Parkinson’s Disease Trials Need Better Markers Of Cognitive Changes
By Deborah Borfitz
May 10, 2023 | The instruments commonly used to assess cognitive decline in Parkinson’s disease (PD) patients enrolled in neuroprotective clinical trials are “poorly suited to the task,” according to industry consultant Travis Turner, Ph.D., assistant professor and director of the neuropsychology division at Medical University of South Carolina, and senior clinical director for movement disorders at WCG. “I strongly suspect that good interventions have been discarded because [of] the tests that were trying to measure efficacy.”
Turner’s conclusions were highlighted in a study that published recently in the Psychopharmacology Bulletin. Cognitive deficits in the first five years of the disease appear to be more myth than reality, based on the results of a battery of standardized measures of memory, visuospatial functions, processing speed, working memory, and verbal fluency taken over a five-year period through the Parkinson's Progression Markers Initiative of the Michael J. Fox Foundation.
Remarkably, no other researcher had mined this repository of information to address this question, says Turner. The landmark study included both newly diagnosed PD patients and healthy controls so rates of change could be examined between the two groups on the various cognitive measures.
After accounting for confounds of motor symptoms (e.g., dominant-hand tremor and rigidity) on a processing speed test, no differences were seen between PD patients and controls. While working memory appeared to dip slightly faster in early PD compared to the healthy controls, all other domains remained similar, says Turner. Faster decline was not associated with lower baseline cognition within the PD group.
For PD trials investigating disease-modifying agents, he says, existing markers of cognitive changes are “unlikely to yield much” in terms of actual cognitive decline in early PD. He wouldn’t recommend their use even as secondary, exploratory efficacy outcomes.
Unexpected findings of Turner’s latest work have implications for clinical trial outcome selection and study design. All the studies for disease modification in early PD he has ever worked on have screened out people with signs of cognitive impairment, he says, and his new advice to industry sponsors is to focus on something other than a cognitive outcome.
“You only have so much time with each participant and every little measure you add is a burden on them and on research coordinators,” Turner says. Testing multiple simultaneous hypotheses in any case raises the risk of type I errors, otherwise known as findings of false significance.
“As a neuropsychologist I use these standardized tests, [and] I like them, but I don’t think they’re suited for the purpose of capturing early changes... [in] disease progression,” says Turner.
For the Parkinson's Progression Markers Initiative, healthy controls were screened in based on having no indication of even mild cognitive impairment (conservatively, a score of 27 or above), Turner says. The screening test was the Montreal Cognitive Assessment (MoCA) made famous when reportedly aced by former President Donald Trump.
A few other studies have looked at these cognitive features in early PD, he adds, but the clinical population has been matched to the control group based on relevant demographics. Here, the reverse happened where researchers ruled out mild cognitive impairment in a control group to make a fair comparison of changes in neuropsychological functioning.
“My suspicion was of those [in the PD group] who had MoCA scores below that cutoff would decline faster over the first five years, maybe [because] they’re getting some dementia with Lewy bodies... or some of the variants of Parkinson’s that tend to progress quicker, like the akinetic-rigid subtype, but they didn’t,” says Turner. “The lines were remarkably parallel over time for all those measures, and I was rather surprised to see that.”
The objective of the study was to learn which of the measures of cognitive deficits routinely used in the clinic best capture a signal of early cognitive change and are thus best suited for use in PD investigational agents that are supposed to be neuroprotective, he says. There is also a lot of industry interest in a global composite that could perhaps capture changes in a more generalized way.
“I was hoping to have some data that would point me toward one of these tests so I could confidently say this is where the signal’s at, and I just don’t,” Turner continues. The tests are still good for studies of symptomatic therapies for people with mild cognitive impairment or dementia. “They are not perfect, but they are well known, well studied, and we have the psychometrics to know their limitations… but there is a lot of room for improvement.”
The takeaway for future trials looking at a medication intended to help with cognition is to “be sure there is at least some measurable mild cognitive impairment [in the study population] to start with because the PD-normal [participants] are performing just like the controls and not declining at a faster rate. Normal is not going to get better.”
To complicate matters further, it is still somewhat of an open question whether it is necessary to start off with those who have impairment when investigating a therapeutic for cognitive functioning in people with PD. For people with anything beyond very mild impairment, it may already be too late to derive any benefit from the drug.
Turner references a study he did years ago with atomoxetine, a non-stimulant medication used for attention deficit disorder, which concluded it didn’t help individuals with PD with mild cognitive impairment. At the time, without the advantage of the new data now in hand, he had been “thinking and debating and almost making the decision to focus on people with normal cognition at baseline, hoping to make some incremental improvement on [scoring around] some of these more challenging tests.”
Moving forward, Turner believes that PD research will need to adopt more personalized approaches as a reflection of the disease’s heterogeneity. “There is an expression that if you’ve seen one person with Parkinson’s, you’ve seen one person with Parkinson’s,” he says, despite the constellation of symptoms indicative of the diagnosis— e.g., bradykinesia (slowed movement), tremor, muscle stiffness, and speech and writing changes.
To find a cure for PD, or stop its progression, will require knowledge of the underlying causal mechanisms “more specifically for each person,” Turner says. The pathways could variably be genetic, neuroinflammatory, or environmental. Drug developers are already working on more targeted interventions based on the understanding that certain gene variants can disrupt the normal production of a protein or prevent the breakdown of different types of molecules.
As an industry consultant, clinical neuropsychologist, and researcher, Turner is working at the ground level on Parkinson’s disease and related disorders, and he says that experiences in one arena tend to naturally benefit the others. Among studies he currently has underway are ones looking at apathy and communication impairment in PD, eye tracking for patients with supranuclear palsy, and deep brain stimulation for treating PD and essential tremor.
In approving new medicines, the U.S. Food and Drug Administration (FDA) has “wisely been looking more and more at functional measures of change” rather than solely focusing on cognitive test performances, says Turner. Most recently for Alzheimer’s disease, the FDA has authorized aducanumab and lecanemab (which seems to elicit amyloid-related imaging abnormalities less often), but he suspects many other such useful medicines have been prematurely rejected because the efficacy yardsticks used in trials weren’t capturing signals of functional cognitive change.
“I want to see better studies done [because] I want answers,” Turner says. “I want to see a cure for Parkinson’s and Alzheimer’s, and I want to see better therapies.” He hopes also to inspire development of objective tests that truly capture early cognitive changes or “subtle progressions that occur over time,” and his life’s work has been in pursuit of that holy grail.