Do subjective cognitive complaints predict future incident cognitive impairment in people with Parkinson's disease?

 Before we discuss a bit more your article obviously dementia is one of the main complications of people with Parkinson's disease, and it is very interesting to try to detect this at the very earliest stages, but some of the listeners may not be familiar with the concept of subjective cognitive complaints.

What does that exactly mean? How can we assess that in clinical practice and how can we evaluate that a bit more formally?

[00:01:08] Dr. Daniel Weintraub: Essentially, a subjective cognitive complaint means asking a patient, or it could be an informed other, whether he or she has experienced any cognitive changes over time. Generally, we mean changes compared with their pre Parkinson's state. The reason that people are interested in this is because we think now, that it may be a sensitive early indicator.

And um, and it's done variably, I would say um, in the early stages of cognitive testing. Um, And um, and it's done variably, I would say, in the early stages of cognitive testing. Um, And um, and it's done variably, I would say, in the early stages of cognitive testing. There are single questions that people might ask.

There's a more detailed questions that might actually constitute a questionnaire where you'll ask about multiple types of cognitive changes. So it can range anywhere from a single question to multiple questions.

[00:02:10] Dr. Eduardo Fernandez: That's one of the main aims of the study that we're going to discuss now. Would you analyze the data from the Fox Insight study comprising a large cohort of over 20, 000 people with Parkinson's disease? Can you tell us a bit more about this data and the Fox Insight study?

How are this type of complaints evaluated in your

study?

[00:02:33] Dr. Daniel Weintraub: Right. And as you already mentioned, Eduardo, I think it's different than previous studies in that the sample size is enormous. It's over 20, 000 patients. It's self completed questions through Fox insight, which is part of the Michael J. Fox Foundation for Parkinson's Research. It's also different in that patients weren't being specifically asked about cognitive complaints, but asked simply to list the five most problematic issues they have with Parkinson's disease to rank them basically.

We then determined how many times a cognitive complaint was one of those five most common problems. That's how it's different than previous studies, and then it was a very complicated statistical analyses and computer based methodology with human input to classify these symptoms, including cognitive symptoms, into different domains and to then determine how often a cognitive complaint was one of the five most common symptoms.

[00:03:29] Dr. Eduardo Fernandez: Going to the results, you found that about a third of the participants had associated dysfunction in day to day life with this cognitive complaints. Can you tell us a bit more about that and how that's, sits in the context of mild cognitive impairment in people with the earliest stages of Parkinson's.

[00:03:49] Dr. Daniel Weintraub: As part of the Fox Insight, and I had mentioned this previously, in addition to reporting their five most common problems with Parkinson's disease, they also complete a questionnaire called the PDAC 15, or the Penn Parkinson's Daily Activities Questionnaire. And that's a questionnaire that is designed to assess cognitive function or cognitive abilities.

How are one's abilities due to cognitive function? How might memory affect day to day functioning or executive abilities affect day to day functioning? We married the cognitive complaints that people were reporting to their self reported cognitive functioning. And as you were just highlighting

this is a 108 percent increase. And it's a percentage increase. So it's closely at us, the major deformations. I think the only problem I see is, I mean, people are really afraid to look. I mean, it's a concern, but we do have a lot of concern about it. I know there are people who are. And I think there are some people that like to know that.

And I mean, we do have a number of people that are knowing that we, that we have this The only problem I see is we have a number of people who have not been able to help themselves with this disease. Having a cognitive complaint, we're also scoring lower on cognitive function on this PDAC 15.

 We found an association or a correlation at baseline between cognitive complaint and worse cognitive function. And then, what we were most interested in was to determine the sensitivity or predictive value of this subjective cognitive complaint. We removed people who had cognitive impairment or cognitive dysfunction at baseline based on their PDAC 15 score and included only those who had normal cognitive function.

We found that those people who had a subjective cognitive complaint at baseline were more likely to develop incident or new onset cognitive dysfunction over time compared with those who did not have a cognitive complaint at baseline. It showed that perhaps the self reporting of a cognitive complaint at a time when their function is normal was predictive of impaired function in the future over the course of several years in this case.

[00:05:50] Dr. Eduardo Fernandez: I find those results very interesting, that those subjective cognitive complaints can predict cognitive deterioration in a relatively short follow up period of time. One of the things also that caught my eye was that you mentioned you managed to classify the cognitive complaints of the patients in several domains, but some of them were not possible to classify,

and there is one category for those. And what, struck me is that even those sorts of more non specific cognitive complaints, they have the higher risk of being associated with a future cognitive dysfunction.

[00:06:23] Dr. Daniel Weintraub: I'd like to elaborate on the point you just made a little bit. First of all, I think the results are consistent with previous smaller studies that have shown that subjective cognitive complaint, even in those with normal cognitive testing. In studies that have administered a cognitive battery, if you classify people as normal at baseline based on their cognitive test results, if you have a subjective cognitive complaint, you're still more likely to decline over time.

So it does seem to be a very sensitive indicator, even when all other cognitive objective results seem to be negative, that a patient may be just sensing something that's off or different in some way. So I think our results are consistent in that regard. The categories we developed based on self report are kind of consistent with the main cognitive domains that are commonly examined in Parkinson's.

 We also found consistent with previous research, that it's not just executive impairment, executive ability impairment or attentional impairment that occurs commonly, but even memory impairment occurs fairly commonly, these complaints in Parkinson's disease. I think that's consistent with recent research showing that you can really have impairments in multiple or any of the commonly tested cognitive domains in Parkinson's disease.

It's not, really specific to executive dysfunction or attentional impairment, as we once thought. And this other category that you mentioned, the not otherwise specified category for cognitive complaint, is really a fascinating category. I'm reading some of the self reports that we put into that category, because we couldn't fit them anywhere else really, but things such as brain fog, confusion mental sharpness, thinking less clear, less coherent. To me, those are kind of worrisome cognitive complaints when a patient has them. It's not surprising to me that when those were occurring, that they were very predictive of incident functional impairment in the future.

[00:08:17] Dr. Eduardo Fernandez: I guess sometimes it may be difficult for patients to describe their own perception of the cognitive dysfunction. And another thing that I wanted to comment was that at baseline that the people with subjective cognitive complaints had more depressive symptoms, more apathy and more fatigue.

But again, when your results were adjusted by all these variables and still were significant. So that means that even this more non specific cognitive complaints cannot be attributed to other secondary causes.

[00:08:49] Dr. Daniel Weintraub: We did try to control for that statistically, as you said. So we feel fairly confident in the results that this is an independent predictor. The results, though, do demonstrate what we also know already, and this confirmation is that there are certain demographic or clinical characteristics that are associated with cognitive changes in Parkinson's as broadly.

So, higher age, typically male sex compared with female sex. More severe Parkinsonism, in this case the MDS UPDRS parts 4, and then a range of psychiatric symptoms more depression, more apathy, more fatigue, all associated with cognitive changes.

[00:09:26] Dr. Eduardo Fernandez: As we discussed at the beginning there are some specific features of the study. Particularly that most of the complaints are self reported and the methodology. How do you think their results fit into the previous literature? Are the results comparable to the previous studies?

[00:09:43] Dr. Daniel Weintraub: I think they're very, very consistent with previous research and really our goal here was to maybe not find novel findings, it would have been fine if we did, but really to replicate was fine and occurred here, but also to show that this can extended to a much larger scale than we typically do in single site or,

even multi site studies that have very specific cohorts they're people that are seen at a particular center and you're not able to reach a large population. Here we're showing, that you can go to a self completed internet or web based platform and survey thousands and thousands of patients with Parkinson's disease and get meaningful clinical information from them in a way that really allows a much larger scale.

And much less resources to be employed to get important clinical information.

[00:10:35] Dr. Eduardo Fernandez: Your results add more evidence to the clinical relevance of this subjective cognitive complaints as a sort of the earliest stages of cognitive dysfunction, predicting dementia. But as you said, sometimes these are not captured with the most common screening cognitive assessments.

 I have a question regarding when you see people in clinical practice, how can we assess this cognitive complaints? And also what advice would you give to clinicians that have this cognitive complaints that are non specific that you do a screening test, but they are relatively normal and the clinic is busy and is running late.

[00:11:13] Dr. Eduardo Fernandez: How can we assess this complaints?

[00:11:16] Dr. Daniel Weintraub: Those are the much bigger and harder to answer question. Partly because we don't really have many demonstrated efficacious management strategies or therapeutic interventions even for the more advanced stages of cognitive decline in Parkinson's disease. Essentially, we have one treatment, at least in the United States, that's FDA approved for the treatment of dementia, and that's a Cholinesterase inhibitor.

But at the earlier stages, whether it's mild cognitive impairment or even earlier than that, we have no approved treatments. There's a couple of points to make. One is just in terms of management I think clinicians can be mindful of the fact that there's other contributing factors to cognitive decline and Parkinson's disease potentially.

So, vascular factors, if someone has high cholesterol, diabetes, hypertension, obesity. So there may be modifications that are more relevant to somebody who's at a higher risk of cognitive decline over time. For those people that are advocates of exercise or even diet, but particularly exercise, I'd say, or cognitive training those could be advocated for, although I think the evidence is somewhat limited at this time.

Use of other medications that may be harmful in terms of cognition, such as anticholinergic medications, medications with anticholinergic properties. It might be prioritized not to use those types of medications in a person who has a cognitive complaint. There's also I had one other point I was gonna make, I know other symptoms that have been associated or disorders that are fairly common in Parkinson's disease that can also impair cognition. So, a couple that come to mind are orthostatic hypertension, it's been documented that people who have orthostatic hypotension perform worse cognitively when in an orthostatic state where people with obstructive sleep apnea tend to do worse in terms of daytime cognitive abilities if not treated.

So there's kind of working around the margins to improve cognitive performance. And I think the other point is just in terms of clinical management, I think it's helpful for clinicians to keep mindful of it.

Regardless of this cognitive complaint, I personally believe that people should be screened and it can be just a 10 minute screening instrument, such as the Montreal Cognitive Assessment or something along those lines. Probably annually from the time they're diagnosed with Parkinson's, it may not be the most sensitive or specific measure, but I think, some kind of cognitive screening should occur every year.

And in the future, I think more and more of that will be self administered computer, computerized testing. There's more and more testing that's coming online, available, simple, affordable. And I think just allowing somebody to do that in their home environment is much easier than actually having to do it in the clinic setting.

As you said, clinicians tend to be very busy. So I think this is just a piece of a, a bigger puzzle in terms of clinical management.

[00:14:02] Dr. Eduardo Fernandez: That's very helpful advice. Thank you. I've got a last question. We have been discussing early interventions for different aspects of Parkinson's disease and obviously cognitive function is one of the main concerns for patients and clinicians and hopefully disease modifying therapists in several aspects of the disease are in the horizon.

 Do you think that people with subjective cognitive complaints, once they are further characterized in different ways, and hopefully with biomarkers, do you think they would be good candidates or the ideal candidates for any sort of disease modifying therapist for dementia in people with Parkinson's

[00:14:42] Dr. Daniel Weintraub: I think yes and no. Yes, without a doubt, because I think to use that phrase, the canary in the coal mine, there are certain clinical indicators that really predict future cognitive decline. So if you want to enrich your population for a clinical trial, which I think is helpful in terms of sample size calculations.

A population such as this would enrich it. A population with rapid eye movement, sleep behavior disorder would be enriched for cognitive decline. There's any number of features that you could choose. It would really enrich your population for cognitive decline. And then in terms, I personally think that cognition should be a part of every randomized clinical trial for Parkinson's disease, whether it's motor focused or not primarily, because it's just an opportunity to learn about the impact of any intervention on cognition, whether it's an acute study or a long term study.

And to the extent that disease modifying therapies, for instance, target synuclein, as many of them do now, I think those are also right for including people, or at least assessing cognition because the strongest correlate of dementia and Parkinson's disease is diffuse Lewy body formation throughout the cortex, so there seems to be a strong association there.

The problem is In terms of using cognition as an outcome, is if you have people that are unimpaired at baseline, as many of these patients are, the time frame for them to become cognitively impaired or to convert to a new disorder or to have a meaningful change in cognitive abilities over time, maybe a long time, several years, and it's hard to run a clinical trial for that long.

[00:16:11] Dr. Eduardo Fernandez: Okay. Thank you very much. It was a very interesting discussion. I don't know if you would like to add anything else about the topic.

[00:16:18] Dr. Daniel Weintraub: When you mentioned treatment, I think there are a lot of clinical trials underway with novel mechanisms. Some of them are disease targeting, but many of them are symptomatic therapies, but with novel mechanisms of action. So, I think there's a lot of investment from many different parties in cognition and Parkinson's disease.

Hopefully in the coming years, we're going to really see some new management strategies available.

[00:16:40] Dr. Eduardo Fernandez: Thank you very much for your time today. And thank you very much to the listeners. And I encourage them to read the full article in Movement Disorders.

​