Super-agers show resistance to tau and amyloid accumulation
July 15, 2020
Science Daily/Society of Nuclear Medicine and Molecular Imaging
Super-agers, or individuals whose cognitive skills are above the norm even at an advanced age, have been found to have increased resistance to tau and amyloid proteins, according to research presented at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2020 Annual Meeting. An analysis of positron emission tomography (PET) scans has shown that compared to normal-agers and those with mild cognitive impairment, super-agers have a lower burden of tau and amyloid pathology associated with neurodegeneration, which probably allows them to maintain their cognitive performance. An image showing the comparison of tau and amyloid distribution patterns in these different cognitive aging trajectories has been selected as SNMMI's 2020 Image of the Year.
"Our cognition reflects who we are as individuals. As we age, most of us lose some of that ability," said SNMMI's Scientific Program Committee chair, Umar Mahmood, MD, PhD. "The Image of the Year provides us with insight into how we can use these PET imaging biomarkers to understand behaviors and therapies that may allow more of us age better and retain more of our cognitive abilities as we get older."
Each year, SNMMI chooses an image that best exemplifies the most promising advances in the field of nuclear medicine and molecular imaging. The state-of-the-art technologies captured in these images demonstrate the capacity to improve patient care by detecting disease, aiding diagnosis, improving clinical confidence and providing a means of selecting appropriate treatments. This year, the SNMMI Henry N. Wagner, Jr., MD, Image of the Year was chosen from more than two thousand abstracts submitted to the meeting and voted on by reviewers and the society leadership.
"The phenomenon of super-aging suggests that cognitively high-functioning individuals have extraordinary mechanisms that resist brain aging processes and neurodegeneration," said Dr. Merle Hoenig, Research Center Juelich & University Hospital Cologne, Germany. Some insights have been collected on amyloid pathology in super-agers, but there is no in vivo evidence on tau pathology due to the former lack of available imaging techniques. "We know that tau pathology is more closely associated with cognitive decline than amyloid pathology," Hoenig continued, "thus, the resistance, in particular against tau pathology, likely allows these individuals to perform cognitively above average even at advanced age."
Data from the Alzheimer's Disease Neuroimaging Initiative was utilized to create three age- and education-matched groups of 25 super-agers, 25 normal-agers and 25 patients with mild cognitive impairment, all above 80 years old. In addition, 18 younger, cognitively normal, amyloid-negative controls were included in the comparison as a reference group. 18F-AV-1451 and 18F-AV-45 PET images obtained for all individuals and researchers compared the tau and amyloid burden between the four groups. A logistic regression was performed to identify genetic and pathophysiological factors best predicting aging processes.
No significant differences between super-agers and the younger control group were observed in terms of in vivo tau and amyloid burden. The normal-ager group exhibited tau burden in inferior temporal and precuneal areas and no significant differences in amyloid burden, when compared to the younger control group. Patients with mild cognitive impairment showed both high amyloid and high tau pathology burden. Differences in amyloid burden dissociated the normal-agers from those with mild cognitive impairment, whereas lower tau burden and lower polygenic risk predicted super-agers from mild cognitive impairment patients.
"While super-agers may be able to resist aging-associated proteinopathies, in particular tau pathology, normal-agers may not and are thus exposed to inevitable cognitive decline due to the accumulation of neurotoxic tau tangles and the advancing aging process," noted Hoenig. "Moving further to the other extreme of aging, namely mild cognitive impairment, the synergistic effects of both amyloid and tau may accelerate the pathological aging process."
These results motivate further research to determine responsible resistance factors, which may also inspire the development of novel treatment concepts. "Given the multitude of factors involved in the aging process, it will certainly be challenging to develop therapeutics to tackle the factors involved. However, if we understand which individuals are resistant to dementia, this will help us identify potential pathways that promote successful aging -- protecting against not only Alzheimer's disease but also other aging-associated diseases, such as vascular disease and other forms of dementia," said Hoenig.
https://www.sciencedaily.com/releases/2020/07/200715111447.htm
Alzheimer 'tau' protein far surpasses amyloid in predicting toll on brain tissue
Tau PET brain imaging could launch precision medicine era for Alzheimer's disease
January 1, 2020
Science Daily/University of California - San Francisco
The results support researchers' growing recognition that tau drives brain degeneration in Alzheimer's disease more directly than amyloid protein, and at the same time demonstrates the potential of recently developed tau-based PET (positron emission tomography) brain imaging technology to accelerate Alzheimer's clinical trials and improve individualized patient care.
Brain imaging of pathological tau-protein "tangles" reliably predicts the location of future brain atrophy in Alzheimer's patients a year or more in advance, according to a new study by scientists at the UC San Francisco Memory and Aging Center. In contrast, the location of amyloid "plaques," which have been the focus of Alzheimer's research and drug development for decades, was found to be of little utility in predicting how damage would unfold as the disease progressed.
The results, published January 1, 2020 in Science Translational Medicine, support researchers' growing recognition that tau drives brain degeneration in Alzheimer's disease more directly than amyloid protein, and at the same time demonstrates the potential of recently developed tau-based PET (positron emission tomography) brain imaging technology to accelerate Alzheimer's clinical trials and improve individualized patient care.
"The match between the spread of tau and what happened to the brain in the following year was really striking," said neurologist Gil Rabinovici, MD, the Edward Fein and Pearl Landrith Distinguished Professor in Memory and Aging and leader of the PET imaging program at the UCSF Memory and Aging Center. "Tau PET imaging predicted not only how much atrophy we would see, but also where it would happen. These predictions were much more powerful than anything we've been able to do with other imaging tools, and add to evidence that tau is a major driver of the disease."
Interest in Tau Growing as Amyloid-Based Therapies Stumble
Alzheimer's researchers have long debated the relative importance of amyloid plaques and tau tangles -- two kinds of misfolded protein clusters seen in postmortem studies of patients' brains, both first identified by Alois Alzheimer in the early 20th century. For decades, the "amyloid camp" has dominated, leading to multiple high-profile efforts to slow Alzheimer's with amyloid-targeting drugs, all with disappointing or mixed results.
Many researchers are now taking a second look at tau protein, once dismissed as simply a "tombstone" marking dying cells, and investigating whether tau may in fact be an important biological driver of the disease. In contrast to amyloid, which accumulates widely across the brain, sometimes even in people with no symptoms, autopsies of Alzheimer's patients have revealed that tau is concentrated precisely where brain atrophy is most severe, and in locations that help explain differences in patients' symptoms (in language-related areas vs. memory-related regions, for example).
"No one doubts that amyloid plays a role in Alzheimer's disease, but more and more tau findings are beginning to shift how people think about what is actually driving the disease," explained Renaud La Joie, PhD, a postdoctoral researcher in Rabinovici's In Vivo Molecular Neuroimaging Lab, and lead author of the new study. "Still, just looking at postmortem brain tissue, it has been hard to prove that tau tangles cause brain degeneration and not the other way around. One of our group's key goals has been to develop non-invasive brain imaging tools that would let us see whether the location of tau buildup early in the disease predicts later brain degeneration."
Tau PET Scans Predict Locations of Future Brain Atrophy in Individual Patients
Despite early misgivings that tau might be impossible to measure in the living brain, scientists recently developed an injectable molecule called flortaucipir -- currently under review by the FDA -- which binds to misfolded tau in the brain and emits a mild radioactive signal that can be picked up by PET scans.
Rabinovici and collaborator William Jagust, MD, of UC Berkeley and Lawrence Berkeley National Laboratory, have been among the first to adopt tau PET imaging to study the distribution of tau tangles in the normally aging brain and in a smaller cross-sectional study of Alzheimer's patients. Their new study represents the first attempt to test whether tau levels in Alzheimer's patients can predict future brain degeneration.
La Joie recruited 32 participants with early clinical stage Alzheimer's disease through the UCSF Memory and Aging Center, all of whom received PET scans using two different tracers to measure levels of amyloid protein and tau protein in their brains. The participants also received MRI scans to measure their brain's structural integrity, both at the start of the study, and again in follow-up visits one to two years later.
The researchers found that overall tau levels in participants' brains at the start of the study predicted how much degeneration would occur by the time of their follow up visit (on average 15 months later). Moreover, local patterns of tau buildup predicted subsequent atrophy in the same locations with more than 40 percent accuracy. In contrast, baseline amyloid-PET scans correctly predicted only 3 percent of future brain degeneration.
"Seeing that tau buildup predicts where degeneration will occur supports our hypothesis that tau is a key driver of neurodegeneration in Alzheimer's disease," La Joie said.
Notably, PET scans revealed that younger study participants had higher overall levels of tau in their brains, as well as a stronger link between baseline tau and subsequent brain atrophy, compared to older participants. This suggests that other factors -- likely other abnormal proteins or vascular injuries -- may play a larger role in late-onset Alzheimer's, the researchers say.
Ability to Predict Brain Atrophy a 'Valuable Precision Medicine Tool'
The results add to hopes that tau-targeting drugs currently under study at the UCSF Memory and Aging Center and elsewhere may provide clinical benefits to patients by blocking this key driver of neurodegeneration in the disease. At the same time, the ability to use tau PET to predict later brain degeneration could enable more personalized dementia care and speed ongoing clinical trials, the authors say.
"One of the first things people want to know when they hear a diagnosis of Alzheimer's disease is simply what the future holds for themselves or their loved ones. Will it be a long fading of memory, or a quick decline into dementia? How long will the patient be able to live independently? Will they lose the ability to speak or get around on their own? These are questions we can't currently answer, except in the most general terms," Rabinovici said. "Now, for the first time, this tool could let us give patients a sense of what to expect by revealing the biological process underlying their disease."
Rabinovici and his team also anticipate that the ability to predict future brain atrophy based on tau PET imaging will allow Alzheimer's clinical trials to quickly assess whether an experimental treatment can alter the specific trajectory predicted for an individual patient, which is currently impossible due to the wide variability in how the disease progresses from individual to individual. Such insights could make it possible to adjust dosage or switch to a different experimental compound if the first treatment is not affecting tau levels or altering a patient's predicted trajectory of brain atrophy.
"Tau PET could be an extremely valuable precision medicine tool for future clinical trials," Rabinovici said. "The ability to sensitively track tau accumulation in living patients would for the first time let clinical researchers seek out treatments that can slow down or even prevent the specific pattern of brain atrophy predicted for each patient."
https://www.sciencedaily.com/releases/2020/01/200101144012.htm
Inflammatory processes drive progression of Alzheimer's and other brain diseases
New insights into disease mechanisms, report in Nature
November 20, 2019
Science Daily/DZNE - German Center for Neurodegenerative Diseases
Inflammation drives the progression of neurodegenerative brain diseases and plays a major role in the accumulation of tau proteins within neurons. An international research team led by the German Center for Neurodegenerative Diseases (DZNE) and the University of Bonn comes to this conclusion in the journal Nature. The findings are based on the analyses of human brain tissue and further lab studies. In the particular case of Alzheimer's the results reveal a hitherto unknown connection between Abeta and tau pathology. Furthermore, the results indicate that inflammatory processes represent a potential target for future therapies.
Tau proteins usually stabilize a neuron's skeleton. However, in Alzheimer's disease, frontotemporal dementia (FTD), and other "tauopathies" these proteins are chemically altered, they detach from the cytoskeleton and stick together. As a consequence, the cell's mechanical stability is compromised to such an extent that it dies off. In essence, "tau pathology" gives neurons the deathblow. The current study led by Prof. Michael Heneka, director of the Department of Neurodegenerative Diseases and Gerontopsychiatry at the University of Bonn and a senior researcher at the DZNE, provides new insights into why tau proteins are transformed. As it turns out, inflammatory processes triggered by the brain's immune system are a driving force.
A Molecular Switch
A particular protein complex, the "NLRP3 inflammasome," plays a central role for these processes, the researchers report in Nature. Heneka and colleagues already studied this macromolecule, which is located inside the brain's immune cells, in previous studies. It is a molecular switch that can trigger the release of inflammatory substances. For the current study, the researchers examined tissue samples from the brains of deceased FTD patients, cultured brain cells, and mice that exhibited hallmarks of Alzheimer's and FTD.
"Our results indicate that the inflammasome and the inflammatory reactions it triggers, play an important role in the emergence of tau pathology," Heneka said. In particular, the researchers discovered that the inflammasome influences enzymes that induce a "hyperphosphorylation" of tau proteins. This chemical change ultimately causes them to separate from the scaffold of neurons and clump together. "It appears that inflammatory processes mediated by the inflammasome are of central importance for most, if not all, neurodegenerative diseases with tau pathology."
A Link between Abeta and Tau
This especially applies to Alzheimer's disease. Here another molecule comes into play: "amyloid beta" (Abeta). In Alzheimer's, this protein also accumulates in the brain. In contrast to tau proteins, this does not happen within the neurons but between them. In addition, deposition of Abeta starts in early phases of the disease, while aggregation of tau proteins occurs later.
In previous studies, Heneka and colleagues were able to show that the inflammasome can promote the aggregation of Abeta. Here is where the connection to the recent findings comes in. "Our results support the amyloid cascade hypothesis for the development of Alzheimer's. According to this hypothesis, deposits of Abeta ultimately lead to the development of tau pathology and thus to cell death," said Heneka. "Our current study shows that the inflammasome is the decisive and hitherto missing link in this chain of events, because it bridges the development from Abeta pathology to tau pathology. It passes the baton, so to speak." Thus, deposits of Abeta activate the inflammasome. As a result, formation of further deposits of Abeta is promoted. On the other hand, chemical changes occur to the tau proteins resulting into their aggregation.
A Possible Starting Point for Therapies
"Inflammatory processes promote the development of Abeta pathology, and as we have now been able to show, of tau pathology as well. Thus, the inflammasome plays a key role in Alzheimer's and other brain diseases," said Heneka, who is involved in the Bonn-based "ImmunoSensation" cluster of excellence and who also teaches at the University of Massachusetts Medical School. With these findings, the neuroscientist sees opportunities for new treatment methods. "The idea of influencing tau pathology is obvious. Future drugs could tackle exactly this aspect by modulating the immune response. With the development of tau pathology, mental abilities decline more and more. Therefore, if tau pathology could be contained, this would be an important step towards a better therapy."
https://www.sciencedaily.com/releases/2019/11/191120131318.htm