AD Paradoxical Lucidity as a goal: Ritalin, caffeine, SAGE-718?

“Paradoxical Lucidity” is a very rare phenomenon in Alzheimer’s Disease (AD) and dementia: a person “returns to their senses”, is seemingly able to converse normally, recognize loved ones, and can even joke a bit!

Sadly, these episodes seem to be temporary, and many times are noted when the person living with dementia may be dying. Striking accounts are documented in news articles and research articles.

Recently, researchers wrote of trying to pin down a definition that would be practical for studying these occurrences.  A parallel situation in cancer and other diseases has been called “terminal lucidity.”

Could it be that someone’s “strength of personality” somehow breaks through the fog?  Does it imply that there is a core of consciousness and ability that is working, but being inhibited until a person’s last days?  Could this be like awakening from a coma?  As mentioned in the last post here, one group recently wrote that perhaps AD is really a “disorder of consciousness,” usually a term for stupor and coma.

Can “lucid recovery” ever be a goal of Alzheimer’s and dementia therapeutic trials?   Most results seem full of incremental, surrogate imaging changes that may or may not be meaningful. The recent FDA approved drug Aduhelm does not seem to provide clearcut cognitive recovery or halt ultimate deterioration.

If it is assumed that amyloid beta may be the “fog,” what lifts it, even temporarily, to allow for paradoxical lucidity? For the next billion dollars spent in research, why not go after the real prize? Surrogate goals can be helpful, but not if one loses sight of the real target.

There is at least one trial for an agent that is showing promising cognitive improvement according to the company,  purported to work on a non-amyloid pathway, called SAGE-718,  in as few as 14 days. The press release is linked.

This arena of research has not been ignored.  Many obvious candidates have been already tested. Thirty years ago a group looked at the drug naloxone, known as an antidote to some of the cognitive effects of opioids; the brain has its own opioid system.  Various dose levels were tried, but none seemed to work.  Modafinil, a stimulant for the excessive sleepiness in narcolepsy, has been used in at least one small trial, so the effects were hard to gauge using Cochrane criteria.

Amphetamine drugs in medical usage reports for the elderly was the subject of a general review in 2020.  The authors tabulate a case report of frontotemporal dementia with cognitive improvement, and two cases of Lewy Body dementia with cognitive improvement. The authors also looked at reports of usage for depression and other conditions without dementia,  concluding that many reports showed “encouraging results.”

Methylphenidate (Ritalin tm) is generally grouped with amphetamines, as in the review above.  Last year, a fairly large study of methylphenidate was reported specifically for apathy in dementia, showing modest results in apathy scores, but there were no significant changes in cognitive or functional tests.

 

“A Brewed Awakening” is the nice pun of a title of a review out this year [behind a paywall] of caffeine effects in dementia, both positive and negative.  They cite a neuroimaging study of ~400 subjects using PET for amyloid beta,  PET- FDG, along with MRI.  Those investigators showed that these subjects had less amyloid if they drank >2 cups of coffee/day, and imply those coffee drinkers also had less imaging neurodegeneration than expected.  Should coffee intake be assessed as a confounding factor in monoclonal trials??

From Kim JW Byun MS et al, Coffee intake and decreased amyloid pathology in human brain, 2019. https://doi.org/10.1038/s41398-019-0604-5 CC0-BY-4.0 Open Access

Non-drug methods, including cognitive training, social stimulation, exercise and music may have positive effects.  There is the famous video of a withdrawn older woman who springs to action when Swan Lake music is played; she was once a principal ballerina.  It is provocative in showing non-verbal reception, understanding, memory and response. As wonderful as that was, one does not hear of sustained lucidity breakthroughs, or salient ways to broaden the effect.

The phenomenon is ripe for mechanistic speculation.  The author of a “theoretical article” linked here provides some ideas from rodent neurotransmitter studies.  Perhaps another small mammal, known for alertness, could also be a good model, right Timon? [that ever alert and talkative meerkat in Disney’s Lion King].

[readers of this blog will know that there are previous postings with similar subject matter, but most of the links here are more recent, so it isn’t just a rehash]