Join Dr. Tania Small, in a compelling 2-part episode featuring Dr. George Grossberg, a world-renowned geriatric psychiatrist who's been at the forefront of Alzheimer’s disease research and innovation for over 40 years. In part 2, they delve into groundbreaking science - from researching novel therapeutic targets and addressing Alzheimer’s psychosis to the power of patient-driven science in research and prevention.
Join Dr. Tania Small, in a compelling 2-part episode featuring Dr. George Grossberg, a world-renowned geriatric psychiatrist who's been at the forefront of Alzheimer’s disease research and innovation for over 40 years. With over 400 papers to his name, Dr. Grossberg brings unparalleled insights into the disease.
In part 2, they delve into groundbreaking science - from researching novel therapeutic targets and addressing Alzheimer’s psychosis to the power of patient-driven science in research and prevention.
It is a forward-looking conversation that equips you with new cutting-edge insights for the future.
Tania (00:01):
Welcome to Doctors Unscripted. I'm Dr. Tania Small, and I'm here to bring you into a different kind of conversation with some of the brightest minds in medicine and research. In part two, I sit down with world renowned geriatric psychiatrist, Dr. George Grossberg. We delve into the exciting world of emerging targets, the hidden crisis of Alzheimer's psychosis, and the science that's shifting this disease from something we manage to something we delay and eventually prevent. So join us as we shatter outdated paradigms because the future of Alzheimer's care is being rewritten. Now, let's get started. Can you take me through when someone is diagnosed with Alzheimer's, what are the different spectrum of mood disorders that can be associated with it?
Dr. Grossberg (00:58):
Yeah, so there's a spectrum of mood disorders and a spectrum of behavioral disorders. Everything from major or clinically significant depression early on and later on as well, as well as more of a situational or reactive depression, which may actually respond very well to interactive psychotherapy, but also very common throughout the disease. I had a patient recently who heard and saw and very much believed that there was a family with small children living in her basement, and she tried to convince her adult children that this family's here, they're living in my basement and they're not supposed to be there. And of course, every time they would go down to the basement, they didn't see the family, and then she would say, well, they must have snuck out because they knew you guys were coming, and so on. So psychotic symptoms are also not rare. So there's a spectrum of what we call neuropsychiatric symptoms that can accompany Alzheimer's disease from the earliest stages to the middle or moderate stage, and then also in the more advanced or severe dementia stage.
Tania (02:01):
Is there an early sign that these patients may develop these types of psychosis or any kind of mood disorder?
Dr. Grossberg (02:09):
That’s a really good question. So I'm not sure that we can predict that,
(02:13):
But what we do know is that people who early on develop these neuropsychiatric symptoms, whether it's agitation or psychosis or depression, the spectrum of behavioral symptomatology, they don't tend to do as well as people who don't have them. They tend to progress more rapidly. They may end up institutionalized more earlier or more frequently than those that don't have them, but we don't really have a good way to predict who's going to have them. Now, of course, if someone has, you mentioned depression before, if they have a history of recurrent depression and now they're diagnosed with Alzheimer's disease, they're going to be at greater risk of developing depression down the road. But as far as the other neuropsychiatric symptoms, they're very hard to predict.
Tania (03:01):
How do we recognize psychosis in Alzheimer's and how is it different than other different mood disorders?
Dr. Grossberg (03:08):
Yeah, those are important issues. So when we treat patients with Alzheimer's disease, we're not just looking at the cognitive aspects, although the newer medications for Alzheimer's disease have been developed with that kind of focus, including the disease modifying kind of therapies that are now becoming available, we're also thinking about the associated, what I call neuropsychiatric symptoms of Alzheimer's disease. And there are several, the most common actually, but not necessarily the most disabling, is apathy or a lack of motivation being kind of a serious couch potato, serious couch potatoes. They don't cause a lot of trouble. So often it's not paid attention to, people are apathetic about apathy, but the ones that you can't be apathetic about, the ones that are really, really impactful are agitation, even overtly aggressive behaviors and psychosis. So psychosis in Alzheimer's disease is very common. To your question, maybe 50% of patients have psychotic symptoms sometime during the course of the disease.
(04:20):
Most often it's going to be delusions kind of firm, false beliefs that a patient has that don't jive with our sense of reality. They could be, for example, accusatory or paranoid a patient recently in the long-term care environment who started believing that the nurses were out to get her and that her food and medicine was actually poisoned. So if she refused to eat, she refused to take her medication. I had another patient recently that had visual hallucinations that were very frightening. There were these frightening creatures coming through the window and people would see her shaking and she would try to describe what she was seeing, but it was very hard to kind of follow her in the more advanced stages of dementia. Patients can't tell you what's going on, but they can't have psychotic symptoms. They can have visual hallucinations, and an evidence of that might be that they're picking at things that nobody else sees.
(05:18):
I had a patient recently also in the assisted living memory care environment with Alzheimer's disease where the nurse's assistant was walking into her room to clean the room or clean her sheets, whatever, and the patient was facing the corner of the room and carrying on an animated conversation with someone that wasn't there. So you can assume that she may be hearing voices and maybe having auditory hallucinations, maybe even visual as well as a manifestation of psychosis. So psychosis, agitation, they can often come together, can be very, very disabling as can depression. So depression is very common throughout Alzheimer's disease, and if we don't recognize it and don't treat it, it can accelerate disease progression. We know that all of these neuropsychiatric symptoms when they occur in Alzheimer's disease, especially early on, are a bad sign because even if we treat them appropriately, there can be more rapid disease progression. And of course, if we don't treat them appropriately and they remain uncontrolled, the family can no longer take care of that kind of individual, and they often end up having to place them in a nursing home or in a long-term care environment. So these are ancillary symptoms beyond the cognitive disturbances that we see in Alzheimer's disease that are just as impactful, if not more so for patients and family than the cognitive disarray that they see with the disease.
(07:01):
But in all patients, there are just a whole range of different risk factors for Alzheimer's disease that are modifiable. So we need to do a much better job educating middle, middle-aged individuals that are moving into their later years to basically try to avoid or to manage and treat these risk factors so that we can decrease the rate of Alzheimer's disease later on or delay the onset of Alzheimer's disease, everything from smoking to obesity to high lipids, cholesterol. I mean, there are many different modifiable risk factors, and the earlier we get them under control, the better one's going to be as far as their risk of Alzheimer's disease later.
Tania (07:45):
So our audience that listens, they're mostly HCPs, and so I would love you to take us through what should we be doing to manage these symptoms or different diseases to delay?
Dr. Grossberg (07:59):
So that's a very important topic. I talk about lifestyle modification.
Tania (08:03):
Yes,
Dr. Grossberg (08:04):
And I always start with the cardiovascular because there's this saying that what's good for the heart is good for the brain. So anything that's going to be decreasing, the risk of heart disease, heart attacks and so on. Things like high blood pressure, hypertension, diabetes, hyperlipidemia, obesity, lack of exercise and so on, and the better those are controlled, the better it's going to be not just for your heart, your cardiovascular system, but also for your brain. Then we talk about habits, things like smoking, things like alcohol, especially in excess, which may be problematic. That leads us to dietary alterations and changes. We now recommend very, very highly what's called the mind diet, which is a combination of the Mediterranean diet with low sodium or low salt, which is the dash diet for hypertension.
Tania (08:59):
Even though the Mediterranean does come with wine,
Dr. Grossberg (09:02):
Mediterranean very limited amounts of wine. That's true. We are learning now that alcohol is a kind of a two-edged sword, that there may be some benefits of very modest drinking, but there may be other liabilities even of modest drinking. So alcohol is very controversial right now, but what we do know is in my older patients who are having cognitive issues, the best amount of alcohol to take is zero. Once you start to have memory problems, we talk about activity, the importance of activity, and I talk about activity in four spheres, all important talk about physical activity, 150 minutes a week or more of walking or some kind of exercise, more is better. Mental activity, challenge your brain, keep your brain active. Social activity, don't be a hermit or a couch. Potato spiritual activity, whether it's religious activity or things like meditation, mindfulness, yoga, all four are very, very important, and we want to make sure that you're doing those on a regular or day-to-day basis.
(10:07):
There can be other things that we want to keep people active in, so people considering retirement, sometimes we'll ask 'em if they have hobbies or other activities to get into. If they don't, maybe you should reconsider retirement. Obviously, depression, if it's recognized, needs to be kind of treated promptly. There are many different risk factors. Hearing vision, if you have hearing loss, get hearing aids, if you have visual issues, get that fixed. All of those are risk factors for Alzheimer's disease if they're not recognized and not addressed. So there are many different risk factors that are modifiable and the more of those that we kind of work on and employ the microbiome. So we do recommend either fermented foods like cultured yogurts and things like that, or a probiotic to introduce good bacteria into the system. That's part of lifestyle modification. If it's not part of your lifestyle, you need to make it part of that together with the mind diet. But the bottom line is the more of these things that we do, the better the likelihood of either delaying or decreasing the risk, even if you have genetic loading, that's very recent data showing that you can even overcome the genetic loading by doing more and more of these lifestyle modification approaches utilizing more of these approaches.
Tania (11:38):
So what do we say to the non-believers? Because we've, there's a lot of discussions talking about the brain, gut connection, health and access, and there's still a lot of non-believers and a lot of physicians still don't believe in it. Can you share a little bit more of the data and how do we convince them? Actually,
Dr. Grossberg (11:54):
It's interesting because I'm actually working with one of our super bright fourth year medical students. We're putting together a presentation on the relationship between dysbiosis, bad bacteria in the gut and how they may actually get into the bloodstream and cross the blood brain barrier and maybe contribute to cell death or inflammation of neurons, which is part of Alzheimer's disease and other brain diseases. But there's really quite a bit of evidence that what happens that bacteria in the gut may actually have systemic effects or benefits or may have deleterious effects on brain functioning. One of the areas that to me also has been always very fascinating is the relationship between gum disease. As people get older, they often have inflammatory changes of their gums. They may lose teeth because of that. So gum disease is caused by a specific bacteria that actually has been found at autopsy in close proximity to the plaques and tangles in all Alzheimer's disease, and we think may contribute to inflammation and cell death.
(13:11):
And there is, in fact, one of the risk factors for Alzheimer's disease is periodontal disease, especially if it's not properly and effectively treated. So that's one evidence or one area of evidence. We also know that there are diseases that are caused by certain bacteria that affect the gastrointestinal system, where if you can introduce healthy bacteria into the GI tract, it pretty much wipes out the pathology. H pylori is the example of that. So there are many little pieces of evidence that kind of show us or are beginning to show us that what happens relative to bacteria in the GI tract may have systemic effects and specific effects on the central nervous system. And we think introducing good bacteria addressing this dysbiosis is what's called maybe beneficial, and it's so easy to do.
Tania (14:11):
Let's talk about microbiomes,
Dr. Grossberg (14:13):
The microbiome. Another hot topic.
Tania (14:15):
Yes.
Dr. Grossberg (14:16):
So we do recommend either taking a probiotic capsule or eating fermented foods like the cultured Greek yogurts. Things like kimchi and sauerkraut and kombucha and things of that nature can introduce good bacteria into the system and may have benefits. Yeah,
Tania (14:36):
There's data, and this is separate in oncology that shows your point that bacteria can increase resistance to certain medications, and so there's a lot of studies happening out there.
Dr. Grossberg (14:47):
Yeah, no, that's a really exciting area and kind of an emerging area. A lot of people don't know much about it. Some of the earliest data actually was in some posters at the international Alzheimer's meetings where some scientists from Asia actually examined bacteria in stool and patients who had Alzheimer's disease versus non Alzheimer's age match sex, match whatever controls and found a lot more of the bad bacteria with Alzheimer's patients versus the good bacteria in those that didn't have it. So that began this inquiry into the importance of the gut bacteria, a microbiota,
Tania (15:38):
So biologically what is happening when it comes to different types of psychosis.
Dr. Grossberg (15:42):
So we think that there are similar phenomena to what we see with psychosis and other neuropsychiatric diseases, maybe related to dopamine, maybe related to the nicotinic system and nicotinic receptors as well that trigger the symptoms of psychosis. And we do know that the current generation of anti-psychotic medications can be helpful for psychosis in Alzheimer's disease. The problem is, and they all work very similarly in that they basically block excessive amounts of dopamine
(16:18):
And older patients, whether with or without Alzheimer's disease, are much more sensitive to the common side effects. They develop the Parkinsonian side effects more readily. We worry about the metabolic side effects, effects on blood sugar and so on. Lipids, high lipids, they already have problems with that. Some of them are too sedating, some of them drop blood pressure, which can increase the risk of falls, which is huge in this patient population. But in many other areas of medicine, we're starting to learn that what we learned at medical school isn't what we now know at the present time. So what I learned in medical school was that psychosis was basically too much dopamine be manufactured and you block the dopamine with one of the older or newer kind of antipsychotics, and you're going to help with the positive symptoms of psychosis in any disease that has those kind of manifestations.
(17:17):
It's only been more recently that we realize that there may be other very important players that precede the excessive amounts of dopamine being secreted, and that would relate to the nicotinic receptors, particularly the M1 M four receptors. You're preceding the excessive synthesis, and these drugs work in the regions of the brain that are most affected not just by psychotic symptoms, but also cognitive symptoms. The M1 receptors can be more involved in the cognitive arena and the M four decreasing the excitatory changes that are triggered by glutamate in the glutamatergic system, and we're looking at parts of the brain like the hippocampus, for example, which are the seed of memory and cognition. So that's a new understanding and I think potentially a big breakthrough.
Tania (18:18):
We spoke about the psychosis piece. I can only imagine the toll that it also takes on a family. I mentioned that my grandfather was diagnosed with Alzheimer's, and I spoke to you about certain behaviors he had, such as thinking someone stole his money and which
Dr. Grossberg (18:44):
Is very common,
Tania (18:46):
And you look at patients who were sometimes head of households and head of families now with Alzheimer's disease plus the added psychosis to it, how do you counsel families, because you spoke about earlier also it's the community, it's the family. How do you manage, help them manage
Dr. Grossberg (19:09):
Through? Those are great questions, and I think it's particularly important because a lot of families are even embarrassed and reluctant to talk about these neuropsychiatric symptoms, whether it's accusatory behaviors or agitation. They don't understand that these are common important parts of the disease. So unless we as healthcare providers ask about, so one of the things I've been advocating is that if you're a primary healthcare provider that's taking care of an older patient, working with them in the family that maybe has a dementia like Alzheimer's disease at every visit, at every visit, you should ask them and ask the family, has there been any behavior change? Has there been any personality change? Is there something going on other than just the memory and cognitive arenas that we need to be aware of? Recognizing that it's these behavior or neuropsychiatric symptom type changes, whether it's agitation, psychosis, depression and so on, that really are most stressful to families
Tania (20:15):
And
Dr. Grossberg (20:15):
They're the number one reason within Alzheimer's disease where families finally just give up, throw in the towel and say, I just can't take care of mom or dad anymore. And they think about institutionalization right now in the US the number one reason for ending up in an institutional setting like a nursing home is false. Number one is false. So when the family can no longer guarantee safety of their loved one, they start thinking about long-term care. But number two, running neck and neck, right behind that are the neuropsychiatric symptoms like psychosis, agitation against a background of a dementia like Alzheimer's disease. Those are the most distressing, much more so than forgetfulness or some of the cognitive changes. So it's very important to recognize them, to diagnose them and to obviously offer treatment and to educate the family that whenever you go see your doctor or your healthcare provider, make sure you tell them about these kinds of changes. Very common and they're very impactful.
Tania (21:17):
So there's something along that line that we call patient driven science. We talk about it all the time on this show, and it's really making sure that we're developing the medicines for patients. So it's not a product-centered drug development process. It's a patient-centered and really following the needs of those patients. With that in mind, because there's a lot of new studies coming forward when it comes to Alzheimer's, yet it's so many have failed, what do you recommend when we're thinking about designing the right medicines, the right studies for patients? And I'm going to start with clinical endpoints. What is most relevant to families, to patients when we're designing these studies?
Dr. Grossberg (21:59):
So we always have to think about patient and family as being one entity, and then of course, they together with us are part of the therapeutic alliance. There's no doubt about that. But we also want to keep in mind that we want to focus on clinically relevant and impactful symptoms. I like the word impact, and we're not just talking about impact on the patient, but also impact on the care partner.
Tania (22:31):
What, in your opinion, are truly impactful clinical endpoints that we should be looking at? Yeah.
Dr. Grossberg (22:36):
Well, behaviors are clinically impactful. There's no doubt that our focus has been primarily on two areas. Cognition and activities of daily living and of the two activities of daily living to me are much more impactful than just memory or cognitive functions. So knowing about how independent or dependent a patient might be, those need to be increasing areas of focus. And we talk about activities of daily living, two different groups, basic and more instrumental activities of daily living, the basic activities of daily living, and we ask about those is how independent is the person in things like dressing and bathing and grooming and feeding themselves and hygiene and so on. Those are not lost until the more advanced stages of Alzheimer's disease. But there's also what are called the instrumental activities of daily living. Those would be things like being able to go to a grocery store and pick up some items that you need, being able to drive, maybe being able to balance a checkbook or being able to participate in healthcare decisions or financial decisions to even decide what you want to order at a restaurant on a menu rather than depending on someone else to kind of order for you.
(23:57):
Those are important and points that often are not paid as much attention to because we're focused on memory and cognitive arenas. And then the other area is what we've been talking about. Another important endpoint is what impact can we have on behaviors that are going to be very distressing to the family, to the care partners, whether it's psychosis, whether it's agitation, whether it's depression, anxiety, irritability, and so on. So those can be built into clinical trials as well and move higher up the totem pole than just looking at what evidence we have that this new treatment might stabilize memory or maybe slow down some of the cognitive changes. Those have been generally considered secondary endpoints, but it would be nice to move them further up the totem pole.
Tania (24:46):
So let's talk about what's new, what's next in this world of Alzheimer's disease as well as Alzheimer's and psychosis?
Dr. Grossberg (24:53):
Yeah, it's very, very exciting, I think, and you talk about it in two arenas. We're talking about the disease itself and then the neuropsychiatric symptoms, and we focused on a couple of the neuropsychiatric symptoms, psychosis, which is very common and very impactful, impacting quality of life of both the patient as well as the family, the care partners. But let's talk about the disease itself. So up until two years ago, we've been treating Alzheimer's disease once it's diagnosed, and we mentioned we're making a lot of headway and biomarkers and more accurately diagnosing Alzheimer's disease, but we've had what are called the symptomatic therapies. Those have been beneficial and may still be useful, but we haven't been able to really make an impact on disease progression up until almost two years ago when the first of the NOW two disease modifying therapies became FDA approved, and a lot of us are combining the symptomatic approach with the disease modifying therapies in a similar way that you and I were talking about the field of oncology.
(26:00):
Oncology, yes, often combines drugs of different mechanisms to better control various neoplastic kind of disorders. So we're using that as a model in Alzheimer's disease. The other exciting, I think, futuristic model for Alzheimer's disease, and these are being tested now, is to see if the disease modifying therapies, which we are giving to people very, very early in Alzheimer's disease, what if we give them to at risk individuals? Can they over time decrease the risk of developing Alzheimer's disease or maybe delay it together with the very, very important disease, very, very important lifestyle modification approaches to Alzheimer's disease. And as you and I were talking, I personally believe that lifestyle modification is as robust a treatment as any medications. And when you combine lifestyle modification with some of the new and up and coming promising medications, that may have a major impact on the prevalence of the disease as far as onset and maybe even potentially delaying it in individuals who are genetically vulnerable.
(27:16):
Similarly, in looking at the neuropsychiatric symptoms now, we talked a lot about how our old thinking about psychosis is now very different. We now have for the first time an FDA approved treatment for agitation specifically in Alzheimer's disease, but we didn't have before. So I think the future looks very bright both as far as potentially prevention and or delay. We're already at a much better diagnostic kind of sensitivity arena than we were before. And the future looks very bright as far as being able to treat the neuropsychiatric symptoms in a tolerable fashion, specifically psychosis and conditions like agitation,
Tania (28:01):
Especially, I mean, you talk about the combination piece and obviously in oncology that is what we do. We do double. It's triplets sometimes quads,
Dr. Grossberg (28:08):
Exactly. We're also worried about drug drug interactions, and we want a medication that's relatively clean in that regard, recognizing that our older patients, they're often on several different medicines that are needed to control their blood pressure or control their diabetes. Now, you had brought up earlier this other exciting future area of the GLP one agonists. They seem to have anti-inflammatory effects in the central nervous system.
Tania (28:35):
So you talked a little bit about prevention. I want to kind of poke at that because I mean, imagine if we could get to the point where we can prevent, not just slow down, but prevent someone from converting to true Alzheimer's disease. Do you think that's in the future?
Dr. Grossberg (28:50):
I hope so. A number of years ago, someone asked me about how long I thought it was going to be before we had a cure. I don't know what that means, but a cure for Alzheimer's disease. And I went out on a limb and I said, well, maybe in the next couple of decades. That was, I think a couple decades ago, we haven't had a cure yet, but we're moving in the direction of prevention.
Tania (29:13):
So
Dr. Grossberg (29:14):
If a combination of different things together may be able to either delay significantly, delay onset, or perhaps decrease the risk even in individuals who are genetically vulnerable. A recent study, which we haven't talked about was in genetically vulnerable individuals, those that had a first degree relative that was diagnosed, specifically diagnosed with Alzheimer's disease, and now we're looking at the progeny. So it's an adult son or daughter with a mom or dad diagnosed with Alzheimer's disease. Strict lifestyle modification approaches have been shown to be beneficial even in those individuals as well as those that already have the early stage of Alzheimer's disease to maybe significantly slow it down. So one of the areas that I like to emphasize is the power of lifestyle modification in addition to the new pharmacotherapies that are being developed, which are pretty amazing.
Tania (30:11):
Yeah. So what advice do you have for healthcare providers in this field?
Dr. Grossberg (30:16):
One of the pieces of advice that I have for treating healthcare providers, whether it's physicians or PAs or advanced practice nurses who are on the front lines, is the importance of always involving the family is the importance that anytime you see an older patient in your office and there's a concern on the part of a family member about that person having issues with memory or cognitive change, that that needs to be taken seriously and should be promptly, thoroughly evaluated. So we can remedy reversible factors and identify individuals that can benefit from the new treatment approaches to Alzheimer's disease.
Tania (30:59):
Thanks for all the work you're doing and all the work you've done to move this field forward. Sometimes it's hard to see within our generation the big changes that have been made, but from the time you've started until now, you've seen the growth in the field and a lot of it has to do with you and the work you've done. So thank you much.
Dr. Grossberg (31:17):
I won't take the credit, but thank you,
Tania (31:24):
Dr. Grossberg. Now, let's go back in time. What would you tell your 1980’s self if you could?
Dr. Grossberg (31:31):
I would pretty much tell myself to do what I've done, which is pursue what you really, really have a passion for doing. And for me, the passion wasn't just in taking care of patients and families, but in also educating the next generation, because that can be as meaningful as all the hopefully good help that we're providing to our patients and their families.
Tania (31:53):
In other words, you wouldn't change a thing?
Dr. Grossberg (31:56):
Well, no. I really like it the way it was, and I hope to influence young doctors in training to do what I do and have a passion for what they do, and particularly a passion for working with older adults and their families who are so needy and can really benefit from our health.