Maintains Overweight
Monday, December 30, 2019
More Doubt That Plaques in the Brain Cause Alzheimer’s
For decades, scientists have known that Alzheimer’s disease is accompanied by the buildup of clumps of amyloid protein between brain cells. Could these plaques be causing the disease?
That’s been a prevailing theory driving Alzheimer’s research for years. But a new study suggests the strategy could be wrong.
Researchers reporting Dec. 30 in the journal Neurology have found that early declines in memory and thinking seen in Alzheimer’s patients tend to occur before amyloid plaques begin to appear in the brain, not after.
“Our research was able to detect subtle thinking and memory differences in study participants and these participants had faster amyloid accumulation on brain scans over time, suggesting that amyloid may not necessarily come first in the Alzheimer’s disease process,” study author Kelsey Thomas explained in a journal news release.
“Much of the research exploring possible treatments for Alzheimer’s disease has focused on targeting amyloid, but based on our findings, perhaps that focus needs to shift to other possible targets,” said Thomas, who conducts research at the VA San Diego Healthcare System.
This isn’t the first indication that amyloid plaques might not cause Alzheimer’s disease.
In April, clinical trial data on an experimental Alzheimer’s drug called verubecestat was published in the New England Journal of Medicine. The drug reduced amyloid plaque levels in patients’ brains and spinal fluid.
However, despite those reductions, patients showed no easing or slowing of their disease.
Those negative results present “pretty strong evidence that amyloid-lowering is the wrong target,” Dr. David Knopman, a professor of neurology with the Mayo Clinic in Rochester, Minn., said at the time. “They hit the target and yet people got worse, consistently worse, both in terms of brain structure and brain cognition,” he added.
Similar poor results were seen with another amyloid-focused drug, aducanumab. Studies on the drug were halted earlier this year because it didn’t appear to be effective. However, in December it was announced that research into aducanumab might resume.
In the new study, Thomas and her team tracked the neurological health of 747 people, average age 72 years. Everyone got a barrage of tests to spot and follow any changes — even subtle ones — in their memory and thinking skills.
Based on test results, 305 people were deemed to have normal thinking and memory skills, 153 had very subtle thinking and memory differences, and 289 people had mild cognitive impairment — often a precursor to Alzheimer’s disease.
The participants also underwent high-tech brain scans at the beginning of the study and then yearly scans over the next four years, looking for signs of amyloid plaque buildup.
The investigators found that amyloid plaque accumulation occurred no faster in people with mild cognitive impairment than it did in people with normal thinking and memory skills.
Other brain changes were seen in conjunction with mild cognitive impairment, however, such as faster thinning of the brain’s entorhinal cortex, as well as brain shrinkage of the hippocampus. Both brain regions are key to memory.
And there could be another culprit at work in Alzheimer’s development, Thomas said.
“From prior research, we know that another biomarker of Alzheimer’s disease, a [brain] protein called tau, shows a consistent relationship with thinking and memory symptoms,” she said. “Therefore, more research is needed to determine if tau is already present in the brain when subtle thinking and memory differences begin to appear.”
The study might lead to a better way to calculate a person’s risk for Alzheimer’s, Thomas added.
“Our study demonstrated a method to successfully detect subtle differences in thinking and memory either before or during the phase when amyloid is accumulating at a faster rate,” she explained. “This could lead to noninvasive screenings that may be able to detect very early who is at risk of developing Alzheimer’s disease.”
One neurologist unconnected to the new study agreed that it helps point to new and potentially fruitful avenues of research.
The thinking that amyloid plaque buildup “leads to clinical problems is no longer a valid one, as this study demonstrates,” said Dr. Gayatri Devi, a neurologist and psychiatrist at Lenox Hill Hospital in New York City.
“Subtle symptoms accompanying or even preceding brain pathology suggest that numerous other factors are involved in the complex risk mixture that leads to Alzheimer’s disease,” Devi said.
More information
Harvard Medical School has more about avoiding Alzheimer’s disease.
SOURCES: Gayatri Devi, M.D., neurologist and psychiatrist, Lenox Hill Hospital, New York City; Neurology, news release, Dec. 30, 2019
Deep Sleep Linked to Early Alzheimer’s Signs
This story was originally published January 10, 2019. As part of MedPage Today’s year-end review of 2019’s top stories, we are republishing it along with an update of new research after this study was published.
Deep sleep was associated with tau pathology, a study of older adults showed.
Non-rapid eye movement (non-REM) sleep slow wave activity was inversely related to Alzheimer’s pathology, especially tauopathy, with the association most evident at the lowest 1- to 2-Hz frequencies, according to Brendan Lucey, MD, and David Holtzman, MD, both of Washington University in St. Louis, and colleagues.
This finding suggests that changes in non-REM slow wave activity might be able to discriminate tau pathology at or before the earliest stages of symptomatic Alzheimer’s disease, the team wrote in Science Translational Medicine.
“What’s interesting is that we saw this inverse relationship between decreased slow wave sleep and more tau protein in people who were either cognitively normal or very mildly impaired, meaning that reduced slow wave activity may be a marker for the transition between normal and impaired,” Lucey said in a statement.
“The key is that it wasn’t the total amount of sleep that was linked to tau; it was the slow wave sleep, which reflects quality of sleep,” he added. “The people with increased tau pathology were actually sleeping more at night and napping more in the day, but they weren’t getting as good quality sleep.”
Previous studies have found that increased napping was associated with increased amyloid beta (Aβ) accumulation over time, and that decreased non-REM slow waves correlated significantly with Aβ burden in the medial prefrontal cortex.
“The hypothesis is that one function of sleep is to clear metabolites out of the brain, and amyloid may be one of those — to the extent that, if you get disrupted sleep, you may get into a vicious cycle where amyloid builds up,” said Ron Petersen, MD, PhD, director of the Mayo Clinic Alzheimer’s Disease Research Center in Rochester, Minnesota, who was not involved with the study.
“The bigger question is a chicken-and-egg one: is it that your sleep is disrupted and the Alzheimer’s proteins build up — or are the Alzheimer’s proteins being deposited in the brain disrupting sleep and that’s where the cycle gets initiated? That still is uncertain,” Petersen told MedPage Today. “Nevertheless, the message is probably the same: disrupted sleep may enhance the buildup of the proteins and enhance the Alzheimer’s process itself.”
For the analysis, the researchers studied 119 people (mean age 74) recruited from the Knight Alzheimer’s Disease Research Center at Washington University. About 80% of the patients were cognitively normal; the rest were very mildly impaired.
Participants had sleep assessments for up to six nights at home through three separate measures: a single-channel EEG device worn on the forehead, wrist-worn actigraphy, and sleep logs to record night sleep and day napping. In addition, participants were studied for sleep-disordered breathing and periodic leg movements. Each participant produced at least 2 nights of EEG data; some had 6. A total of 38 people had PET scans for amyloid and tau tracers, 104 had cerebrospinal fluid (CSF) collected, and 27 had both.
After adjusting for multiple confounders — including age, sex, race, Clinical Dementia Rating, apolipoprotein E (APOE) genotype, apnea-hypopnea index, periodic limb movement index, and sleep medications — the researchers found that non-REM slow wave activity decreased with increased evidence of Aβ deposition and tau accumulation. This relationship was stronger with tau than with Aβ pathology on PET.
The team also observed that increased CSF tau/Aβ42 ratio — another marker of Alzheimer’s pathology — was inversely tied to non-REM slow wave activity.
The findings have potential application in both clinical trials and patient screening, Lucey and colleagues observed: periodically measuring non-REM slow wave activity in conjunction with other biomarkers may help assess Alzheimer’s risk or response to a treatment.
The study has several limitations, Lucey and co-authors said, including the fact that only 38 participants had imaging. Covariates such as sex, race, APOE, and sleep medications need additional study in larger cohorts, the researchers noted, adding that further longitudinal studies are needed to determine when non-REM slow wave activity decreases in relation to increased Aβ deposition and tauopathy.
Disclaimer
The study was supported by the National Institutes of Health, the Ellison Medical Foundation, the Willman Scholar Fund, the Foundation for Barnes-Jewish Hospital, and the American Sleep Medicine Foundation. Avid Radiopharmaceuticals (Eli Lilly) provided support for PET scans.
The authors reported financial relationships with C2N Diagnostics, Genentech, AbbVie, Proclara, Denali, Eli Lilly, Biogen, Roche, Janssen, Fujirebio, Araclon/Grifols, and DiamiR.
Primary Source
Science Translational Medicine
Erytech Pharma SA (NASDAQ:ERYP) Sees Significant Drop in Short Interest
Erytech Pharma SA (NASDAQ:ERYP) was the target of a significant decrease in short interest in the month of December. As of December 13th, there was short interest totalling 1,700 shares, a decrease of 15.0% from the November 28th total of 2,000 shares. Approximately 0.0% of the shares of the stock are sold short. Based on an average daily volume of 1,900 shares, the days-to-cover ratio is presently 0.9 days.
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