Gut microbiome influences ALS outcomes

Scientists identify gut-brain connection in ALS

May 13, 2020

Science Daily/Harvard University

Scientists have identified a new gut-brain connection in the neurodegenerative disease ALS. Researchers found that in mice with a common ALS genetic mutation, changing the gut microbiome using antibiotics or fecal transplants could prevent or improve disease symptoms. The findings provide a potential explanation for why only some individuals carrying the mutation develop ALS, and point to a possible therapeutic approach based on the microbiome.

Harvard University scientists have identified a new gut-brain connection in the neurodegenerative disease amyotrophic lateral sclerosis, or ALS. The researchers found that in mice with a common ALS genetic mutation, changing the gut microbiome using antibiotics or fecal transplants could prevent or improve disease symptoms.

Published in the journal Nature, the findings provide a potential explanation for why only some individuals carrying the mutation develop ALS. They also point to a possible therapeutic approach based on the microbiome.

"Our study focused on the most commonly mutated gene in patients with ALS. We made the remarkable discovery that the same mouse model -- with identical genetics -- had substantially different health outcomes at our different lab facilities," said Kevin Eggan, Harvard professor of stem cell and regenerative biology. "We traced the different outcomes to distinct gut microbial communities in these mice, and now have an intriguing hypothesis for why some individuals carrying this mutation develop ALS while others do not."

Different facilities, different outcomes

The researchers initially studied the ALS genetic mutation by developing a mouse model at their Harvard lab facility. The mice had an overactive immune response, including inflammation in the nervous system and the rest of the body, which led to a shortened lifespan.

In order to run more detailed experiments, the researchers also developed the mouse model in their lab facility at the Broad Institute, where Eggan is the director of stem cell biology at the Stanley Center for Psychiatric Research. Unexpectedly, although the mice had the same genetic mutation, their health outcomes were dramatically different.

"Many of the inflammatory characteristics that we observed consistently and repeatedly in our Harvard facility mice weren't present in the Broad facility mice. Even more strikingly, the Broad facility mice survived into old age," said Aaron Burberry, postdoctoral fellow in the Eggan lab and lead author of the study. "These observations sparked our endeavor to understand what about the two different environments could be contributing to these different outcomes."

Searching the gut microbiome

Looking for environmental differences between the mice, the researchers honed in on the gut microbiome. By using DNA sequencing to identify gut bacteria, the researchers found specific microbes that were present in the Harvard facility mice but absent in the Broad facility mice, even though the lab conditions were standardized between facilities.

"At this point, we reached out to the broader scientific community, because many different groups have studied the same genetic mouse model and observed different outcomes," Burberry said. "We collected microbiome samples from different labs and sequenced them. At institutions hundreds of miles apart, very similar gut microbes correlated with the extent of disease in these mice."

The researchers then tested ways to change the microbiome and improve outcomes for the Harvard facility mice. By treating the Harvard facility mice with antibiotics or fecal transplants from the Broad facility mice, the researchers successfully decreased inflammation.

Gut-brain connection

By investigating the connection between genetic and environmental factors in ALS, the researchers identified an important gut-brain connection. The gut microbiome could influence the severity of disease -- whether individuals with the genetic mutation develop ALS, the releated condition frontotemporal dementia, or no symptoms at all -- and could be a potential target for therapy.

"Our study provides new insights into the mechanisms underlying ALS, including how the most common ALS genetic mutation contributes to neural inflammation," Eggan said. "The gut-brain axis has been implicated in a range of neurological conditions, including Parkinson's disease and Alzheimer's disease. Our results add weight to the importance of this connection."

https://www.sciencedaily.com/releases/2020/05/200513111432.htm

Lifestyle choices could slow familial frontotemporal dementia

Patients can influence outcomes despite a genetic diagnosis, study suggests

January 8, 2020

Science Daily/University of California - San Francisco

A physically and mentally active lifestyle confers resilience to frontotemporal dementia (FTD), even in people whose genetic profile makes the eventual development of the disease virtually inevitable, according to new research by scientists at the UC San Francisco Memory and Aging Center.

The research aligns with long-standing findings that exercise and cognitive fitness are one of the best ways to prevent or slow Alzheimer's disease, but is the first study to show that the same types of behaviors can benefit people with FTD, which is caused by a distinct form of brain degeneration.

FTD is a neurodegenerative disease that can disrupt personality, decision-making, language, or movement abilities, and typically begins between the ages of 45 and 65. It is the most common form of dementia in people under 65 (accounting for 5 to 15 percent of dementia cases overall) and typically results in rapid cognitive and physical decline and death in less than 10 years. There are currently no drugs to treat FTD, though numerous clinical trials for the disease are underway at UCSF Memory and Aging Center and elsewhere.

"This is devastating disease without good medical treatments, but our results suggest that even people with a genetic predisposition for FTD can still take actions to increase their chances of living a long and productive life. Their fate may not be set in stone," said Kaitlin Casaletto, PhD, assistant professor of neurology at the UCSF Memory and Aging Center and corresponding author of the new study, published January 8, 2020 in Alzheimer's and Dementia.

'If This Were a Drug, We Would Be Giving it to All Our Patients'

About 40 percent of people with FTD have a family history of the disease, and scientists have identified specific dominant genetic mutations that drive the development of the disease in roughly half of these cases. But even in these individuals, the disease can have very different courses and severity.

"There's incredible variability in FTD, even among people with the same genetic mutations driving their disease. Some people are just more resilient than others for reasons we still don't understand," said, Casaletto, a member of the UCSF Weill Institute for Neurosciences. "Our hypothesis was that the activities people engage in each day of their lives may contribute to the very different trajectories we see in clinic, including when the disease develops and how it progresses."

To test this hypothesis, Casaletto and colleagues studied how lifestyle differences affected FTD progression in 105 people with dominant, disease-causing genetic mutations who were mostly asymptomatic or had experienced only mild, early-stage symptoms. The research participants were drawn from two large multisite studies, called ARTFL and LEFFTDS (recently combined into a study known as ALLFTD), led by co-authors Adam Boxer, MD, PhD, and Howie Rosen, MD, also of the UCSF Memory and Aging Center.

As part of these larger studies, all participants underwent initial MRI scans to measure the extent of brain degeneration caused by the disease, completed tests of thinking and memory, and reported on their current levels of cognitive and physical activity in their daily lives (e.g., reading, spending time with friends, jogging). At the same time, their family members completed regular gold-standard assessments of how well the study participants were functioning in their lives -- managing finances, medications, bathing themselves, and so on. All of these measures were repeated at annual follow-up visits to track the long-term progression of participants' disease.

Even after only two to three visits (one to two years into the ongoing study), Casaletto and her team have already begun to see significant differences in the speed and severity of FTD between the most and least mentally and physically active individuals in the study, with mentally and physically active lifestyles showing similar effects across participants.

Specifically, the researchers found that functional decline, as assessed by participants' family members, was 55 percent slower in the most active 25 percent of participants compared to the least active five percent. "This was a remarkable effect to see so early on," Casaletto said. "If this were a drug, we would be giving it to all of our patients."

The researchers found that participants' lifestyles did not significantly alter the inexorable degeneration of brain tissue associated with FTD, as measured by follow-up MRI scans a year into the study. But even among participants whose brain scans revealed signs of atrophy, the most mentally and physically active participants continued to perform twice as well as the least active participants on cognitive tests. These results suggest that active lifestyles may slow FTD symptoms by providing some form of cognitive resilience to the consequences of brain degeneration.

Findings Could Illuminate Biology of Brain Resilience Across Dementias

The researchers anticipate seeing even larger differences in cognitive decline between more and less active groups as the merged ALLFTD study continues to follow these participants over time. "We've seen such significant effects in just the first year or two in people with very mild disease -- if these results hold, we may see that an active lifestyle sets individuals on a different trajectory for the coming years," Casaletto said.

The next step for the research is to include more detailed and objective assessments of participants' physical and mental activity -- including fitting them with wearable FitBit activity sensors -- to begin to estimate exactly how much activity is needed to promote cognitive resilience.

Casaletto cautions that the results, though exciting, so far only report a correlation: "It is possible that some participants have less active lifestyles because they have a more severe or aggressive form of FTD, which is already impacting their ability to be active. Clinical trials that manipulate cognitive and physical activity levels in people with FTD mutations are needed to prove that lifestyle changes can alter the course of the disease."

With this caveat in mind, Casaletto hopes the findings will not only encourage care teams and individuals with family histories of FTD to adopt lifestyle changes that could provide more productive years of life, but also that the ongoing study will lead to a better biological understanding of the drivers of resilience in people with FTD.

"We can see that lifestyle differences impact people's resilience to FTD despite very penetrant genetics, so now we can start to ask more fundamental questions, like how these behaviors actually affect the brain's biology to confer that resilience." Casaletto said. "Is that biological effect something we could replicate pharmacologically to help slow the progression of this terrible disease for everyone?"

https://www.sciencedaily.com/releases/2020/01/200108074801.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

Dementia spreads via connected brain networks

Brain maps allow individualized predictions of frontotemporal dementia progression

October 14, 2019

Science Daily/University of California - San Francisco

Scientists used maps of brain connections to predict how brain atrophy would spread in individual patients with frontotemporal dementia (FTD), adding to growing evidence that the loss of brain cells associated with dementia spreads via the synaptic connections between established brain networks.

In a new study, UC San Francisco scientists used maps of brain connections to predict how brain atrophy would spread in individual patients with frontotemporal dementia (FTD), adding to growing evidence that the loss of brain cells associated with dementia spreads via the synaptic connections between established brain networks. The results advance scientists' knowledge of how neurodegeneration spreads and could lead to new clinical tools to evaluate how well novel treatments slow or block the predicted trajectory of these diseases.

"Knowing how dementia spreads opens a window onto the biological mechanisms of the disease -- what parts of our cells or neural circuits are most vulnerable," said study lead author Jesse Brown, PhD, an assistant professor of neurology at the UCSF Memory and Aging Center and UCSF Weill Institute for Neurosciences. "You can't really design a treatment until you know what you're treating."

FTD, the most common form of dementia in people under the age of 60, comprises a group of neurodegenerative conditions with diverse linguistic and behavioral symptoms. As in Alzheimer's disease, the diversity of FTD symptoms reflects significant differences in how the neurodegenerative disease spreads through patients' brains. This variability makes it difficult for scientists searching for cures to pin down the biological drivers of brain atrophy and for clinical trials to evaluate whether a novel treatment is making a difference in the progression of a patient's disease.

Previous research by the study's senior author, William Seeley, MD, a professor of neurology and pathology at the Memory and Aging Center and Weill Institute, set off a sea change in dementia research by showing that patterns of brain atrophy in many forms of dementia map closely onto well-known brain networks -- groups of functionally related brain regions that work cooperatively via their synaptic connections, sometimes over long distances. In other words, Seeley's work proposed that neurodegenerative diseases don't spread evenly in all directions like a tumor, but can jump from one part of the brain to another along the anatomical circuits that wire these networks together.

In their new study -- published October 14 in Neuron -- Brown, Seeley and colleagues provided further evidence supporting this idea by examining how well neural network maps based on brain scans in healthy individuals could predict the spread of brain atrophy in FTD patients over the course of a year.

The researchers recruited 42 patients at the UCSF Memory and Aging Center with behavioral variant fronto-temporal dementia (bvFTD), a form of FTD that causes patients to exhibit inappropriate social behaviors, and 30 patients with semantic variant primary progressive aphasia (svPPA), a form of FTD that mainly impacts patients' language abilities. In their first visits to UCSF, each of these patients underwent a "baseline" MRI scan to assess the extent of existing brain degeneration and then had a follow-up scan about a year later to measure how their disease had progressed.

The researchers first estimated where the brain atrophy seen in each patient's baseline scans had begun, based on the hypothesis that brain degeneration begins in some particularly vulnerable location, then spreads out to anatomically connected brain regions. To do this, the researchers built standardized maps of the main functional partners of 175 different brain regions based on functional MRI (fMRI) scans of 75 healthy adults. They then identified which of these networks best matched the pattern of brain atrophy seen in a given FTD patient's baseline brain scans, and defined that network's central hub as the likely epicenter of the patient's degeneration.

They then used the same standardized connectivity maps to predict where the patient's brain atrophy was most likely to have spread in the follow-up scans done one year later, and compared the accuracy of these predictions to others that didn't take functional network connectivity into account.

They found that two particular connectivity measures significantly improved their predictions of a given brain region's chances of developing brain atrophy between the baseline and follow-up brain scans. One, called "shortest path to the epicenter," captured the number of synaptic "steps" that region was from the estimated disease epicenter -- essentially the number of links in the neural chain connecting the two areas -- while the other, called "nodal hazard," represented how many regions connected to a given region were already experiencing significant atrophy.

"It's like with an infectious disease, where your chances of becoming infected can be predicted by how many degrees of separation you have from 'Patient Zero' but also by how many people in your immediate social network are already sick," Brown said.

The researchers showed that on average these two measures of network connectivity did better at predicting the spread of disease to a new brain region than its simple straight-line distance from a patient's existing atrophy. In many cases the disease completely bypassed brain areas that were adjacent but not anatomically connected to already-atrophied regions, instead jumping to more functionally linked regions.

Although this method shows great promise, the researchers emphasize that it is not yet ready for clinical use. They hope to improve the accuracy of their predictions by -- among other approaches -- using individualized network maps for each patient rather than using average connectivity maps, and by developing more specialized prediction models for particular subtypes of FTD.

In addition to the biological insights the discovery provides about the mechanisms of spreading brain atrophy in FTD, which will inform ongoing efforts to develop treatments, the researchers also hope the findings will lead to improved metrics for evaluating therapies already entering clinical trials -- for instance by giving trial scientists early insights into whether the treatment is altering a predicted course of disease progression. Researchers could also use better predictions of how atrophy will spread through the brain to help prepare patients and their families for the symptoms they are likely to experience as their disease progresses.

"We are excited about this result because it represents an important first step toward a more precision medicine type of approach to predicting progression and measuring treatment effects in neurodegenerative disease," Seeley said.

In the future, Brown said, scientists might be able to develop therapies that specifically target the likely next site of disease and perhaps prevent atrophy from spreading from one region to another.

"Just like epidemiologists rely on models of how infectious diseases spread to develop interventions targeted to key hubs or choke points," Brown said. "Neurologists need to understand the underlying biological mechanisms of neurodegeneration to develop ways of slowing or halting the spread of the disease."

https://www.sciencedaily.com/releases/2019/10/191014111730.htm

Is it Alzheimer's disease or another dementia?

New, noninvasive method may help with diagnosis

July 26, 2017

Science Daily/American Academy of Neurology

A new method may help determine whether a person has Alzheimer's disease or frontotemporal dementia, two different types of dementia that often have similar symptoms, according to a preliminary study.

"Making the correct diagnosis can be difficult," said study author Barbara Borroni, MD, of the University of Brescia in Brescia, Italy. "Current methods can be expensive brain scans or invasive lumbar punctures involving a needle inserted in the spine, so it's exciting that we may be able to make the diagnosis quickly and easily with this non-invasive procedure."

For the technique, called transcranial magnetic stimulation (TMS), a large electromagnetic coil is placed against the scalp. It creates electrical currents that stimulate nerve cells.

Once thought to be rare, frontotemporal dementia is now believed to make up 10 to 15 percent of dementia cases. It is often initially misdiagnosed as a psychiatric problem, Alzheimer's disease or Parkinson's disease because of its wide range of symptoms. The disease generally affects people in their mid-40s to mid-60s and is characterized by severe behavior changes and language problems. While there is no cure for frontotemporal dementia, it is important to accurately identify the disease so that doctors can help patients manage their symptoms and avoid unnecessary treatment.

For the study, researchers looked at 79 people with probable Alzheimer's disease, 61 people with probable frontotemporal dementia, and 32 people of the same age who did not have any signs of dementia.

Using TMS, researchers were able to measure the brain's ability to conduct electrical signals among various circuits in the brain. They found that people with Alzheimer's disease mainly had problems with one type of circuit, while people with frontotemporal dementia had problems with another type of circuit.

Researchers were then able to accurately distinguish frontotemporal dementia from Alzheimer's disease with 90 percent accuracy, Alzheimer's disease from healthy brains with 87 percent accuracy and frontotemporal dementia from healthy brains with 86 percent accuracy. The results were almost as good when researchers tested only people with mild forms of the disease. The accuracy of the results for a comparison of the two patient groups was comparable to tests with positron emission tomography (PET) brain scans or through testing spinal fluid through lumbar punctures, Borroni said.

Limitations of the study include that those operating the stimulation device were aware when they were conducting the procedure on a healthy person, but they did not know whether the other participants had Alzheimer's disease or frontotemporal dementia. In addition, the dementia diagnoses were not confirmed by autopsy after death.

"If our results can be replicated with larger studies, this will be very exciting," Borroni said. "Doctors might soon be able to quickly and easily diagnose frontotemporal dementia with this non-invasive procedure. This disease unfortunately can't be cured, but it can be managed -- especially if it is caught early."

https://www.sciencedaily.com/releases/2017/07/170726161142.htm