Emily Paolillo: What is MCI and How Is It Diagnosed?

For people living with dementia and their caregivers, the term Mild Cognitive Impairment (MCI) may be familiar. Often the first diagnosis many patients receive, MCI is associated with early stages of neurodegenerative diseases like Alzheimer’s and other dementias. In addition, many people living with dementia cite symptoms of MCI as an early sign. Yet, there’s lots of confusion about what might be “normal” memory loss that comes with aging or a sign to see a doctor. Plus, with new diagnostic tools like blood tests, many people have questions about how to approach getting cognitive screening and what testing they should pursue. 

Neuropsychology Postdoc Fellow Emily Paolillo, for her clinical and research work at UCSF, aids patients in navigating MCI diagnosis and treatment. As an Assistant Professor at the UCSF Memory and Aging Center, her clinical work includes providing neuropsychological evaluations to aid in diagnosing and treating patients with possible neurodegenerative diseases. Her research focuses on evaluating digital health tools for early detection and monitoring of neurobehavioral changes in Alzheimer’s disease and understanding how lifestyle behaviors can grant risk and resilience to dementia.

Bringing her expertise in MCI diagnosis, treatment, and lifestyle behaviors, Paolillo joins Being Patient EIC Deborah Kan to discuss the link between MCI and dementia and on seeking a diagnosis. The live talk also discusses diagnostic tools like the newer blood tests and the impact of lifestyle behaviors post-diagnosis. 

Read or watch the full conversation below. 

Being Patient: Many people tell us they’re diagnosed with MCI before another type of diagnosis. How is MCI diagnosed?

Emily Paolillo: That’s a great question. This can be a really confusing term because oftentimes, physicians might not give a lot of background and context to what this really is. As you said, this is mild cognitive impairment, and this term is really used to characterize a mild level of cognitive impairment. And what does that mean, exactly? So, typically, we have some criteria to determine what is mild versus what’s more severe. At the more severe stage, we would call that dementia. Both of those things characterize the severity of cognitive impairment, but MCI is really defined by a mild level of cognitive impairment where you can still function independently. This means that maybe the person is noticing cognitive changes. 

During an evaluation, we pick up on some mild difficulties during cognitive testing, whether that’s comprehensive cognitive testing or a cognitive screener, but that they can still function for themselves independently. To determine this, clinicians like myself will often ask about things that we call instrumental activities of daily living. These really include things like managing finances, managing medications, being able to shop independently, preparing meals, completing household chores, navigating transportation, and getting places independently. And so you know, if there’s evidence of cognitive impairment, but you can still do all of those things independently, the person’s cognitive difficulties are characterized at this level of mild cognitive impairment or MCI.

Being Patient: There are a lot of reasons why our memory doesn’t function as well as it did. There are issues with memory in normal aging, and some people have hormonal fluctuations during menopause. When we think of MCI, are you at a point of no return, or are you in this gray area where things could improve?

Paolillo: I do think it’s a gray area. It really depends on what your doctor is thinking: what is the cause of the MCI? As you’re describing, lots of things can cause cognitive change, some of which are pretty normal, just like normal aging.

Age is related with a lot of declines in functioning that are pretty typical. There are other things that can cause cognitive changes and MCI that are related to disease, one of which being Alzheimer’s disease. There are lots of other neurodegenerative diseases that can cause MCI and other health conditions as well — things like stroke and other forms of cerebrovascular disease. The course will really depend on what is the underlying cause of those changes.

As you described, things like hormonal fluctuations, sometimes even people, are having difficulties with sleep that really affect their cognition. Sometimes there’s imbalances in vitamins and other metabolic processes. When those things are underlying the MCI, those have potential to be treated. Sometimes, people can see an improvement or at least stability. 

Being Patient: How do you tell the difference if a patient comes in experiencing memory issues outside the norm? Are they treated like people you may think have dementia and given those preliminary screenings like the MOCA test? Tell us about that diagnostic process.

Paolillo: There’s lots of different forms of evaluation and lots of different tests that we can give to try to tap into what is causing this MCI. I’m a neuropsychologist, and what that means is that I’m in the clinic, I’m the one who’s administering cognitive tests and interpreting people’s performance.

On these different cognitive tests, we tap into all sorts of cognitive functions like memory, attention, processing, speed, language, and executive functioning, which [is a] really complex collection of higher-order thinking skills.

Based on people’s performance in all of these domains, people have different patterns of strengths and weaknesses. 

Some patterns indicate a higher likelihood that it may be caused by a neurodegenerative disease. Other patterns, for example, might indicate that their weaknesses might be caused by other, maybe more treatable, things like sleep or depression.

In addition to that, I work really closely with neurologists, who are the people who more closely manage the long-term care of our patients. They’ll often order additional evaluations and diagnostic tests. For example, getting a brain scan, brain MRI, a blood draw, or a lumbar puncture to examine what proteins are existing in these fluids that we have that can indicate whether or not a disease is present.

“I’m a neuropsychologist, and what that
means is that I’m in the clinic, I’m the
one who’s administering cognitive tests
and interpreting people’s performance.”

Being Patient: As a doctor, what would make you give someone an early-stage Alzheimer’s diagnosis versus MCI? Or would that just not happen?

Paolillo: We can absolutely, when we see someone, make informed and educated hypotheses that would lead us to say, “Okay, we think this is MCI due to Alzheimer’s disease.” Those types of things would be the collection of all the things that I just mentioned.

For example, Alzheimer’s disease most commonly manifests as difficulties with memory. It doesn’t always, actually, so we want to be aware of those things, too. Sometimes, it can manifest as difficulties primarily with executive functioning or even visual-spatial problems, but most commonly, it would be difficulties with memory.

If I’m seeing a patient, and I see that on their neuropsychological testing, their primary difficulty is in memory, and maybe there’s some weaknesses and other domains as well, and then I pair that with other findings. For example, in an MRI, one of the brain regions that most commonly is associated with memory difficulties in Alzheimer’s disease is our hippocampus or also within the medial temporal lobe.

If we see damage to that area on a brain MRI in conjunction with memory problems on testing, then we have more evidence to say, “This is likely due to AD.” Then, on top of that, we’ll order these additional diagnostic tests through the blood or the cerebral spinal fluid, looking for Alzheimer’s disease proteins. Then, at that point, we can say, “OK, we really have evidence to say that this MCI might be due to Alzheimer’s disease.” 

“If I’m seeing a patient, and I see that
on their neuropsychological testing, their primary
difficulty is in memory, and maybe there’s some
weaknesses and other domains as well, and
then I pair that with other findings.”

Being Patient: We have been told that PET scans or a spinal tap are the best way to determine whether or not there are plaques and tangles, though we do have blood tests now, and we are keeping an eye on that space. I’ve always been curious about an MRI because that’s the first line of screening. What exactly are you looking for in that MRI? Because all brains atrophy with age, what’s the difference, looking at an MRI, between dementia and normal aging?

Paolillo: That’s a really great question. It also depends on who’s looking at this brain MRI too. The first person who usually looks at a brain MRI is a radiologist, and they’re looking for really glaring issues, things like a tumor or other abnormalities. Then, when it gets to the neurologist, especially at a specialty dementia clinic, they have a much higher level of detail to look at these patterns of atrophy. 

You’re right. As a person ages, there’s going to be more atrophy or decreased tissue in the brain in general because that’s just what happens with aging. But seeing sort of a holistic view of the brain, and seeing that some parts are more atrophied than you would expect, given sort of the rest of the global atrophy in the context of their age, that really hints to a neurologist, that something extra is happening in there, that is not just due to normal aging. For example, even if the brain has sort of general atrophy, but those medial temporal lobes, those hippocampi, are doing much worse than the rest of the brain, that can be a sign.

Being Patient: That is a great answer. I wasn’t thinking of it that way. Thank you for that. For any people or loved ones that have just been diagnosed, what percentage of cases eventually become dementia, with Alzheimer’s being the most common?

Paolillo: It’s hard to say exact numbers because it is so dependent on what the MCI is looking like. MCI is just this sort of broad term that tells us about the overall level of impairment, but it doesn’t tell us about the symptoms that people are experiencing.

And in what other context, right, and we’ve already discussed, you know, there are so many contexts that can alter somebody’s cognition that may be treatable, you know, like mood, sleep, you know, other cardiovascular risk factors, things like that. But in the context of, you know, it being an MCI that aren’t, you know, your providers are really suspecting might be due to a neurodegenerative disease, there is a much larger risk for that to progress to dementia.

“MCI is just this broad term that
tells us about the overall level of impairment,
but it doesn’t tell us about the symptoms
that people are experiencing.”

Being Patient: What is your recommendation to the patient population or their loved ones if they do receive an MCI diagnosis? Often, people are told, “It’s MCI, do your best, and I’ll see you in six months.” Do you have advice on what types of questions they should ask their doctor and what they should monitor? Or what should they be insisting on for further diagnosis?

Paolillo: I’ll [give] a little bit of background about why oftentimes physicians will say, “You know, we’ll hold on to this. Come back in six months. We’ll evaluate you again.” Because that’s sort of the best marker to know if there’s true change over time as these repeat evaluations.

That being said, each patient’s own individual experience also tells them whether or not there’s been change over time, and being really clear about that with yourself to say, “OK, have I experienced these kinds of progressive changes in my memory over time? Do I feel that it’s getting worse?” If you really do, be super clear and communicative about that with your doctor. 

Bring examples, and tell them specific reasons why these are concerns to you. If that’s the case, you know, push for further evaluation. Any doctor that may be telling you to just forget about it and come back in six months for a reevaluation, you can really push for these additional diagnostic tests. I think being aware of what exists is step number one so that you can know what to ask for. 

Being Patient: How does the scanning work? If you first give cognitive assessments, you understand other things are going on, then would the patient be given an MRI right away? Or what’s the standard care practice?

Paolillo: Not at all clinics, no. UCSF is very different; we get brain MRIs on pretty much every patient that we see, but that’s not the standard of care across the country and across different clinics with different resources. But, you can advocate for that, especially if there’s an indication and your provider can refer you to get additional brain scans, get these fluid biomarker tests through lumbar, putting as much comprehensive information as possible for you to know what the next steps are. So really helpful.

Being Patient: We know that some people with beta-amyloid plaque in their brains may never get Alzheimer’s. Is there a scenario where you would see plaque and just have an MCI diagnosis? Or, at that point, would you say it’s early-stage Alzheimer’s?

Paolillo: At that point, somebody could still absolutely have an MCI diagnosis. Again, the MCI is sort of separate from what’s causing the cognitive impairment. If there was evidence that there were beta-amyloid plaques, at that point,  the provider might say, this is MCI due to Alzheimer’s disease. Only until you know a person progresses and can no longer complete those activities of daily living independently would it be classified as a level of dementia versus MCI. 

Being Patient: We’re getting a question from our audience asking when the blood tests will be available. What is UCSF doing? Are you going to have blood tests available to people?

Paolillo: We are starting to roll out blood tests for phosphorylated tau, which is an indicator of Alzheimer’s disease. It is more preliminary. 

Being Patient: Why are you using them for tau and not amyloid? I’m just curious.

Paolillo: The research in blood is showing that these phosphorylated tau markers are the most indicative of Alzheimer’s disease in the brain. There’s lots of things that can affect what’s in our blood, and it’s not necessarily directly connected to our brain. So, we have to find these markers that are more closely correlated with the things that are in our brain. That’s why the lumbar punctures have been the gold standard because it draws the fluid that is directly surrounding the brain. So, we’re getting a closer one-to-one connection with the brain as compared to blood. We kind of have to find all these different markers that closely relate to the brain.

“We kind of have to find all these
different markers that closely
relate to the brain.”

Being Patient: But doesn’t the tau indicate a later progression of the disease? Like you start with a plaque, then you get the tangles?

Paolillo: Yeah, so the tau tangles represent a stage of Alzheimer’s disease that more directly correlates with cognitive functioning, actually. But what people are finding in the blood is that our markers of tau in blood relate really strongly to amyloid in the brain. There are lots of studies that are coming out now showing that these phosphorylated tau markers in blood correlate very closely to our amyloid PET scans and the level of amyloid that’s detected via PET scans. So, people are really thinking that, in the blood, these are markers of amyloidosis. 

Being Patient: If someone has tau, would you say they have early-stage Alzheimer’s and not MCI?

Paolillo: Again, I think the tau is another indicator that Alzheimer’s disease is in the brain, and the MCI is just characterizing your level of cognitive impairment, regardless of how much protein or if any protein of Alzheimer’s disease at all, isn’t there. So, someone could absolutely still have tau tangles and be characterized as MCI based on their level of cognitive impairment and level of functioning if they’re still independent.

Being Patient: We have a coming in from one of our viewers who said, “I have heard the lack of beta-amyloid plaque in an LP may be indicative of Alzheimer’s, not the presence.” Is that true?

Paolillo: That’s exactly right. Lower levels in our fluid indicate that more amyloid is accumulating in the brain. 

Being Patient: Can you have plaques swirling around in your bloodstream, but it doesn’t reach your brain for whatever reason? Or if it’s in your blood, will it be in your brain?

Paolillo: The interesting thing is that, actually, everybody has amyloid. It’s just a part of our normal functioning. There’s amyloid in my blood and everybody’s blood. The problem is when it starts to aggregate in the brain. So, the aggregations are the plaques. That’s because it’s aggregating; it’s not clearing from the brain. That’s why we have lower levels in the fluid that indicate Alzheimer’s disease plaques are accumulating.

“There’s amyloid in my blood
and everybody’s blood. The problem is when it
starts to aggregate in the brain.”

Being Patient: At UCSF, for people coming in with memory problems, are you going to offer the blood test to everyone, or is it just for certain people?

Polillo: There are certain indications. For example, if somebody comes and we find that they’re performing pretty normally on testing and that there’s a clear indication that there’s something else driving this cognitive impairment. For example, a lot of times, we get people with sleep apnea who don’t know that they have sleep apnea and they’re not being treated for it. And it’s really disruptive to their sleep and their day-to-day, we say, “Okay, let’s treat that first.” Then, if problems persist, or if you’re feeling like things are getting worse, then we’ll explore these diagnostic tests through the blood or the CSF.

Being Patient: Our audience has another question from someone who had a P-Tau test three years ago in a clinical trial. Because it was a clinical trial, they weren’t able to tell him what it meant. Are there different tau levels once you detect it, and is that associated with memory loss?

Paolillo: That’s a really good question. I mean, there is this issue in clinical trials where they’re not allowed to give you information sometimes. I think there’s a push away from that.

Being Patient: We hear about that all the time.

Paolillo: Exactly. [We’re] all on board for sharing as much information with the people who are contributing to research as possible. That’s the reason why research happens, and [the reason why] advancement happens is because of people’s participation. So, we want to give back. 

To answer the original question, depending on the exact test, there are cut-offs that people use to say whether or not it’s an elevated or an abnormal value. There are these sorts of established cut-offs, and when it is an abnormal value, there’s pretty good sensitivity and specificity to determine that Alzheimer’s disease is present in the brain.

Being Patient: Should patients insist on testing, specifically blood testing, if they’re ready for that information?

Paolillo: This is an absolutely individual decision if somebody is really ready and determined to and wanting to know whether or not Alzheimer’s disease may be driving their symptoms. You’re in control of your healthcare, and your provider should be supportive of helping you achieve these healthcare goals. If part of that is gaining more information about what’s going on, then absolutely. I think, oftentimes, as patients, we have to advocate for ourselves. I would absolutely support anything that a patient wants to have more information on.

“You’re in control of your healthcare,
and your provider should be supportive
of helping you achieve these healthcare goals.”

Being Patient: If you’re experiencing memory loss, what other things should you consider in terms of testing and causes?

Paolillo: We’re thinking about a lot of different modifiable factors, right? Of course, there are things that affect our other aspects of health, including these cardiovascular risk factors. A saying that we often say a lot is a healthy heart is a healthy brain.

So, you really want to take control of managing things like blood pressure, cholesterol. If there’s an indication for diabetes, you’ll really want to get that under control. If you have any changes in mood that can really affect how you function in day-to-day life, engage in treatment for those sorts of things. Those can all be really helpful not only in improving your own day-to-day life but in determining what is really going on. Because if I treat those things, and it gets better, then maybe that’s kind of a good sign.

Being Patient: Do you see a higher association between people with MCI and people who are overweight or perhaps have diabetes?

Paolillo: Yeah, there are a couple of studies showing that those sorts of factors are risks for developing cognitive impairment down the line, and the exact mechanisms for those things,  people are still really digging into. I think there are both direct and indirect effects on the brain when we’re thinking about things like diabetes, cholesterol, and blood pressure. In particular, I think high blood pressure has one of the strongest correlations with future cognitive decline.

Being Patient: All of this is getting so interesting because the more data we get about our health, the more we can be proactive, and now you have all these monitors and things like that. Can the damage be reversed if you are already experiencing memory loss related to cholesterol, glucose levels, or metabolism? Do we know if it is like Alzheimer’s, where if the damage has already started in the brain, it’s tough to reverse? Or could it be slowed down by lifestyle factors?

Paolillo: Some of the research that’s been done in this area has shown that once some damage has already been done, it is hard to revert that and improve from there. But treating those medical factors and really getting those stable can stabilize your cognitive trajectory as well and at least slow any decline. For example, you know, if Alzheimer’s now is on board, and your diabetes is way out of control, that could potentially accelerate the cognitive decline. But if you get your diabetes under control your glucose levels are stable and really optimal, then that can slow that decline.

Being Patient: How long is a period of MCI typically? For patients later diagnosed with early-stage Alzheimer’s after MCI, what would you say the general time period for that is?

Paolillo: It really ranges, especially depending on what level of MCI people are sort of at. It can range anywhere from a year to a couple of years, and there are so many factors that can influence this, too. I work with a lot of people, including some of the research that I do at UCSF, showing that these lifestyle modifications can make a really big difference in the trajectory of cognitive decline. One of the most important things we often emphasize for people is staying physically active. Even something as simple as reducing your sedentary time, or the time you just sit all day, can be a step in the right direction. So there’s quite a range, and it’s because of some of these individual factors.

Being Patient: I don’t have early-stage MCI or Alzheimer’s, but I worry about that because I have a mom with Alzheimer’s. If I called UCSF about this, would I be able to get a baseline cognitive assessment, or would they be too busy? In general, how do people establish their baseline?

Paolillo: I do think baselines are really helpful because everyone starts at a different level, and the best comparison is a comparison against yourself. However, you’re hitting the nail on the head because our clinics are often overrun and really busy. If someone calls saying that they don’t really have any cognitive concerns but just want an evaluation to know where they’re at, that can be really difficult and potentially just not achievable, depending on the ALMA clinic.

My recommendation would be: just [keep] an eye on symptoms, and once you start to notice significant changes for yourself, that is the time when the earliest decline if we can catch you at a moment when you’re having the earliest signs of decline that can be pretty close to baseline.

“I do think baselines are really helpful because
everyone starts at a different level, and the
best comparison is a comparison against yourself.”

Being Patient: What does a baseline assessment look like for a healthy person?

Paolillo: Again, I’m a neuropsychologist. I think about this in terms of how a neuropsychologist would approach it, but it would be a comprehensive cognitive evaluation. Neuropsychological testing is done with people of all age ranges, from kids to adults, older adults, and so we would give an evaluation that taps into all aspects of functioning as we would with anyone who’s coming in with a specific complaint. You would know strengths and weaknesses, and then at a later time point, you’d have the performance on each of these tests to compare to. 

ONE SENTENCE AUTHOR BIO:  Katy Koop is a writer and theatre artist based in Raleigh, NC.