from, uh,

41:10

one company where it will, for aria e it will give you, uh, the, uh,

41:14

the lesion burden and the count, uh, what's new, what's enlarging,

41:18

what's shrinking over time for Aria E and for aria H, again, the, uh,

41:23

count, um, the, for Aria h the count is mandatory. It's, uh, um,

41:28

so it's very important here.

41:29

We'll do the same thing for superficial synosis and compare dynamically since

41:34

the prior study. So here's sort of a, uh, summary report here for R E A E,

41:39

um, lesion one, it's giving the, uh,

41:41

diameter and size because this is what's required for the grading system. Um,

41:45

so you get the diameter, uh, for, uh, the, all four of these lesions,

41:50

and you get the change from the prior study. It tells you where it is,

41:53

right frontal lobe. Um,

41:55

and then it gives you a severity score for Aria E.

41:59

And this is based on this criteria that we talked about before, um, for mild,

42:04

moderate, and severe. Here's in our sample Aria H report, uh,

42:08

that is in development, and again, counting the current micro hemorrhages,

42:13

uh, uh, as well as the baseline. And you can get the change in the number.

42:17

So baseline had one, and then there was nine new ones at the follow up. Uh,

42:21

imaging will tell you where they are in the brain, and, um, and, and again,

42:25

we'll give you a severity grading, uh,

42:28

for both superficial cirrhosis and for micro hemorrhages.

42:31

So happen to be moderate, um, for super, uh, uh,

42:34

for micro hemorrhages and mild for superficial cirrhosis according to this

42:38

radiologic severity chart. This is another ARIA screening report, um,

42:42

from a different company. So, uh,

42:44

let's talk about sort of the future of dementia imaging. Uh,

42:48

AAI is actively working on a subcutaneous, um, autoinjector, uh,

42:52

for the lecan, uh, type molecule, um,

42:55

to bypass the need for bimonthly infusion. So trials were in progress with that,

43:00

and they aim to file for f D a approval in April, 2024. And actually,

43:04

another great benefit of that is not only the ease of use to be able to do it

43:08

from home, but it will also cut down on the infusion reactions. Uh,

43:12

over 10% of patients will develop an infusion reaction,

43:15

which sort of presents like flu-like symptoms, you know, fever,

43:17

flu-like symptoms, uh, following, uh, infusion.

43:20

That tends to happen more at the beginning of treatment.

43:22

So that will also help mitigate against that. Uh, in the future. We also,

43:26

we would like reimbursement, uh, for blood tests like the Quest ad detect test,

43:31

that's $400 out of pocket and the proc ad, which is 1250 out of pocket.

43:36

Um, and then we need, uh,

43:37

we really need C M SS coverage for that amyloid pet for beta amyloid

43:41

confirmation to bypass the need for a lumbar puncture.

43:44

Patients do not like having to get a lumbar puncture. Uh,

43:47

so currently right now, one amyloid PET is covered per lifetime,

43:49

but in a trial setting only. But again,

43:52

as we spoke about earlier on July 18th, 2023,

43:56

C M S proposed to rescind the national coverage determination that is currently

44:01

restricting amyloid PET coverage. Um,

44:03

so that then permits the individual Medicare administrative contractors,

44:07

these Macs to make coverage determinations.

44:10

So right now it's unclear when C M SS will start reliably, uh,

44:14

reimbursing for amyloid pet, um, nationally and at what rate.

44:17

But we are hoping that this is coming down the pipeline because C M SS did make

44:21

movement on this, uh, with this decision. Uh,

44:24

other things in the future will be new drugs on the horizon.

44:27

We're expecting umab to apply for conventional approval, um,

44:31

hopefully this fall. Um, uh, but if not, at least by, uh, this winter,

44:35

and then we still need a cure. There's no cure. Um, uh, but prevention trials,

44:39

as I mentioned before, are in progress. Okay,

44:43

so let's look at some cases here. Uh, just dementia cases. Um,

44:47

this is, uh, there's, it's several cases that we can review,

44:51

but I'm gonna limit it here,

44:52

just primarily to Alzheimer's and a couple of the other major, uh, dementia, um,

44:56

disorders. This is a 79 year old with memory loss. They came in in 2013 here,

45:01

and you see some mild to moderate right temporal lobe atrophy.

45:04

They had quantitative analysis done in 2013 when they returned three years

45:08

later, their atrophy had significantly progressed and repeat quant was done.

45:13

So here's a look at this quant study. Uh, in 2013,

45:16

there was statistically significant, uh, hippocampal atrophy in the, uh, uh,

45:20

I'm sorry,

45:20

hippocampal atrophy and enlargement of the inferior lateral ventricles that all

45:25

progressed at the follow-up study.

45:26

Now we have all these areas of statistical significance, and the H O c,

45:30

the hippocampal occupancy score, which is a measure of mesiotemporal atrophy,

45:34

um, was statistically significant, uh, on the normative reference charts.

45:38

You can see here how the hippocampal volumes are dropping, uh,

45:41

rapidly off the normative curve,

45:43

as well as the anti-real cortical volumes and other measures here in the

45:47

temporal parietal frontal and occipital cortex. Uh,

45:50

this is a triage brain atrophy report, which is, again,

45:53

broken down into substructures and lobes of the brain.

45:56

Anything in blue here is getting smaller, uh, so the cortex is getting smaller.

46:00

Anything in red is getting bigger,

46:01

so the ventricles and the SCI are getting bigger over time.

46:04

This is the type of thing that you would see sent to your packs when you order

46:07

quantitative, uh, m r I imaging. It's very usual useful visual indicator here.

46:12

Um, this is another, uh, company's report here where again,

46:16

it's measuring the volumes of the pertinent substructures over time and

46:19

comparing over time so you can see things that have progressed in 2016.

46:24

This is also from their report where it's pointing to areas of statistical

46:28

significance. You can see in 2013 here,

46:30

the hippo campi on segmentation and significantly smaller in size three years

46:34

later, this patient also had on G R E multiple little micro hemorrhages.

46:38

So they had cerebral amyloid angiopathy. This was not a treatment patient.

46:43

And then they went on to get an amyloid pet,

46:44

which was positive diffuse binding throughout the cortex.

46:47

So this patient had both Alzheimer's disease and cerebral amyloid angiopathy.

46:52

This is an 86 year old with memory loss and mild right temporal lo atrophy. Um,

46:56

there was statistically significant mesiotemporal, um,

47:00

hypometabolism on, uh, this is the PET CT images,

47:04

and this is the PET M R I, which I fused to the flare sequence here. Um,

47:09

and I run all these through the MIM neuro analysis software. So again,

47:11

it was statistically significant.

47:13

Look at the dramatic progression in atrophy by 2016,

47:17

at which time quantitative post-processing was done,

47:20

and multiple areas of statistical significance on this quant study.

47:24

And same with here on the other. This is another company's quant study here.

47:29

And so this patient went on to have an amyloid PET diffuse binding throughout

47:32

the cortex, a positive amyloid pet. So this patient has Alzheimer's disease.

47:36

Case three is a 73 year old with memory loss,

47:39

and we see here moderate right temporal lobe atrophy. Um,

47:42

we see some reduction in the volumes on quant imaging in 2016.

47:47

Um, so here's the reference charts here on one, uh, company.

47:50

Here's another company, triage Brain Atrophy.

47:53

This patient went on to have amyloid PET in 2015.

47:56

This is the Amyloid PET CT Fusion and PET Mr. Fusion,

47:59

which I fused the T two weighted images. And this was positive.

48:02

So this patient has Alzheimer's disease. Um,

48:04

this patient is a 70 year old here that had some atrophy, um, and,

48:09

but not a lot. And if you look here on the flare images,

48:12

we see this cortical infra here. Uh, another small cortical infra here.

48:16

This one's on the primary motor cortex. A few little, uh,

48:20

lacuna infarcts in the cerebral white matter. Um,

48:22

this was their D W I in 2020. They came back in in December,

48:27

and now we have an acute infarct in the ref,

48:29

right cerebellar hemisphere on the G R E. Again,

48:32

this is a non-treatment patient.

48:33

We see superficial cirrhosis and other little micro hemorrhages, uh,

48:37

scattered around on the F D G PET CT in 2020.

48:41

We see cortical hypometabolism diffusely in the parietal lobes and the temporal

48:45

lobes, and particularly in areas where we have infarcts here in the brain.

48:50

This is the F D G PET CT cortical hypometabolism that was statistically

48:54

significant in the temporal lobes, uh, and in the BIAL lobes.

48:58

Here's the F D G PET ct again, with color fusion.

49:02

We have all the temporal lobes are hypometabolic,

49:05

as are the parietal lobes and the posterior cingulate gyrus. Um,

49:08

this is the FDG praying PET Mr. Fusion, which I fused to the, uh,

49:12

flare and again, statistical significance, temporal and parietal. Uh,

49:16

that was a patient, obviously that had Alzheimer's disease.

49:19

Moving on to this next patient.

49:20

This is a 73 year old male with profound visual hallucinations, delusions,

49:24

gait difficulties, resting tremor, frequent falls, and only minimal memory loss.

49:29

Uh, on the M R I here we see, uh, atrophy,

49:33

moderate atrophy in the bilateral parietal lobes,

49:34

as well as atrophy in the bilateral occipital lobes. Uh,

49:38

when we look here on quantitative imaging, we have, um,

49:41

some atrophy here in the occipital cortex as well as within the, uh,

49:46

hippo campi and amyloid pet, uh, was done. Here's the PET ct,

49:50

amyloid PET, mr.

49:51

And this was positive diffuse finding of the tracer throughout the cortex.

49:55

So the patient went on to have a tau PET in 2019,

49:59

and we do see some tau deposition here in the ox, uh,

50:03

in the occipital lobe on the right,

50:05

a little bit in the posterior cingulate gyrus,

50:06

and a little in the temporal lobe.

50:08

The patient then came back for an M R I in 2021, and, uh,

50:12

we have some progression of atrophy in the parietal and occipital lobes.

50:15

Here's an F D G, uh, brain PET CT that was done in 2021,

50:20

and we see statistically significant cortical hypometabolism in the bilateral

50:23

parietal lobes as well as within the bilateral occipital lobes and in the, uh,

50:28

temporal lobes. Um, and this is the F D G brain PET Mr.

50:33

Uh, again,

50:34

where you see statistical significance in the occipital parietal posterior

50:37

cingulate gyrus. And here's the fusion with the M R I. Um, as well.

50:42

This is the FT G pet surface map in 2021, where again,

50:46

we see parietal and occipital, statistically significant cortical, um,

50:50

hypometabolism. So this actually was a patient with dementia with Lewy bodies.

50:54

The,

50:54

you get abnormal deposition of alpha synuclein where these Lewy bodies here, um,

50:59

in the, uh, uh, uh, cells.

51:02

Now you notice that this patient had a positive amyloid pet,

51:05

which typically you would think of Alzheimer's disease.

51:07

But as you probably remember when we went through one of the earlier slides,

51:11

you can get beta amyloid deposition with D L B. And in this case,

51:15

it was enough a deposition to turn the amyloid PET positive. Um,

51:19

it's much less common than Alzheimer's disease,

51:21

1 million in the US versus 6.7 million with Alzheimer's. Um,

51:25

survival rate is typically five to eight years after diagnosis.

51:29

The important thing is, is 80% of them will present with visual hallucination.

51:32

So if you get a history of this, be thinking D L B. Um,

51:35

and so that's the presenting symptom in most cases. Um, and then again,

51:40

you can have that, um,

51:42

amyloid deposition and neurofibrillary tangles with D L B,

51:45

but not as much as with Alzheimer's. This, uh,

51:47

last case is a 74 year old woman with personality change and memory loss.

51:52

This is the patient's F D g brain PET CT in 2018. And we see, uh,

51:56

here statistically significant cortical hypometabolism in the bilateral temporal

52:00

and bilateral frontal lobes.

52:02

This is what it looks like when I run it through the MIM neuro analysis

52:05

software. Uh, anything in red here is above the midline, and,

52:08

and the blue is below, um, I'm sorry,

52:11

below the mean in this is statistically significant if it's more than two

52:14

standard deviations below the mean and the left and right hemisphere by Z-score

52:19

analysis.

52:19

So we're statistically significant here in the temporal lobes and in the frontal

52:23

lobes. And then this was a negative amyloid, uh, pet, uh,

52:28

on this patient in 2017. Um, this is what the, uh,

52:32

CT looks like. You see the dramatic progression in atrophy and just one year.

52:37

I mean, look at these temporal SU site compared to what they were a year ago.

52:40

Look at the size of the temporal horn that's really has progressed over time.

52:44

And then in 2017 and 18, look at the frontal, uh, uh, lobe socy.

52:49

Here's the superior, uh,

52:50

frontal sulcus compared to what it was just one year earlier. So this was a, uh,

52:54

frontotemporal dementia case. Uh, there are three main subtypes. Uh,

52:58

the behavioral variant, the non fluent and semantic. This is the most common,

53:02

this behavioral variant here,

53:03

which manifests as personality and behavioral changes,

53:06

which is what this patient had. Uh, 30% are hereditary, uh,

53:10

most notably, uh, the behavioral variant, which is an autosomal, uh,

53:15

dominant type. And there are different, um, uh,

53:17

genetic mutations that can occur with this. Um,

53:20

this pre tends to present in younger people, um, between 45 and 60 years of age.

53:25

It's much less common than Alzheimer's disease of 55 k, um, uh,

53:29

with frontotemporal dementia in the US as opposed to the 6.7 million with

53:33

Alzheimer's. But interestingly,

53:35

it is the most common dementia in young people less than the age of 60.

53:38

The survival rate is typically six to eight years after diagnosis. Uh,

53:42

they should have a negative amyloid pet.

53:45

You should not get amyloid deposition with F T D and other diseases, uh,

53:49

that are part of the F T D spectrum can involve motor changes such as a l s and,

53:54

uh, corticobasal degeneration and progressive sup supernuclear palsy.

53:59

So in summary, the, uh,

54:00

dynamic landscape of Alzheimer's disease will have a profound effect on both

54:05

patients and on neurologists as well as neuroradiologist and imaging

54:10

enterprise. So we all really need to be geared up for this. Uh,

54:14

neuroradiologist are gonna play a key role in clinical decision making about the

54:18

eligibility and continuance of disease modifying therapy.

54:22

So it's important that neuroradiologist are trained in how to read these aria

54:26

cases. I can tell you at our imaging enterprise, we are doing, um, internal,

54:30

I'll do an internal webinar,

54:31

which all of our neuroradiologist will participate in the training and they'll

54:36

actually get a certificate if they complete. Um, both A S N R and R S N A are,

54:40

um, also actively thinking about issuing certificates after training programs as

54:44

well. Now imaging centers will need, uh,

54:47

to have agility to adapt to the significantly increased scan volumes.

54:51

And finally,

54:52

just remembering that this is a really exciting and pivotal time in the history

54:56

of neuroradiology, uh, we're, I feel like we're up for the challenge and we're,

55:00

uh, willing to play a key role in the struggle against this, uh,

55:03

absolutely devastating disease. Thank you so much for joining us.

55:08

Thanks so much for your lecture, Dr. Bash.

55:10

We can take some questions now if folks wanna put those in the q and a box.

55:14

We've got a few already in here. Um, Dr. Bash,

55:18

how do we bill for Q M R I?

55:21

Um, okay, so for quantitative, M r I, uh,

55:24

traditionally people have billed under the old three D code,

55:26

but it really was not meant specifically for quantitative, uh,

55:30

post-processing in the brain.

55:31

And so a really exciting event happened on July 1st, 2023,

55:36

just recently here,

55:37

where the A m a granted specific CCPT three category, uh,

55:41

codes for quantitative, uh, imaging of the brain. So that is wonderful.

55:46

Those will go into effect on January 1st, 2024.

55:50

So we strongly encourage everyone to transition from billing under the old three

55:54

D code to the dedicated Q M R I codes. Now,

55:58

these CPT three codes are tracking codes,

56:00

so there's gonna be inconsistency in payment initially. Um,

56:04

but if everyone starts billing under these new codes, that will really drive,

56:09

um, you know, uh, uh, conversion to a category one code,

56:13

which then will become reimbursable.

56:15

So it's very important for people to be aware that the co dedicated codes are

56:19

out there and to bill under those starting January 1st.

56:22

Awesome.

56:24

What are the biggest practical challenges awaiting us in therapeutic dementia

56:28

imaging and how do we overcome them?

56:31

Yeah,

56:31

so I think one of the biggest challenges is gonna be communication between the

56:35

neuroradiologist and their referring neurologist. Um,

56:39

because if the neuroradiologist doesn't know that the patient is on treatment,

56:42

then they know, know to screen for aria, right? So they see, uh, blood products,

56:46

they may think progression of cerebral amyloid angiopathy, they see edema,

56:50

they don't know what is causing the edema. So, um,

56:53

one strategy that you could use that I suggest would be to have the referring

56:58

neurologists have that conversation and maybe have them order their studies as

57:03

ad therapeutic baseline. Uh,

57:05

if it's for the patients on treatment that will alert the neuroradiologist and

57:09

scheduling that the patient is on treatment and they're doing their baseline M R

57:12

I and then ad therapeutic monitoring for when they come back to do their

57:16

scheduled MRIs or if it's an unscheduled after they are already on

57:21

treatment. And then if it's a patient that has dementia, but they,

57:24

they're either not in treatment category, they're not, um, uh, uh,

57:27

eligible for treatment, maybe they're more advanced Alzheimer's, you could, uh,

57:30

just have them order it as a routine non-treatment dementia study.

57:34

But if you have consistent language every time when you order the study,

57:38

that's gonna trigger the correct, uh, dementia protocol.

57:41

So that communication is very important.

57:42

And then also the backwards communication from the neuroradiologist to the

57:46

neurologist if, uh, dosing must be suspended, uh, if the category of aria,

57:51

uh, warrants such. And then the other thing is really planning, uh,

57:54

consistent protocols should be in place already. So, um,

57:58

at our imaging enterprise, you know,

58:00

we'd like to do a dementia protocol on all of these patients. So again,

58:03

the mandatory sequence, we're just gonna do a routine brain, but you know,

58:06

we'd like to add the three d T one, uh, instead of the traditional, um,

58:11

T one so that the patient is eligible. If we wanna do quantitative M R i,

58:15

you need the three D T one to do quantitative M r i. Uh, so, you know, every,

58:19

you know, protocol should include A G R E A flare, uh,

58:22

D w I in a three d T one at a minimum. And then to accommodate for the,

58:27

be aware of and plan for the increase in M R I volumes. So, you know,

58:31

one thing that you can do to, um, you know,

58:34

mitigate the high volumes is things like deep learning for imagery

58:37

reconstruction,

58:38

this AI tool that will allow you to scan your patients 50 to 75% faster,

58:43

um,

58:43

but still actually have in fact better image quality than if you hadn't applied

58:47

this AI solution. That's something we use throughout our imaging enterprise. Um,

58:51

and it's an extremely useful tool,

58:53

which really I is moving into standard of care at at this point in time.

58:58

The other thing is, is to plan for, you know,

59:00

staffing to cover increased volumes. Um, and then, uh,

59:03

the other component is training neuroradiologist.

59:06

If neuroradiologists don't know what RA is,

59:08

they don't know how to read r e a cases,

59:10

they cannot play that key role that is expected of them.

59:14

So a training is very important. So again, in our imaging enterprise,

59:17

we're gonna do an internal webinar that all of our neuroradiologist on the east

59:20

and west coast will attend and they'll get a certificate.

59:23

But as S N R is gonna also offer training and R S N A,

59:26

and so training is very key and the, you know,

59:29

a big educational initiative is needed there.

59:33

Great. Okay.

59:35

What about the controversy surrounding or identifying amyloid as causing

59:39

Alzheimer's disease?

59:41

Well, I think everyone's pretty much in agreement that amyloid and tau are both

59:46

biomarkers for Alzheimer's disease. Um, there's always, you know,

59:49

a bit of a question of the balance between causality and association,

59:53

but we know that causality is at least at some part a component because, uh,

59:57

a p o E four homozygous, uh,

60:00

homozygote carriers have a 12 times increased risk of developing Alzheimer's

60:04

disease. And they also have an increased risk of developing hemorrhages.

60:07

And we know that APO E four is tied to impaired clearance of the, uh,

60:12

beta amyloid plaque from the brain. So that is a sort of a causality component.

60:17

And we also know that, uh, from the disease modifying trials,

60:21

that when you effectively clear the beta amyloid plaque, which all of the, uh,

60:25

monoclonal antibodies do that there is a slowing in cognitive decline.

60:30

So that is another argument for that. So I would say, you know,

60:33

I wouldn't worry about it so much, just worry about what the end result is.

60:36

You know, is the patient getting better, um, you know,

60:38

over time or not getting better, but at least slowing the rate of progression.

60:43

All right. One more question, and this one's a little bit more specific. Um,

60:46

we utilize s w i in our routine m r i brain protocol.

60:50

Just wanna confirm that counts for Aria H must be done on A G R E.

60:55

Yes. So the, the Aria grading scale was based on G R E,

60:59

not on SS w I.

61:00

The trials purposely only use G R E because pretty much any scanner can do A

61:05

G R E. Not all scanners have the capability to do s w I,

61:08

certainly the newer ones do. And then, you know, also sometimes they, you know,

61:12

it's a longer sequence. Um,

61:14

and so they wanted the trials wanted to incorporate something that everyone

61:17

could do consistently, which is G R e. Now,

61:20

if the grading was done on the s w i, it would be probably a different, uh,

61:24

grading scale because SS w i is more sensitive for bleeds. So again,

61:28

it's not a problem if you're doing SS w i, it just,

61:32

if you can also then add the G R E for, uh,

61:35

the grading of ARIA so that everyone is consistent across the board just

61:40

because there is a higher sensitivity for blood products with, uh, S W I.

61:44

And then the other component also is, you know,

61:46

sometimes s w I is harder to interpret. Not all neuroradiologist love it,

61:50

just because sometimes it's hard to tell if something is an endon vessel versus

61:54

a micro hemorrhage. Whereas on G R E it's much, you know, you're,

61:57

you feel much more confident that it's always a micro hemorrhage and not a an

62:01

or, you know, a a, you know, a vessel.

62:04

So those are kind of the reasons behind that.

62:07

Awesome. Dr. Bash,

62:09

thank you so much for your lecture today and for everybody for participating in,

62:13

in the question and answer session.

62:15

You can access a recording of today's conference in all our previous noom

62:19

conferences by creating a free M r I line account.

62:21

Be sure to join us next week on Thursday,

62:24

August 17th for a lecture with Dr. Petra Lewis entitled,

62:28

getting Promoted as Clinician Ed Educator.

62:31

You can register for this free lecture@mriline.com.

62:33

Follow us on social media for updates on future NOOM conferences. Thanks again,

62:37

Dr. Bash, and have a great day. Thanks.