Alzheimer Disease: A 3-Step Diagnostic Formulation Process

Alireza Atri, MD, PhD: Turning to you, Brad, what are the decision points in the 3-step diagnostic formulation at this point? And once you have a thought that this may not be normal aging and you’ve developed an idea by the kind of functional status, and then are thinking about the kind of behavioral syndrome, and you’re defining it a little bit, and then you’re going forward to determine, potentially, cause, how do you choose your tests, your tiers? How do you think about that?

Bradford C. Dickerson, MD: It really is fairly uniform, yet personalized, I guess I would say, in the sense that, for example, I was seeing a patient earlier this week who, clearly, the first time he came to me he had seen others before me, but had dementia. He had given up driving himself. He was in his 50s and was no longer able to work. It was very clear from the beginning, with the history being provided by his family and not very clearly by him—he wasn’t really able to provide it—that he had dementia and it might not even be mild any more. It might be bordering on moderate stage dementia. It was a bit surprising that he had only undergone a more detailed work-up at this stage of the game, because it clearly had been going on for a couple of years. He really didn’t have a lot of other medical issues to speak of.

And so, after some cognitive testing that he performed poorly on, I ordered an MRI [magnetic resonance imaging] and had him come back with his family. It was very clear that he had a cortical atrophy, a medial temporal lobe atrophy that was consistent with Alzheimer disease, and the history was consistent with that. I felt pretty comfortable with the 3-step formulation of dementia with an amnestic dysexecutive multi-domain syndrome likely due to Alzheimer disease based on the history, examination, and an MRI.

In some cases you can be pretty comfortable with the diagnosis just using what I consider to be that first tier of looking at the brain. I think it’s really fundamental that if we’re entertaining the possibility of a diagnosis of Alzheimer or related dementia syndrome that we look into the organ that is of interest. It could be with a CT [computed tomography] scan. But I think in most practice settings an MRI is very readily obtainable and provides much more detailed information, particularly about whether there’s also cerebrovascular disease or the common accompaniment to Alzheimer disease, which is cerebral amyloid angiopathy that might have already produced some microhemorrhages that can be seen on MRI but would otherwise be unrecognized, in part because that type of a finding increases a person’s risk for a major cerebral hemorrhage, especially if they’re given anticoagulant medication.

So MRI is useful for a variety of purposes. In more complex patients, like some of the ones that Lynn was just talking about, even establishing whether the person has mild cognitive impairment or subjective cognitive decline, or mild dementia may require the involvement of my neuropsychologist colleagues, and doing the kinds of detailed testing that are available by working with a neuropsychologist. And so, that first tier can sometimes really require the involvement of a neuropsychologist or a dementia subspecialist to establish.

I think it may also be necessary, to establish the cognitive behavioral syndrome, to involve a multidisciplinary team of experts including, potentially, a speech-language pathologist, if the person has an aphasia. And so, that may require additional consultations and referrals.

And then in thinking about level 3, step 3, or the likely etiology, it’s so common that even when we think a person may have Alzheimer disease or another neurodegenerative disease that the MRI is not diagnostic, even if you look carefully at it yourself and have training. In that case, an FDG-PET [fluorodeoxyglucose positron emission tomography] scan can be very valuable if it’s accessible in your practice setting, because it’s a basic measure of brain function that Medicare approved more than 15 years ago now for the diagnostic evaluation of possible FTD [frontotemporal dementia] or Alzheimer disease.

With a Medicare beneficiary, if you’re in the right practice setting and have access to this specialized test called an FDG-PET scan, which isn’t that difficult to access—it’s commonly used in cancer monitoring and there are often imaging centers that are accessible to most, not even major metropolitan areas, but even some more rural areas—that often is more sensitive to patterns of reduced brain function that might be suggestive of 1 of these diseases.

And then in more specialized practice settings, you may consider cerebral spinal fluid measures or more specialized PET scans looking for evidence or for biomarkers of Alzheimer disease or a related diagnosis.

That’s when you’re really entertaining a concern for these conditions, and are considering taking it to the subspecialty level. There are obviously many patients who need other kinds of tests that might be considered second-, third-, or fourth-tier tests, whether they’re blood tests, spinal fluid tests, or things like sleep studies, depending on the concern for some of these other conditions that may be medical conditions or may be brain conditions that could be causing or contributing to the person’s overall symptom profile.

Alireza Atri, MD, PhD: I think you make a great point out of really targeting in a stepped way, and not doing too little, or ignoring, and not shot-gunning everything. And I think we’ve seen that in practice from our colleagues one way or another. Where you draw that line depends on your proficiency and what the patients and the families need as far as the confidence in the diagnosis.

We used to always hear that Alzheimer disease was a diagnosis of exclusion. We weren’t sure, you know? But it sounds like it’s becoming a diagnosis of inclusion with some of the tests and the biomarkers you mentioned.

Mary, you had mentioned the kinds of laboratory panels, and Brad mentioned the MRI scan. Do you send those in in your practice? And what blood test would you send as the first tier?

Mary A. Norman, MD: I think when we have somebody who comes in with this with a cognitive concern, there is a group of labs that we generally would recommend, mainly looking for other things that could contribute to cognitive loss—things like a simple CBC [complete blood count] related to dementias, the blood, anemia. A CMP [comprehensive metabolic panel] that would look at kidney function, renal function, and electrolyte abnormalities, or hypocalcemia. That could all, potentially, affect cognition.

Thyroid testing. Vitamin deficiencies. B12. Folate. Markers of inflammation. Homocysteine levels. All of these may contribute. It’s rare that we find a truly reversible cause, but frequently we will find other contributing causes. And I agree with you completely with the brain imaging. To have an MRI is, I think, gold standard for most. In my practice, I have a lot of very senior patients who, for other reasons, may not be able to, or refuse to do an MRI. So at least having a CT scan of the head is, I think, essential in any diagnostic work-up.

Alireza Atri, MD, PhD: Great. And I know that due to participation, for the first time, the Alzheimer’s Association is putting out clinical practice best guidelines for evaluation. It sounds like the guidelines will be out early in 2020, which actually gives a stepped approach to the diagnostic process, evaluation process, including what to ask, and specific recommendations about tests and when to use them. So that’s something we can all look forward to seeing.

Transcript edited for clarity.