Dr. Agronin: The first priority is to establish some rapport with the person and his or her caregiver. I emphasize the caregiver because if you don’t have a reliable informant you simply will not be able to do an accurate evaluation. There is a tremendous amount of uncertainty and misdiagnosis; it is a very complex evaluation to do for several reasons. Number one is that we have no simple, reliable, accurate test as of today to make a diagnosis of Alzheimer’s disease or any other neurocognitive disorder. We are getting closer, but when you look at the accuracy rates for Alzheimer’s disease, for example, it depends on looking at multiple sources of data over time. To me that relies on having some rapport with the individual so you can get a sense of the whole range of their strengths and limitations. You can get the most accurate information from the caregivers, and that helps put together the story. The other thing is that unlike many other disease states we can’t look at tissue; we don’t do a brain biopsy per routine, and even with the new imaging it only approximates what we are trying to look at in the brain. I have learned this lesson when we have done several clinical trials that involved autopsies, and the postmortem results of the brain biopsy are always a whole grab bag of different pathology. In several cases, the results were not consistent with what we thought the patient had after years of observation.
TCPR: Let’s say a patient comes in to the psychiatrist’s office complaining that his memory isn’t what it once was and he is worried that he has Alzheimer’s disease. How should the psychiatrist proceed?
Dr. Agronin: Memory concerns should always be taken seriously and psychiatrists should be able to do a basic workup. Obviously, the older the person is, the more likely there might be a memory disorder. But at any age, it is very important that we do an evaluation that includes basic lab work, an examination, and some questions about changes in mood and daily function—such as sleep and appetite—just to get a sense of whether there is depression or anxiety that could be a contributing factor. Psychiatrists should always ask about substance use because lots of older individuals are drinking more alcohol than they should be or that they may admit to. I find that this is often a hidden factor and sometimes, without an informant, you are not getting a clear history.
TCPR: If somebody is drinking, is the memory problem limited to the times when they are intoxicated or hung over, or does it extend to other periods as well?
Dr. Agronin: Well it depends. If someone has memory issues, often what happens is that they have their one cocktail and then an hour or two later they have what to them is their one cocktail because they have forgotten that they’ve had one before. I find, especially in couples in which this is a lifelong habit, the partner often doesn’t notice that there is an issue or a problem and they might even be part of it. There may be reversible factors that are either causing or worsening the memory issue, which can be addressed. With drinking, if there is no underlying brain pathology, memory problems may just extend to the time around which they are drinking. But individuals who are drinking more than they should have higher rates of falling and injury, which can contribute to memory problems. And, while alcohol might help people fall asleep initially, it disrupts sleep architecture and that, in turn, can have a negative impact on memory. Also, a lot of individuals are taking anxiolytics and/or sleeping pills at the same time they are drinking alcohol, so you can have an additive effect. This is why you need to review all medications. Sometimes statin medications in a small percentage of people can cause some mental fuzziness. Narcotics and anticholinergic medications also can have significant effects on memory.
TCPR: You mentioned labs. Go through with us the basic labs that should be ordered in a workup.
Dr. Agronin: In general, it is rare to find a lab value correlating with a cognitive disorder. But what you are looking for are lab abnormalities that point to certain conditions—severe anemia, hypothyroidism, and parathyroid issues such as an adenoma leading to excess calcium in the blood—all of which can lead to some cognitive problems. If someone is diabetic, I would look into how well their blood sugar is controlled, and hypertension might indicate that someone is having small strokes. Individuals with both hypertension and diabetes are some of the highest risk individuals for vascular dementia and Alzheimer’s disease. So these are everyday factors that can loom very large in terms of causes, or probably more likely, exacerbating factors.
TCPR: So we do our basic labs and we don’t find anything obvious. The patient is complaining of some kind of memory loss. How do we determine if this is a normal part of aging, mild cognitive impairment, or early Alzheimer’s dementia?
Dr. Agronin: In early stages, it can be impossible to know. So for psychiatrists, what I recommend is to have some screening instrument: either the Mini-Mental Status Examination (MMSE), the Montreal Cognitive Assessment (MOCA), or the Mini-Cog. Have someone in the office trained to conduct the screening so they do it consistently and can be rather expeditious with it. If someone fails the Mini-Cog, or if on the MMSE or the MOCA they are scoring below 25 to 26 or they have a higher score but they have very significant complaints, then I would refer them to either a memory center or a geriatric psychiatrist or neurologist who specializes in neurocognitive disorders to do a more thorough evaluation. The important things for psychiatrists to look for would be: is there any depression or anxiety that might be compromising memory or other cognitive function? Individuals with severe depression can have a pseudodementia in which their concentration and attention and motivation are so poor due to the depression that their memory suffers as well. With those individuals, once you successfully treat the depression, their memory should get better. Though it should be noted that some research indicates that they are at a much higher risk for later developing dementia or that depression may itself be a prodromal symptom of neurocognitive disorders including Alzheimer’s disease (Alexopoulos GS et al, Am J Psychiatry 1993;150(11):1693–1699). It’s important for clinicians to realize that even if there is depression and even if it does appear to be affecting cognition, it still might be comorbid with an actual neurocognitive disorder. Sometimes the mistake that psychiatrists make in these cases is that they put someone on an antidepressant, but they may not follow up quickly enough and deeply enough to assess cognition once they have had a trial of the antidepressant. Often the depression goes hand-in-hand with Alzheimer’s disease or some other neurocognitive disorder.
TCPR: What kind of neuroimaging should these patients have?
Dr. Agronin: An MRI is always best because it will show everything that you are looking for on a CT scan, but will also pick up smaller subcortical lesions. And what I am looking for, especially in more acute onset of cognitive changes, would be meningiomas, subdural hematomas, and lacunar infarcts.
TCPR: So we’ve done the labs and neuroimaging and nothing jumps out in terms of comorbid depression, or substance abuse, or anything else that’s obvious. You now have a patient with some degree of cognitive impairment but no clear cause. What’s next in the evaluation?
Dr. Agronin: Neuropsychological testing is pretty much the gold standard in terms of knowing whether there is any significant cognitive impairment and what is the extent of it.
TCPR: Do we send everyone who comes in complaining of memory issues to neuropsych testing?
Dr. Agronin: Not necessarily. If I meet with someone and find that there is just mild intermittent forgetfulness and they are very articulate about what they are forgetting, I am less concerned. I am more concerned about someone who is not aware of forgetfulness, or not aware of being repetitive and the informant is telling you that, or you are seeing changes outside of memory such as word-finding difficulty, disorientation, visual-spatial changes—I would order testing in any of these kinds of patients. But even if you decide to hold off on neuropsych testing, I would reassess what is going on after three to six months and if there are persistent problems or changes, then I think you are obligated to get a neuropsychological profile done.
TCPR: And what are you likely to find on neuropsych testing?
Dr. Agronin: Technically speaking, neuropsychological testing should show that they are at least about a standard deviation below their peers as the formal criteria for mild cognitive impairment (MCI). In practice, if we see someone who has persistent memory changes that are a nuisance but they are still functioning pretty well, we usually will label that MCI as a provisional diagnosis, with or without testing.
TCPR: Let’s say the neuropsych testing comes back a standard deviation below the norm and the report says something about mild cognitive impairment. How do you communicate that to the patient without being overly alarmist while at the same time providing an accurate picture?
Dr. Agronin: I meet with them and I basically lay all the puzzle pieces out on the table. I will recap the history that they reported to me, factor in any medical issues, any medication issues, and psychiatric issues that might be a concern and what the neuroimaging showed. I will then bring in the neuropsychological test results and we look at the big picture and I will give them an impression based on that. I may say, “When we look at your history of slow but steady cognitive decline over the last year or two, we haven’t identified any specific factors that appear to be causing this. For instance, the brain scan didn’t show anything different than a normally aged brain. The neuropsychological testing showed memory impairment more than we would expect relative to your age, and the concern is that this may be early Alzheimer’s disease. We can’t say this with certainty and we have to monitor you over time. We are here to work with you, to be a partner with you, to follow you over time. And we can also talk about some of the different treatment options ranging from lifestyle changes—what we call brain healthy lifestyle—to cognitive enhancement medications to clinical trials.”
TCPR: I am going to pretend I’m the patient here. “Does this mean I have dementia and why can’t you tell me for sure?”
Dr. Agronin: I would explain, “The information indicates what we call a neurocognitive disorder and of the different types, it is most consistent with early stage Alzheimer’s disease. The only way to know with 100% certainty is you have to actually look at the brain tissue and obviously we are not going to do that here.”
TCPR: Then the patient might ask, “What does this mean in terms of my future? Does this mean that next year I am not going to be able to do anything?”
Dr. Agronin: I would then say, “Well, if this is Alzheimer’s disease we know that it is a progressive illness. I would liken it to a glacier moving. It is very, very slow; the changes unfold differently for different individuals. We don’t have a cure for it, but there is a tremendous amount we can do to not only lessen the impact of other factors that can worsen it, but there are also some symptomatic treatments we can consider and there are also clinical trials that might offer the hope of slowing down the course of the disease itself.” At this stage of the disease I emphasize with individuals that we are going to work together and we will address every management issue. I don’t get into details about later stages of it because I think that may only worry individuals and I don’t think it is helpful to the discussion. For someone with early stage Alzheimer’s disease, if you can address anxiety and depression in both them and the caregiver, they do better. If you can help them understand the benefits and limitations of a cognitive enhancing regimen, they will be more likely to adhere to it and to maximize its benefits. If you can make certain that their lifestyle is healthy—getting enough exercise, a good diet, having appropriate supervision, not doing dangerous things that are going to cause more problems—they are going to do better in the long run. This is just the tip of the iceberg in terms of management issues so I work with a whole team. I have a neuropsychologist, a social worker, research staff, and support staff to enwrap the patient and their caregivers in a supportive system and I find that everyone does better over time when you take this approach.
If you can make certain that their lifestyle is healthy—getting enough exercise, a good diet, having appropriate supervision, not doing dangerous things that are going to cause more problems—they are going to do better in the long run.
~ Marc Agronin, MD
TCPR: What is your approach to prescribing cognitive enhancers and explaining to patients what they can expect in terms of efficacy?
Dr. Agronin: Well, what I tell patients is that there are a number of cognitive enhancing medications that are approved by the US Food and Drug Administration, but they are not cures. In general, what the data indicate is that people tend to do better on them than off of them so it is worth a trial. We are doing this over the long haul because this is a disease that can go on for a decade or more. I will start one of the acetylcholinesterase inhibitors and I will make sure I maximize the dose because if you don’t, you are simply not getting the benefit from it. Then once they are stabilized and if they are tolerating it, I will add memantine (Namenda). For more on medications, see “Namzaric and Other Cognitive Enhancers for Dementia” on p. 1).
TCPR: How long do you continue using the dementia medications?
Dr. Agronin: There are limited data showing that you get the same benefit with some of the acetylcholinesterase inhibitors over years and not just the several months that most clinical trials look at (Rountree SD et al, Alzheimers Res Ther 2009;1(2):7). In clinical practice, that has been my experience and my impression, so I continue people on them for the duration. I have had a few instances where in later stages when you stop the medication, sometimes you can get declines or changes and that it is hard to get back to their previous baseline if you restart it. You know, arguably, the benefit you get in later stages is quite modest. There are diminishing returns with these medications as you progress in disease because you just have fewer cells that even are producing acetylcholine. If someone is in a terminal phase, it is usually appropriate to withdraw the medication because you might not be seeing any benefit at that point. I take just a very practical approach to it. I want to emphasize that, to me, the use of medications is within the whole context of working with the person and treating them.
TCPR: Thank you, Dr. Agronin.