Encephalomalacia

Mild to moderate cerebrovascular disease, which occurs when blood flow in the brain is impaired, is a characteristic brain signature in adults with Fabry disease, according to a new study.Nearly half of those examined showed signs of white matter damage, for which impaired kidney function was the sole predictive factor. Also, more than two-thirds had signs of cognitive impairment.Blood levels of neurofilament light chain (NfL), a biomarker for nerve damage, may represent a potentially sensitive and easy test to perform for brain involvement in Fabry, according to the study’s researchers. The study, “Prevalence and Clinical Correlates of Cerebrovascular Alterations in Fabry Disease: A Cross-Sectional Study,” was published in Brain Sciences.Fabry is a rare inherited disorder characterized by the toxic buildup in cells of a fatty substance known as globotriaosylceramide, or Gb3, which disrupts organ function, especially the kidneys and heart. Cerebrovascular disease is another manifestation of Fabry, where blood flow in the brain is slowed or stopped, increasing the risk of stroke, damage to the brain’s white matter, and cognitive decline.Because so few studies have described the impact of Fabry on the brain, a research team in Italy assessed the cerebrovascular and cognitive manifestations of Fabry in a study group of 40 adults with the disease, of whom 23 (57.5%) were women. Most (60%) were diagnosed with classic Fabry, while the remaining had late-onset Fabry disease (40%). Nearly all (80%) were undergoing Fabry-specific treatment at the time of the assessment.About 1 in 4 patients (22.5%) had had major cardiac events, including irregular heartbeats, heart attack, or congestive heart failure. About half (55%) had high blood pressure, cardiac hypertrophy (45%), a thickening of the heart muscle, or kidney impairment (50%).Four (10%) patients had had a stroke, one of whom also had multiple transient ischemic attacks, a temporary blockage of blood flow to the brain. All the strokes occurred in late-onset Fabry patients.Of the 32 patients who received an MRI scan, 13 (40.6%) showed signs of white matter damage. Seven (21.9%) had mild damage, three (9.4%) had moderate damage, and three (9.4%) had severe white matter damage. No MRI differences were noted between those treated or untreated, or men and women.Among the 39 patients who underwent a battery of cognitive assessments, more than two-thirds (69.2%) showed impairment on at least one test, with no differences between men and women. Most prominently, roughly 1 in 3 patients (28% to 33%) had problems copying and recalling Rey’s complex figure, an assessment to evaluate visual memory and visuospatial skills.Blood levels of NfL were higher in Fabry patients than in healthy people matched for age and sex (median, 11.5 vs. 7.12 picomoles/mL), although the difference wasn’t statistically significant. Mean NfL levels didn’t differ according to sex or clinical presentation (classic vs. late-onset).In a statistical analysis, impaired kidney function, as assessed by the estimated glomerular filtration rate (eGFR), was the sole significant predictor of white matter damage. Among individual comparisons, high NfL levels significantly correlated with worse kidney function via eGFR and cognitive impairment, as indicated by the Mini-Mental State Examination.“Our study confirms that mild to moderate [cerebrovascular disease] is a characteristic brain ‘signature’ in [Fabry] patients, regardless of [sex] and phenotype, but coherent with overall disease severity,” the authors wrote. “NfL might represent a potential sensitive and easy to perform biomarker of [brain and spinal cord] damage in [Fabry], either to monitor disease progression and response to treatments.”

In experiments using neonatal mice, researchers have identified a fatty molecule in breast milk that triggers a process in which stem cells in the brain produce cells that create new white matter, reversing brain injury. While it's known that the white matter loss will lead to neurological deficits, there is currently no treatment to help these infants avoid the outcome. In experiments using neonatal mice, researchers at Duke Health have identified a fatty molecule in breast milk that triggers a process in which stem cells in the brain produce cells that create new white matter, reversing the injury. The study appears Aug. 3 in the journal Cell Stem Cell. Eric Benner, M.D., Ph.D., is the study's corresponding author and is a distinguished assistant professor in the Department of Pediatrics at Duke University School of Medicine. Benner said further study in a clinical trial is needed, but the finding is promising. "Developing therapies for children -- especially such medically fragile children -- is very difficult to do because there are justifiably strict safety concerns," Benner said. "The fact that this molecule is already found in something that is safe for premature babies -- breast milk -- is extremely encouraging. "It's been known that fats in breast milk benefit a child's brain development, but there are many types of fats in breast milk," Benner said. "This work has identified a lipid molecule in breast milk that promotes white matter development. Now, we can begin to develop a therapy that isolates and delivers this lipid in a way that is safe for the unique challenges of these infants." Benner is a neonatologist at Duke University and one of the co-founders of Tellus Therapeutics, a Duke spinout company developed with the help of the Duke University Office for Translation & Commercialization to bring this therapy from the bench into the neonatal intensive care unit. The fatty molecule identified in the study will be administered intravenously to patients in an upcoming clinical trial. This is significant because many of the infants who are part of this vulnerable population also have gastrointestinal issues and cannot safely be given milk or medication by mouth. The lipid molecule enters the brain and binds with stem cells there, encouraging the stem cells to become or produce a type of cell called oligodendrocytes. The oligodendrocytes are like a hub that allow for the production of white matter in the central nervous system. This newly produced white matter in pre-term infants prevents the neurological damage that would otherwise impact the child's ability to move -- the hallmarks of cerebral palsy. "The timing of brain injury is extremely difficult to predict, thus a treatment that could be safely given to all preterm babies at risk would be revolutionary," said Agnes Chao, M.D., a former fellow in the Division of Neonatology and first author of the paper. "As a neonatologist, I'm so excited that I may be able to offer a treatment to families with babies that are affected by preterm brain injury who would otherwise have no other options," Chao said. In addition to Benner and Chao, study authors include Pavle Matak, Kelly Pegram, James Powers, Collin Hutson, Rebecca Jo, Laura Dubois, J. Will Thompson, P. Brian Smith, Jason R. Gibson, Noelle E. Younge, Blaire Rikard, Simon G. Gregory, Ronald N. Goldberg, Mari L Shinohara, Estefany Y. Reyes, Chunlei Liu. The study was funded by the National Institutes of Health (1R01NS114578, T32HD094671, K12HD043494, T32HD043728, R01AG070826, R01MH127104, P41EB015897, 1UL1-TR002553), Jean and George Brumley Jr. Neonatal Perinatal Research Institute, with additional support from the Duke Scholars Award from the School of Medicine, Duke University Center for In Vivo Microscopy, and the National Center for Advancing Translational Sciences.

THURSDAY, May 11, 2023 -- Poor sleep brought on by sleep apnea may ultimately undermine the brain health of older men and women, new research suggests. The concern stems from a new brain scan investigation that involved 140 sleep apnea patients. “Sleep apnea is a medical condition in which patients ... stop breathing during sleep, which can affect their sleep quality by causing multiple arousals and dropping oxygen levels,” said lead study author Dr. Diego Carvalho . He is an assistant professor of neurology at the Mayo Clinic Center for Sleep Medicine in Rochester, Minn. Sleep apnea “has been associated with increased risk of high blood pressure, diabetes, heart attack, stroke, cognitive impairment and dementia,” Carvalho said. And, he noted, it is known to “cause a range of harmful effects in the brain,” as blood pressure and heart rate rise, oxygen levels drop and sleep is disrupted. Importantly, sleep apnea can limit a person’s ability to get and maintain “deep sleep.” Deep sleep, which begins about an hour after falling asleep, is essential to the body’s ability to repair and regenerate tissue, bolster the immune system, and build bone and muscle, according to the Cleveland Clinic. Getting enough of it is, therefore, considered a key indicator of good quality shut-eye. With that in mind, Carvalho and his team set out to see whether the impact of sleep apnea on deep sleep might somehow be linked to the long-term risk for stroke, dementia and Alzheimer’s disease. The study included 140 participants (average age, 73 years). None had any signs of dementia, Alzheimer’s or trouble with thought processing when the study was conducted. Their sleep apnea ranged in severity from mild to severe. Each participant underwent brain scans and an overnight study in a sleep lab. The scans offered insight into the health of nerve fibers that make up the brain's white matter. White matter damage can undermine communication between different parts of the brain. It often shows up as tiny lesions that accumulate with age. The overnight study allowed researchers to track sleep patterns. The result: After comparing sleep to scans, the researchers found that patients who got the least deep sleep — and, therefore, had the poorest overall sleep quality — were also the most likely to show telltale signs of white matter damage. For every 10-point drop in the percentage of deep sleep, the investigators found an increase in white matter damage similar to the effect of aging an additional 2.3 years. “Poor sleep from severe sleep apnea or decreased deep sleep may be involved in white matter abnormalities thought to contribute to the risk of cognitive impairment, dementia and stroke,” Carvalho said. But the study authors also pointed out some key caveats. For one thing, the association between less deep sleep and more white matter damage “was just evident in patients with severe sleep apnea,” not among those with less advanced disease. And investigators placed a heavy emphasis on “association.” The findings, they said, only highlight a link between poor sleep quality and higher risk for mental decline and stroke down the road. They don't yet prove that one actually causes the other. “That being the case, future studies should assess whether strategies to improve sleep quality and enhance this stage of sleep could help prevent development of progression of white matter abnormalities,” Carvalho added. Dr. Ivana Rosenzweig , head of the Sleep and Brain Plasticity Center at King's College London in the United Kingdom, reviewed the new study findings. She stressed that “sleep apnea is a serious public health problem that affects most of our body organs and our brain,” with the number of affected patients predicted to rise in coming years. “Whilst the jury is still out regarding how the deep sleep may exactly affect memory, a number of studies show strong links between normal aging, less time spent in deep sleep and memory issues,” Rosenzweig said. She added that the new findings “appear to support a growing body of literature which suggests that sleep apnea may in some susceptible individuals lead to accelerated aging processes in the body and the brain.” Rosenzweig’s take: “Studies such as this are important, as they help to raise awareness of the importance of sleep quality in our battle against dementia,” while also indicating “how important certain sleep building blocks and rhythms may be for the health of our brain.” The findings were published online May 10 in the journal Neurology . Sources Diego Carvalho, MD, MS, assistant professor, neurology, Center for Sleep Medicine, Mayo Clinic, Rochester, Minn. Ivana Rosenzweig, MD, PhD, head, Sleep and Brain Plasticity Center, Institute of Psychiatry, Psychology and Neuroscience, King's College London, U.K. Neurology , May 10, 2023, online Posted May 2023