A genetic reason for cognitive impairment among men on ADT?

In a paper just published on line, we finally have some sound, prospective, comparative data confirming that androgen deprivation therapy (ADT) is associated with significant risk for effects on mental cognition among men with prostate cancer when used for 6 months or longer.

In their paper in the Journal of Clinical Oncology, Gonzalez et al. discuss data from a cohort of 238 men in three groups:

  • Group A comprised a set of 58 men with prostate cancer who were all treated with ADT for at least 12 months.
  • Group B comprised a set of 88 men with prostate cancer who had all been treated by radical prostatectomy alone and who were matched (by age and education) to the men in Group A.
  • Group C comprised a set of 84 men who did not have prostate cancer, received no treatment, and who were again matched (by age and education) to the men in  Group A.

All 238 patients were evaluated for cognitive function (and were genotyped) at baseline and then re-evaluated for cognitive function at 6 and 12 months. The baseline evaluation of the men treated with ADT was carried out before initiation of ADT.

Let us be clear: This was not a randomized, double-blind controlled trial. It was only a matched, controlled trial. But is was prospective and it was controlled, which is a lot better than any retrospective data analysis.

Here are the findings presented by Gonzalez et al. (which are also discussed by Susan Slavin, MD, on an ASCO podcast dated May 11 that is freely accessible on line):

  • Groups did not differ in their cognitive performance at baseline.
  • Men treated with ADT
    • Had higher rates of impaired cognitive performance over time relative to all controls (P = 0.01).
    • Were more likely to demonstrate impaired cognitive performance within 6 and 12 months (P for both comparisons < 0.05).
  • Baseline age, cognitive reserve, depressive symptoms, fatigue, and hot flash interference did not moderate the impact of ADT on impaired cognitive performance (P for all comparisons ≥ 0.09).
  • In exploratory genetic analyses, GNB3 single nucleotide polymorphism rs1047776 was associated with increased rates of impaired performance over time in the ADT group (P < 0.001).

The authors conclude that men treated with ADT

were more likely to demonstrate impaired cognitive performance within 6 months after starting ADT relative to matched controls and to continue to do so within 12 months after starting ADT.

They go on to state that

If confirmed, findings may have implications for patient education regarding the risks and benefits of ADT.

Now we understand that the degree to which men’s cognitive performance can be affected by ADT is variable: some men are severely affected quickly; other men may be affected only after some time on ADT (a couple of years or so); and then there are men who seem to be very minimally affected. We are distinctly pleased to see the publication of the results of this research. However, …

Let us also be very clear that every physician giving ADT to a man with prostate cancer should already have been aware that impairment of cognitive function is a risk factor for treatment with ADT. There has been good and extensive case evidence for this for years. The paper by Gonzalez et al. now makes any failure to advise patients of this risk and to monitor patients for this effect unacceptable.

What is particularly interesting in this paper, and which most certainly requires further study, is the suggestion that a particular single nucleotide polymorphism or SNP seems to be strongly associated with this risk. One has to wonder whether this is a “real” association that may be manageable in some way or whether it is an inevitable consequence of massively reduced serum testosterone levels in men with this particular SNP.

9 Responses

  1. It certainly pleases me that despite over 5 years on continuous Lupron, then on/off Lupron for another 13+ years, then adding Zytiga to Lupron for the past 44 months, I have not experienced any loss of cognitive function!

  2. Within 3 months of starting ADT, my husband began showing signs of cognitive impairment. No one took our concerns seriously. We were assured that once his testosterone levels returned to “normal”, his cognition would return to normal as well. It didn’t. … He is now dealing with early to mid-stage Alzheimer’s disease. Did the ADT trigger the Alzheimer’s? Is there some genetic anomaly which makes some individuals more susceptible? The ADT might have saved hubby’s life from the prostate cancer, but the Alzheimer’s is going to take him from me.

    Thanks for, posting this, Mike.

  3. It might be interesting to see if there is a correlation between cognition and the patients’ careers.

  4. @mcpomaack How do you know that? I told two doctors that I wanted a full battery of neuropsychological tests, as I had been on ADT for 3 years. One looked at me like I was nuts, but I had read enough about cognitive impairment from ADT to take the cognition threat seriously. Right now, all I know is that I do not know if Zoladex got me cognitively impaired.

  5. Dear George:

    The only way to know whether you have cognitive impairment now as opposed to the situation 3 years ago would be if you had baseline data from 3 years ago to compare new data to. The same is true for Chuck Maack over near to 20 years. And since we are all getting significantly older anyway, it might be hard to tell the degree to which a small amount of cognitive impairment was a function of ADT or the aging process. If you “do not know if Zoladex got you cognitively impaired”, then it probably didn’t. The people who are affected in this way are usually very conscious of it. It’s not like Alzheimer’s or dementia. What tends to happen is that you become unable to do two things at once or think as fast as one used to be able to do or concentrate as effectively. And one knows it.

    You both appear to still have decent cognitive function to me (after I have been watching your posts and comments for 5+ years on this site).

    By contrast, I am well aware of patients whose cognitive capabilities have been severely damaged, who are much younger than either of you, and for whom that loss of cognitive capability has been seriously problematic. (Bill Manning, who writes his blog posts on this site, is a publicly “out” case in point.)

  6. Dear Sitemaster:

    That is bad, I didn’t know it could be that serious. I had only read about multitasking and spatial impairment. I had both but seem to have recovered now (seem to myself?). The point about neuropsychology concerned other deficits, say reading speed and list comprehension. I am curious but should have realised the baseline problem. The point about knowing is philosophical. What can we know about our own minds, with or without help. But you can ask “Do I know X about myself”, with regards to many mental capacities X. Opinions differ.

  7. Here again we have a problem with the term ADT. Did this study define what type of ADT was evaluated, testosterone suppression (Lupron) or DHT suppression (Avodart) or anti-androgen (Casodex)? I was on Lupron, and noticed the cognitive decline and switched to the last two and regained my brilliance! My testosterone is 600+, but my DHT is 1.6 and my PSA stays low.

  8. My brilliant father, athlete, and writer, who has kept himself in peak condition even though 89, just hosted a dinner party for 40 of his prior students in May, but now walks into oncoming traffic, cannot find nouns, and is confused about how to use a credit card or make a phone call! Being a clinically trained psychotherapist myself I decided to check the literature for current research. I am dumbfounded to find the 2015 study. We’ve been complaining about his cognition and are told it is his age! I just hope the cognitive changes can be reversed. This is no quality of life.

  9. Dear Carol:

    As someone who has seen several relatives in their late 80s and early 90s quickly lose their mental capabilities over a matter of a few months (although none of them had prostate cancer), I sympathize with you about you father’s sudden loss of his ability to “think well” for himself. We still know very little indeed about why this happens. The problem is that it appears to be able to happen quite quickly for all sorts of different reasons — and treatment with ADT may stimulate just one of these. However, such effects as a consequence of ADT are far from inevitable. Chuck Maack — who wrote the first comment above — has been on ADT for years now, and while he and I don’t always agree about everything, as far as I can tell his mental acuities appear to be very similar to those he had nearly 20 years ago when I first met him — although I think he is now 91 or 92.

    Unfortunately I am not aware of any form of management that can reverse this effect once it has started (whether the patient was on ADT or not), and it does need to be appreciated that this loss of mental acuity is an extremely common, age-related effect in people of 80 years and older.

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