. . . borne back ceaselessly into the past

A perennial question for researchers studying neurodegenerative disease is how long before the onset of symptoms the cause of the disease (whatever THAT may be) starts to act on the individual.  This is important for several reasons: 

  • Epidemiological efforts to identify an external cause of a disease such as (in the case of PSP) toxins, infections or trauma could sure use some clue as to how far in advance of the individual’s symptom onset to focus the search.
  • Trials of drugs to slow the progression of PSP would like to initiate treatment as early in the disease course as possible, so identifying patients before they display symptoms would be great.
  • If we ever find a vaccine or some other way to prevent the underlying disease process from starting in the first place, we’d need to know the age by which it should be administered.

Now the very productive Cambridge Centre for Frontotemporal Dementia and Related Disorders at University of Cambridge, led by behavioral neurologist James Rowe, has shed some light on that question.  The PSP study’s first author was Duncan Street, a clinical research fellow working under Prof. Rowe. They have mined the database of the UK Biobank, a non-profit organization operating what’s called a prospective, cohort risk factor study. A famous U.S. study of this type, but just for cardiovascular disease, is the Framingham Heart Study, which started in 1948 and is the source of most our present knowledge of risk factors for hypertension, heart attack and stroke.

The UK Biobank project enrolled 502,504 randomly selected, healthy people between 2006 and 2010, when their average age was 57.  At baseline, they received a raft of neurological and many other tests and were then monitored for the development of diseases of any type.

By the end of 2020, 176 people in the cohort had developed PSP diagnosable by standard clinical criteria.  The researchers found several subtle ways in which the average baseline scores among those 176 differed from the average baseline scores of the group who did not develop PSP or Parkinson’s.  (All of these differences were statistically significant, which means each has less than a 5% chance of being a random fluke.)   

  • Those developing PSP were heavier, on average, by 7.9 pounds though the PSP group had a slightly lower proportion of men (60% vs 62%).
  • Their reaction time was slower by 7.6% and their right-hand grip strength was weaker by 5.2%.
  • They did 15.4% less well in a test of fluid intelligence and 13.7% less well in a test of digit recall. 

The fluid intelligence test posed 13 questions requiring logical reasoning over a 2-minute span and the digit recall score was the longest string of digits that could be repeated immediately, in the same order. 

The researchers also compared the 176 people developing PSP to a group of 2,526 developing Parkinson’s.  Here, as you’d expect, there were fewer differences, the only one being a 10.5% lower performance in the PSP group’s fluid intelligence score.   

The database did not include the year of onset of PSP symptoms, but it did have the year of initial PSP diagnosis. That allowed the average time from the baseline evaluations to that point to be calculated at 7.8 years.  Other research has found a delay from symptom onset to diagnosis to average around 3 years. So, the take-home from this research article is that abnormalities hinting at PSP can be detected, if one looks for them, at an average of about 5 years (7.8 minus 3, rounded off) before symptoms appear. That, in turn, means that the underlying disease process must start some time before that, though we don’t yet know how long before.  The average symptom onset age of PSP is about 63, so any screening test for PSP should be given no later than the mid-50s.  But would giving the test in the early 50s or late 40s — the better to institute treatment early — be too soon to detect many cases of PSP?  We don’t know.  Once we settle on a test or a battery of tests that works in early-stage symptomatic PSP – an “early trait biomarker” – we can try it out in a pre-symptomatic cohort of people in their 40s and 50s who score below a certain cutoff on a screening battery.

One final thought:  Back in 1996, I published a paper showing for the first time that people with PSP had completed slightly fewer years of formal education than matched control individuals without PSP.  That has been confirmed by multiple subsequent studies, but the reason for it is unknown.  Here are three possibilities:

  • Does the disease start subtly in the first couple of decades of life and reduce one’s ability to do schoolwork? 
  • Or is it that people less inclined to stay in school for whatever social or economic reasons develop fewer synapses in their brains, which makes any subsequent neurodegenerative process more likely to produce symptoms and to come to medical attention? 
  • Or is it that people with less education are more likely subsequently to live or work in areas with toxins that contribute to the cause of PSP?

If the first explanation (early-life onset) is correct, then administering a screening test battery at any point in adult life might be able to detect early stages of PSP, providing opportunity for disease prevention to be instituted even earlier.

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