Frontotemporal Lobar Degeneration

TAICHUNG, Taiwan, April 4, 2024 /PRNewswire/ -- In clinical practice, neurologists scrutinize dementia patients with using numerous tools, including medical history, blood tests, cognitive testing, mental assessment, medical imaging and electro-physiological signal testing. Patients usually spend more than an hour to complete complex questionnaires, and health check-up schedules at hospitals for patients, however, are full up and overloaded. To fulfill patient needs and assist physicians to determine severity of dementia more efficiently and accurately, China Medical University Hospital (CMUH, Taiwan) developed ' BrainHealth ' , an AI system powered by AI Brain Age Prediction System and Neural Gene Discrimination System to facilitate complex assessments of dementia severity. The AI model takes only one minute to help physicians diagnose dementia, with an AUC of 87% and a sensitivity of 91.7%. Mr. Chang (81-year-old) has encountered growing difficulty in recalling what he has been told, become reluctant to interact with family and speaks in a way that is difficult to comprehend. Conventional examinations including blood testing, mental capacity questionnaires and brain MRI were performed at CMUH. Chang was found to have a lower Mini Mental State Examination (MMSE) score than the mean for his age and MRI images showed brain atrophy (but not stroke or tumor). These data, along with the findings of gray matter degeneration and increased cerebrospinal fluid volume, were put into CMUH's BrainHealth system. The AI model predicted that Mr. Chang's brain-age is 5 years older than would be expected and indicated that he had early-stage dementia. The routine examination findings were in line with BrainHealth's prediction of Mr. Chang having early-stage dementia and suggested that further management is warranted. Dementia is a brain disorder causing diminished mental capacity and memory, and can lead to mood disorder, loss of verbal expression and reduced mobility. Dementia as a neurocognitive disorder presented in a range of severities and subtypes (each with specific pathophysiology). Depending on the area affected and the presentation, it may be termed as Alzheimer's disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia or Parkinson's disease. It is usually seen in people of middle or advanced age and progresses with time. An estimation by Taiwan Ministry of Health and Welfare suggested that there are more than 300,000 people affected by dementia in 2022, with 96% being elderly (65 years or older), but with more younger cases reported recently. The number of dementia patients is projected to exceed 500,000 by 2030. According to AI Center at CMUH, BrainHealth, theAI Brain Age Prediction System, incorporates a normal distribution curve derived using MRI slides of brain areas (gray/white matter, cerebrospinal fluid, hippocampus) from nearly three thousand healthy individuals and approximately five hundred dementia patients. With this database, CMUH AI Center discovered that dementia patients generally show less gray matter and a noticeable increase of cerebrospinal fluid (due to brain degeneration) compared to the general population. AI Center at CMUH cited a medical article published in 2022 that the brain age of ordinary people is typically within 3 years of physiological age. The Brain Age Prediction System helps clinicians determine severity of dementia in an efficient manner. Additionally, the hereditary neurological disorder testing system of BrainHealth determines the presence of Alzheimer's disease based on an AI model that compares the brain wave and genetic characteristics extracted by algorithm with data from the geriatric population both with and without neurological disorders.Dementia patients show significantly lower brain wave intensity and complexity at specific frequency bands, as well as functional connections between brain areas, than dementia-free individuals. As Taiwan enters an aged society, the prevention and treatment of early-stage dementia diseases have become urgent tasks. The AI scrutiny system ' BrainHealth ' at CMUH would keep to assist medical professionals in diagnosing dementia. Media Contact: Carolyn Chen 100709@tool.caaumed.org.tw View original content to download multimedia: SOURCE China Medical University Hospital

A traumatic brain injury (TBI) can quadruple your risk for developing dementia and increase your chances of developing neurodegenerative diseases such as ALS. In a new study scientists use lab-grown human brain structures known as organoids to offer insights into why this is the case and how to mitigate the risk. A traumatic brain injury (TBI) can quadruple your risk for developing dementia and increase your chances of developing neurodegenerative diseases such as ALS. In a new study published in Cell Stem Cell, USC scientists use lab-grown human brain structures known as organoids to offer insights into why this is the case and how to mitigate the risk. In the study, former postdoc Jesse Lai and PhD student Joshua Berlind from the USC Stem Cell laboratory of Justin Ichida used human patient-derived stem cells to grow rudimentary brain structures known as organoids in the lab. They then injured these organoids with high-intensity ultrasound waves. The injured organoids showed some of the same features seen in TBI patients, including nerve cell death and pathological changes in tau proteins, as well as in a protein called TDP-43. The scientists found that the pathological changes in TDP-43 were more prevalent in organoids derived from patients with ALS or frontotemporal dementia, making their nerve cells more suspectable to dysfunction and death following injury. This suggests that TBI might increase the risk of developing these diseases even more for patients with a genetic predisposition. The worst injuries were sustained by nerve cells that share information -- called excitatory neurons -- located in the deep layers of the organoids. In their search for ways to protect these neurons against the effects of TBI, the scientists identified a gene called KCNJ2, which contains instructions for making channels that selectively allow potassium to pass through the cell membrane, helping to enable muscle contraction and relaxation. Inhibiting this gene had a protective effect on organoids derived from patients with and without ALS, as well as on mice, following a TBI. "Targeting KCNJ2 may reduce the death of nerve cells after TBI," said Ichida, who is the John Douglas French Alzheimer's Foundation Associate Professor of Stem Cell Biology and Regenerative Medicine at USC, and a principal investigator at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. "This could have potential as either a post-injury treatment or as a prophylactic for athletes and others at high risk for TBI." About the authors and the study Co-corresponding author Ichida is also a co-founder of AcuraStem and Modulo Bio, a Scientific Advisory Board (SAB) member at Spinogenix and Vesalius Therapeutics, and an employee in the Research and Early Development group at BioMarin Pharmaceutical. Co-corresponding author Lai and co-author Violeta Yu were both employees of Amgen during the study, and currently work at Dewpoint Therapeutics. Named companies were not involved in this research project. First author Berlind is a PhD student in the Ichida Lab. Additional co-authors are Gabriella Fricklas, Cecilia Lie, Jean-Paul Urenda, Kelsey Lam, Naomi Sta Maria, Russell Jacobs, and Zhen Zhao from USC. Fifty percent of the work was supported by federal funding from the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (grant F31NS117075), NINDS (grant R01 1R01NS097850-01), and the Department of Defense (grant 12907280). The project was also privately funded by an Amgen postdoctoral fellowship, the New York Stem Cell Foundation, the Tau Consortium, the Harrington Discovery Institute, the Alzheimer's Drug Discovery Foundation, the Association for Frontotemporal Dementia, and the John Douglas French Alzheimer's Foundation.

A spectrum of neurodegenerative diseases, including frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are due to the accumulation of abnormal, misfolded tau proteins in the brain. Scientists have now found potential ways to interrupt this process by targeting 'sticky' sites along the long form of mutated tau, preventing the misfolding and spreading of the neurofibrillary tangles. A spectrum of neurodegenerative diseases, including frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are due to the accumulation of abnormal, misfolded tau proteins in the brain. A team of researchers led by UC Santa Barbara scientists has found potential ways to interrupt this process by targeting "sticky" sites along the long form of mutated tau, preventing the misfolding and spreading of the neurofibrillary tangles. "This is a true collaboration of biology and chemistry," said UCSB neuroscientist Kenneth S. Kosik, who with chemistry professors Songi Han, Joan-Emma Shea and chemical engineering professor Scott Shell, presents findings in the Proceedings of the National Academy of Sciences. The study presents molecular-level insights on the way pathological tau spreads, and according to the researchers, this understanding could lead toward "a therapeutic intervention potentially capable of disaggregating tau or preventing its aggregation" in the long form of tau accumulates. A sticky hairpin Tau is an essential structural protein in the brain, giving cells form and stability and allowing the transport of necessary nutrients. However, when it mutates and misfolds, it can get sticky and tangled. Moreover, this error in folding can become a template for faulty instructions that direct normal tau proteins to misfold and collect until the condition spreads over wide regions of the brain, interfering with brain functions. The specific locations where these neurofibrillary tangles occur in the brain differ among the neurodegenerative disorders. There are two particular forms of tau, which serve as the starting point for this category of neurodegenerative diseases, called tauopathies, and for which Alzheimer's is the most well-known. Tau is produced in both a short "three-repeat" version and a longer "four-repeat" version; the latter the focus of this research. Tauopathies far less common than Alzheimer's such as FTD, PSP and CBD are exclusively tauopathies of the 4R type, though neurodegenerative diseases can also be associated with the 3R form, or, as in the case of Alzheimer's, a combination of both. The discoveries in this research pertain to diseases that accumulate 4R tau. Merging advanced techniques such as transmission electron microscopy and molecular dynamics simulations with in-vitro experiments involving cell cultures, the research team was able to get a sense of the conditions under which pathological 4R tau begins to misfold, template other tau proteins, and aggregate. "Tau folds in a unique way in each of these diseases," Kosik explained. "One part of it folds into a hairpin structure only in the 4R tau." Within the hairpin, he explained, is a sticky segment called PHF6 that can bind and stack up other tau proteins into large aggregations. But what if it were possible to induce tau aggregation in cell culture and use the system to interfere with this sticky site? "Creating conditions for tau propagation serves as a high throughput system for the discovery of compounds that may interfere with tau aggregation," Kosik commented. They found, for instance, that a single amino acid substitution along the protein adjacent to the sticky region was enough to prevent tau aggregation by weakening access to the vulnerable portion of the peptide. In other investigations the researchers also found that nanobodies -- fragments of antibodies -- synthesized from the blood of camelids (camels, llamas and other members of the Camelidae family) were able to bind to the PHF6 region, inhibiting aggregation of tau. Whatever the therapy, the region encompassing the hairpin segment of 4R tau is the apparent active zone to target. The researchers still have a long way before targeted therapeutics can be developed and approved to inhibit the formation of the neurofibrillary tangles that characterize tauopathies. But the findings in this paper unveil exciting potential pathways to arresting critical steps toward the accumulation of mutant tau. "We would want to continue to test this technology in animal models," Kosik said, crediting postdoctoral researcher and lead author Andrew Longhini for his "enormous contributions" to ideas and the experiments reported. On the chemistry side, the work of graduate student researchers Austin DeBose and Samuel Lobo in engineering protein interactions and doing the computational heavy lifting was also essential to the project, he said. "It's so interdisciplinary, it's amazing," Kosik said. "I learned so much from this project." In addition to advancing research on some forms of neurodegenerative disease, these findings can serve as a jumping-off point for potential clues toward therapies for the 3R Pick's disease and for the more complex Alzheimer's disease. Kosik is optimistic. "We'll try to apply our findings to the more complicated forms," he said. "We'll get there." Research in this project was supported by the Keck Foundation.