Tanz Centre for Research in Neurodegenerative Diseases

Researchers propose biologically based classification system for Parkinson’s disease

rahul.kalvapalle — Tue, 20 Aug 2024 16:17:45 +0000

Researchers propose biologically based classification system for Parkinson’s disease

rahul.kalvapalle Tue, 08/20/2024 - 12:17

Cutline

The "SynNeurGe" classification system for Parkinson's disease, proposed by researchers led by Professor Anthony Lang of the University Health Network and �鶹��Ƶ, is based on three key biomarkers (photo by FG Trade/Getty Images)

Eileen Hoftyzer

Topic

Breaking Research

Department of Medicine

Temerty Faculty of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

Parkinson's

University Health Network

Subheadline

The classification system could enable advancements in the development of tailored treatments for Parkinson's disease

A team of researchers led by Anthony Lang of the University Health Network and the University of Toronto have proposed a novel classification system for Parkinson’s disease that considers biological features and not just clinical symptoms.

The "SynNeurGe" system, described by Lang and collaborators in a paper published in The Lancet Neurology, classifies Parkinson’s disease based on three biomarkers: presence or absence of misfolded alpha synuclein protein, which is believed to cause or contribute to the underlying neurodegeneration; evidence of neurodegeneration using imaging techniques; and presence of gene variants that increase disease risk.

The researchers argue that such a classification system is necessary to advance the development of tailored treatments for Parkinson’s disease.

Professor Anthony Lang (supplied image)

“This is a complex group of disorders that may cause similar symptoms, but biologically they're very different,” says Lang, a senior scientist and Lily Safra Chair in Movement Disorders at UHN and a professor in the department of medicine and the Tanz Centre for Research in Neurodegenerative Disease at �鶹��Ƶ’s Temerty Faculty of Medicine, where he holds the Jack Clark Chair for Parkinson’s Disease Research

“If we cannot find ways to subdivide patients biologically, then applying a therapy designed to affect one biological pathway may not be effective in another group of patients that doesn't have that same pathway involved – and we won’t really have precision or personalized medicine for Parkinson’s disease.”

Currently, Parkinson’s disease is classified based on clinical presentation and symptoms, but the disease can affect the brain for years, possibly even decades, before symptoms appear. For future therapies to treat the underlying disease rather than just the symptoms, patients will need early intervention and treatments tailored to the biological features of the disease, researchers say.

Similar approaches are being used for other diseases – cancer treatments vary not only by the location of tumors but also their molecular features, and the development of drugs for Alzheimer’s disease is increasingly guided by the specific biological mechanisms involved in the disease.

The SynNeurGe classification system, while based on the three key biomarkers, also considers whether clinical features are present. The different combinations of biomarkers classify the disease into various sub-types.

Lang and co-authors note that such a classification should only be used for research at present, although it will almost certainly have clinical applications.

“Eventually we will see a biological approach influencing clinical care, particularly when we finally have effective disease-modifying therapies,” says Lang. “We currently don’t know how important these biomarkers actually are.

"We need large-scale prospective studies of biomarkers, imaging and clinical features to interpret the results, give patients accurate information about their diagnosis and provide appropriate treatment.”

Lang’s team plans to start conducting such studies of cerebrospinal fluid, skin and blood to look for biomarkers of different sub-types of Parkinson’s disease that will help inform the classification system and the development of tailored therapies.

“Now is the time to think about these diseases not solely based on their clinical manifestations, but to look at the biology and try to separate different biological subtypes so we can ultimately improve treatment for this disease,” Lang says.

Professor Graham Collingridge, director of the Tanz Centre, says Lang and his team’s “landmark paper” is poised to have a significant impact on clinical practice around Parkinson's. “I am delighted that our researchers have played such a key role in this important biological classification,” Collingridge says.

Lang says research by Tanz Centre scholars has contributed significantly to the body of knowledge used to develop the proposed biological classification.

For example, Professor Ekaterina Rogaeva’s research on the genetics and epigenetics of Parkinson’s disease has shown that multiple genes and environments can influence Parkinson’s risk, highlighting the need to tailor therapies based on a patient’s genetic makeup.

Other researchers – including Anurag Tandon, Joel Watts, Martin Ingelsson and Gabor Kovacs – have been studying the role of misfolded alpha synuclein in neurodegeneration as well as cases of Parkinson’s disease where alpha synuclein is absent – which informed how Lang’s team included the protein in the classification.

Study suggests two-pronged approach to treatment for neurodegenerative disease

Christopher.Sorensen — Mon, 28 Aug 2023 14:08:07 +0000

Study suggests two-pronged approach to treatment for neurodegenerative disease

Christopher.Sorensen Mon, 08/28/2023 - 10:08

Cutline

Shelley Forrest, a neuropathologist and research associate in the lab of Gabor Kovacs, co-authored a study that uncovered the subtypes of brain cells associated with the production of a key protein involved in the development of a neurodegenerative disease (supplied image)

Eileen Hoftyzer

Topic

Breaking Research

Temerty Faculty of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

Research & Innovation

Researchers at the University of Toronto’s Tanz Centre for Research in Neurodegenerative Diseases have used novel techniques to uncover which subtypes of brain cells express genetic material that produces tau, a key protein involved in the development of the neurodegenerative disease progressive supranuclear palsy (PSP).

The study, published recently in the journal Acta Neuropathologica, suggests that a two-pronged approach to treatment that targets two key mechanisms in disease development may be more effective than current methods.

“This study uses a novel methodology to show that the glial cells – the supporting brain tissue – can produce tau themselves and become diseased without taking up tau from nerve cells. Therefore, glial cells are more important in disease pathogenesis than previously assumed,” says Gabor Kovacs, investigator at the Tanz Centre and a professor in the Temerty Faculty of Medicine’s department of laboratory medicine and pathobiology.

“This study also shows that RNA expression of tau, thus the production of tau, is preserved during disease and providing a continuous supply of tau, which should be kept in mind in therapy development.”

One of the most common features of neurodegenerative diseases such as PSP and Alzheimer’s disease is the accumulation of misfolded tau protein in neurons and their supporting cells, impairing the function of these cells.

Researchers have long debated which brain cells express the gene MAPT, which codes for tau. For decades, the dominant view has been that neurons express MAPT RNA, but glial cells do not.

Shelley Forrest, a neuropathologist and research associate with Kovacs’ team, says that neuropathologists have observed that glial cells contain tau aggregates, but there was no solid evidence about where it was coming from.

“In these neurodegenerative diseases, we find pathological tau aggregates in the glia, so there’s always been active debate on why tau pathology accumulates in glia, and whether it’s produced by neurons and taken up by glia or whether glia can make it themselves independently,” says Forrest.

The research team, which included collaborators in Australia and Dubai, examined brain tissue samples from three patients who had PSP and three who did not. Having access to these post-mortem patient samples – which Forrest describes as “the most generous gift anyone can give” – allowed the researchers to have a more complete and realistic view of the RNA expression in different brain cell types compared to using animal models or cell cultures.

The team used innovative RNAscope technology to visualize RNA molecules under the microscope, as well as single nucleus RNA sequencing, in order to map RNA expression in different brain regions and different types of brain cells. The patient samples combined with the new technology allowed the researchers to visualize for the first time where MAPT RNA is expressed in the brain.

The team found that different brain regions and brain cells differ in the amount of MAPT RNA they express. And, importantly, they identified that glial cells do express MAPT RNA – providing the first solid evidence of its presence in these cells. This means that glial cells are not only taking up misfolded tau produced by neurons, but are also making it themselves.

“We’ve long had this suspicion, but now we’ve been able to get the evidence to demonstrate that this is the case,” says Forrest. “How and why tau accumulates in glia in PSP is not entirely clear, but our study highlights two novel mechanistic pathways for the cell-to-cell transmission of misfolded tau and accumulation in the brain, which is an exciting result.”

The study results suggest that a two-pronged approach to therapy – targeting both the misfolded tau protein and MAPT RNA expression – could be the best strategy for treating PSP and similar diseases.

“Because we’re proposing two different pathways for the pathogenesis of the disease, if you only focus on one, you’re just getting half the picture,” says Forrest. “If you block one pathway, it will just proceed with the other pathway. You’ve got to block both.”

Kovacs’ team will now use similar techniques to study this same question in other neurodegenerative diseases. They will also follow up on their results to understand RNA expression across the different brain regions.

“Our team is one of the first to use these techniques in neurodegenerative-diseased human brain samples. We will now expand this examination to other diseased proteins and map how changes in the tau RNA expression affect expression of crucial genes at the cellular level, focusing on glial cells,” Kovacs says.

“Ultimately, this work will inform basic researchers to focus on glial cells – not just neurons – when trying to unravel the pathogenesis of PSP, and will inform therapy developers to not only remove misfolded tau as they currently do, but also decrease production of normal tau using RNA-based therapies.”

Research challenges long-held view of early-stage Alzheimer's disease

siddiq22 — Wed, 05 Jul 2023 03:12:54 +0000

Research challenges long-held view of early-stage Alzheimer's disease

siddiq22 Tue, 07/04/2023 - 23:12

Cutline

Gerold Schmitt-Ulms, a professor in the Temerty Faculty of Medicine's department of laboratory medicine and pathology, was one of the authors of the new study (supplied image)

Eileen Hoftyzer

Topic

Breaking Research

Temerty Faculty of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

Laboratory Medicine and Pathobiology

Medical Research

Research & Innovation

Subheadline

A new study by researchers from �鶹��Ƶ's Tanz Centre for Research in Neurodegenerative Diseases examines how a hormone called somatostatin influences the earliest stages of the disease

Recent research from the Tanz Centre for Research in Neurodegenerative Diseases in the University of Toronto's Temerty Faculty of Medicine is challenging long-held views of how a hormone called somatostatin influences the earliest stages of Alzheimer’s disease.

“Importantly, for the first time, this research indicates the extent to which somatostatin could be important in Alzheimer’s disease,” says Gerold Schmitt-Ulms, co-author of the study published in Scientific Reports.

“The answer is that somatostatin has a significant effect, but it’s not black or white. It doesn’t prevent clumping of the amyloid beta protein, but slows it down. This is important, but we don’t know what this means for treatment yet,” says Schmitt-Ulms, an investigator at the Tanz Centre and professor in �鶹��Ƶ’s department of laboratory medicine and pathology.

The dominant hypothesis of how Alzheimer's disease begins – the amyloid cascade hypothesis – says that too much amyloid beta protein is produced, which clumps together to form oligomers (small clumps of varying numbers of amyloid beta monomeric building blocks), which then continue to accumulate to form larger plaques that damage neurons.

As early as the 1970s, researchers observed that brains of people with Alzheimer’s disease had lower levels of the hormone somatostatin than people who did not have Alzheimer’s, and that the plaques of amyloid beta that are characteristic of the disease tend to form near neurons that produce somatostatin.

These observations suggested a relationship between somatostatin and amyloid beta aggregation, but researchers did not know what it was.

Then, in the early 2000s, a team from Japan published research describing that somatostatin drives production of an enzyme called neprilysin that can degrade amyloid beta. This finding suggested that if somatostatin was decreased, the levels of neprilysin would decrease – without neprilysin to degrade amyloid beta, the plaques would continue to grow, and Alzheimer's disease would progress.

This understanding of the role of somatostatin is where the field stood for more than a decade.

An image from the study summarizing its key findings (supplied image)

Several years ago, Schmitt-Ulms and his team investigated amyloid beta in its monomer and oligomer forms, specifically looking for molecules in the brain that would bind to the toxic oligomeric forms. They found that, of all proteins in the brain, somatostatin was the smallest to bind to amyloid beta – and the most selective, as it only interacted with the oligomers.

They then observed that somatostatin blocked the formation of oligomers, with higher concentrations of somatostatin having a greater effect. This earlier study provided the first evidence that somatostatin interacts directly with the oligomeric amyloid beta that are known to be the earliest stages of Alzheimer's disease, providing an alternative perspective on the impact of somatostatin on the disease.

“We didn’t actually intend to work on somatostatin, but these results made us very curious about what would happen if somatostatin was absent in an animal model that was genetically engineered to develop amyloid beta aggregations,” Schmitt-Ulms explains.

To answer this question, the research team crossed a somatostatin-deficient mouse line with an amyloidosis mouse model.

They found that when somatostatin was absent, there were more amyloid beta aggregates, consistent with what is seen in Alzheimer’s disease in humans.

Remarkably, the result did not seem to be caused by an effect of somatostatin on neprilysin levels, as there were no differences – a contradiction to the long-held understanding of the mechanism through which somatostatin impacts Alzheimer’s disease. Instead, the data suggested that somatostatin blocks oligomer formation independent of neprilysin by interacting with amyloid beta.

“There isn’t a lot of literature that explains how the environment in the brain can promote or inhibit amyloid beta forming into oligomers, so this is a nice vignette that shows that one molecule – somatostatin – seems to influence that first small oligomeric aggregation step,” Schmitt-Ulms says.

“And if you get fewer of these oligomeric forms, then you get fewer of the small clumps, which are the next step of amyloid beta aggregation – so the process made sense, and it was a striking finding.”

While the results have challenged the conventional view of somatostatin in Alzheimer’s and prompted discussions in the scientific community, what they mean for treatment is still uncertain.

Somatostatin plays important roles in the gastrointestinal, endocrine and nervous systems, so selectively promoting its role in blocking amyloid aggregation would be challenging. Schmitt-Ulms says that it is also unclear whether augmenting somatostatin, and thereby arresting the growth of amyloid beta aggregates, is beneficial.

Still, the results have shaken up the research field.

“The evidence speaks for itself, and we stand by our conclusions, but the data can’t answer what this means for therapeutics,” Schmitt-Ulms says.

“They do, however, indicate that somatostatin – one of the first-ever molecules that were biochemically linked to Alzheimer’s disease – may play a different role in the earliest stages of the disease than expected, and that in itself is important.”

The study was supported by Alberta Innovates Bio Solutions, Ontario Centres for Excellence/MaRS Innovation and the Borden Rosiak family.

Researchers identify a potential new therapeutic target in Parkinson’s disease

siddiq22 — Mon, 24 Apr 2023 13:50:47 +0000

Researchers identify a potential new therapeutic target in Parkinson’s disease

siddiq22 Mon, 04/24/2023 - 09:50

Cutline

A new study by researchers from UHN and �鶹��Ƶ examined how to prevent the accumulation in the brain of a protein that contributes to Parkinson's disease (photo by Christian Wiediger via Unsplash)

Topic

Breaking Research

Temerty Faculty of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

Donnelly Centre for Cellular & Biomolecular Research

Medical Research

Neurology

Parkinson's

University Health Network

A team of researchers from the Krembil Brain Institute (KBI) and the University of Toronto have identified a protein-protein interaction that contributes to Parkinson’s disease.

In a study published in Nature Communications, KBI scientists Lorraine Kalia and Suneil Kalia and �鶹��Ƶ researcher Philip M. Kim examined a protein called alpha-synuclein (a-syn) that accumulates in the brain in patients with Parkinson's and leads to cell death.

Much research is currently focused on clearing a-syn with antibodies or using small molecules to prevent a-syn from aggregating. In their study, the researchers took an alternate approach by looking for protein-protein interactions that may be promoting the accumulation of a-syn in Parkinson’s disease.

Protein-protein interactions govern most inner workings of the cell, including breaking down disease-causing proteins. Inhibiting certain interactions has emerged as a promising approach to treat diseases such as stroke and cancer.

“Identifying a particular interaction that contributes to a disease, and then finding ways to disrupt it, can be a painstaking and incredibly slow process,” says Lorraine Kalia, who is also a staff neurologist at University Health Network, a scientist at �鶹��Ƶ’s Tanz Centre for Research in Neurodegenerative Diseases and an assistant professor in the division of neurology and in the department of laboratory medicine and pathobiology in the Temerty Faculty of Medicine.

“We all started out a bit skeptical that we would have something useful at the end, and so the fact that we do have something that warrants further work is much more than we anticipated.”

Kim, who is a professor in �鶹��Ƶ’s Donnelly Centre for Cellular and Biomolecular Research and in the department of molecular genetics in the Temerty Faculty of Medicine, notes the team took an approach they hoped would expedite the discovery of potential therapies.

“We developed a platform to screen molecules called peptide motifs – short strings of amino acids that can disrupt protein-protein interactions – for their ability to protect cells from a-syn,” Kim says. “Once we identified candidate peptides, we determined which protein-protein interactions they target.”

Through this approach, the team identified a peptide that reduced a-syn levels in cells by disrupting the interaction between a-syn and a protein subunit of the cellular machinery called “endosomal sorting complex required for transport III” (ESCRT-III).

“ESCRT-III is a component of a pathway that cells use to break down proteins, called the endolysosomal pathway. We discovered that a-syn interacts with a protein within ESCRT-III – CHMP2B – to inhibit this pathway, thereby preventing its own destruction,” Lorraine Kalia says.

“We were impressed that the platform worked. But I think what was more interesting is that by doing this kind of screening, we were able to find an interaction that was really not previously characterized, and we also found a pathway that’s not yet been targeted for therapeutics.”

Once the group identified this interaction, they confirmed that they could use their peptide to disrupt it – preventing a-syn from evading the cell’s natural clearance pathways, notes Suneil Kalia, who holds the R.R. Tasker Chair in Stereotactic and Functional Neurosurgery at UHN and is an associate professor in the division of neurosurgery in the Temerty Faculty of Medicine.

“We tested the peptide in multiple experimental models of Parkinson’s disease, and we consistently found that it restored endolysosomal function, promoted a-syn clearance and prevented cell death,” he says.

These findings indicate that the a-syn-CHMP2B interaction is a potential therapeutic target for the disease, as well as other conditions that involve a buildup of a-syn, such as dementia with Lewy bodies (another disease associated with abnormal deposits of a-syn in the brain).

The next steps for this research are to clarify exactly how a-syn and CHMP2B interact to disrupt endolysosomal activity. Ongoing studies are also determining the best approach for delivering potential therapeutics to the brain.

“This research is still in its early stages – more work is definitely needed to translate this peptide into a viable therapeutic,” cautions Lorraine Kalia. “Nonetheless, our findings are very exciting because they suggest a new avenue for developing treatments for Parkinson’s disease and other neurodegenerative conditions.”

This study also highlights the value of multidisciplinary collaborations in health research.

“We simply could not have conducted this study in a silo. The endolysosomal pathway is underexplored, so it was not an obvious place to look for potential disease-related protein-protein interactions. Dr. Kim’s screening platform was critical for pointing us in the right direction,” Suneil Kalia points out.

“It is really extraordinary to see this platform – which we initially used to find potential therapeutics for cancer – yielding advances in brain research. The pathways that cells use to stay healthy are fundamentally very similar across tissues, so the insights that we gain about one organ system or disease could have important implications in other contexts,” Kim says.

“It’s really brand-new science and targets that haven’t been a focus for drug development for Parkinson’s," Lorraine Kalia adds. "We hope this changes the landscape for treatment of this disease, which is so in need of new therapies.”

The research was supported by the Canadian Institutes of Health Research, the Michael J. Fox Foundation for Parkinson’s Research, Parkinson’s UK, the Canada Foundation for Innovation, the Ontario Research Fund, the Krembil Research Institute and the UHN Foundation.

This story was originally published on the website of the Krembil Brain Institute, University Health Network.

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Loss of key protein could be crucial to understanding ALS: Study

Christopher.Sorensen — Fri, 31 Mar 2023 15:57:59 +0000

Loss of key protein could be crucial to understanding ALS: Study

Christopher.Sorensen Fri, 03/31/2023 - 11:57

Cutline

Janice Robertson, left, and Philip McGoldrick, right, found that the loss of the C9orf72 protein may contribute to the underlying cause of amyotrophic lateral sclerosis and frontotemporal dementia (supplied images)

Eileen Hoftyzer

Topic

Breaking Research

Temerty Faculty of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

Research & Innovation

University Health Network

Researchers at the University of Toronto have shown that loss of a key protein in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) may contribute to the underlying cause of both diseases.

The protein, known as C9orf72 (C9) and expressed by a gene with the same name, affects movement of molecules between the nucleus and the cytoplasm in the neurons affected in ALS and FTD, the researchers found.

“Here we have uncovered a role for C9orf72 in regulating nucleocytoplasmic transport, a crucial mechanism that causes cellular dysfunction if disrupted,” says Janice Robertson, a professor in the department of laboratory medicine and pathology in �鶹��Ƶ’s Temerty Faculty of Medicine and scientist at the Tanz Centre for Research in Neurodegenerative Diseases.

The journal Cell Reports published the findings.

A mutation in the gene C9 is the most common genetic cause of ALS, found in about 40 per cent of familial cases and 10 per cent of sporadic cases. Mutations in this gene may cause disease in two different ways: gain of function, where the mutation leads to the creation of abnormal RNA and proteins; or loss of function, where the C9 protein is reduced, affecting its normal function.

While many research teams have focused on the gain-of-function mechanisms, Robertson’s lab has been studying what happens in cells when C9 protein is absent or reduced.

“Most of the research in the field has been done on the gain-of-function mechanisms, but recent clinical trials targeting these mechanisms have not been entirely successful, suggesting that gain-of-function mechanisms may not be the sole contributors to disease,” says Philip McGoldrick, a research associate in Robertson’s lab and first author on the study. “Our previous research has suggested that normal C9 protein levels could be protective against disease, and other researchers have shown that the gain-of-function mechanisms are exacerbated when C9 protein is lost; however, we don’t know through which pathways this modifying effect occurs.”

In the past, researchers have proposed that interruptions in the mechanism that shuttles molecules between the nucleus and the cytoplasm, known as nucleocytoplasmic transport, may be an underlying cause of ALS. And Robertson’s lab has previously uncovered that the C9 protein interacts with other molecules that are important in this transport system.

In their newest research, they focused specifically on how the loss of C9 affects nucleocytoplasmic transport. They used cell lines, motor and cortical neurons and animal models to visualize the activity of the key transport molecules when C9 was reduced or absent.

In each case, they were able to show that loss of the C9 protein affected nucleocytoplasmic transport such that important molecules and proteins that perform functions related to gene expression and translation are not where they should be.

“Previously, researchers thought that loss of function was having a very minor effect, but there’s been lots more work that has showed that you actually may need multiple mechanisms to result in disease,” says McGoldrick. “Our work makes an important contribution because it shows for the first time that loss of C9 can affect nucleocytoplasmic transport mechanisms that we know are also affected by the gain-of-function mechanisms.”

McGoldrick recently received a Career Transition Award from the ALS Society of Canada and Brain Canada that will support his continuing studies on the topic and help his transition to an independent research career in Canada. The award provides both salary support and research funding for three years.

“The Career Transition Award is a well-deserved accolade for Philip and exemplifies the importance of his research toward findings a cure for ALS and FTD,” says Robertson.

With the award, McGoldrick plans to continue studying transport between the nucleus and the cytoplasm and the nuclear pore – the structure through which transport takes place – to gain more insight into the underlying mechanisms of ALS and how the C9 protein may be involved.

“This is a massive boost to my career,” he says. “It will enable me to pursue this research for the next few years and will make a substantial contribution to what we know about C9 loss of function contributing to disease.”

The research was supported by the ALS Society of Canada, Brain Canada, the James Hunter ALS Initiative and ALS Double Play.

Sean Nuttall completes record-breaking Lake Ontario swim to raise money for �鶹��Ƶ brain research

mattimar — Wed, 17 Aug 2022 15:57:23 +0000

Sean Nuttall completes record-breaking Lake Ontario swim to raise money for �鶹��Ƶ brain research

mattimar Wed, 08/17/2022 - 11:57

Cutline

(Photo courtesy of Sean Nuttall)

Topic

Breaking Research

Temerty Faculty of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

In honour of his late father, marathon swimmer Sean Nuttall recently completed a 100-kilometre swim across Lake Ontario and back to raise funds for brain research at the University of Toronto’s Tanz Centre for Research in Neurodegenerative Diseases.

Nuttall’s father, a criminal defence lawyer in Toronto, died five years ago after a brief struggle with a neurodegenerative disease that doctors were unable to indentify.

“Having grown up in Toronto, I have a lot of respect for the University of Toronto, the Tanz Centre and what they do,” Nuttall told �鶹��Ƶ writer Deanna Cheng before embarking on the swim last weekend. “I’m hoping this swim inspires others to dream big while also supporting a wonderful cause. Every little bit helps.”

Nutall swam from Toronto to St. Catherine’s and back non-stop, marking the longest unassisted open-water swim in Canada or by a Canadian. He did not use a wetsuit or flotation devices and completed the journey in 42 hours, according to the Toronto Sun.

�鶹��Ƶ researchers find key differences in symptoms between early- and late-onset Alzheimer's

geoff.vendeville — Thu, 20 May 2021 14:04:15 +0000

�鶹��Ƶ researchers find key differences in symptoms between early- and late-onset Alzheimer's

geoff.vendeville Thu, 05/20/2021 - 10:04

Cutline

Carmela Tartaglia and Melisa Gumus of the Temerty Faculty of Medicine are among the co-authors of a study that found key differences in symptoms between people with early- and late-onset Alzheimer's (photos courtesy of UHN and Melisa Gumus)

Andrea Haman

Topic

Breaking Research

Insulin 100

Temerty Faculty of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

Graduate Stories

Neurology

University Health Network

While Alzheimer’s disease most often appears in late life, as many as one in 10 people who develop it begin to experience the disease before age 65. This young-onset version is often undetected and misdiagnosed, with debilitating results.

In a recent study, University of Toronto researchers have found key differences in symptoms between people who develop Alzheimer’s earlier versus later. The researchers showed that two mental illness symptoms – depression and anxiety – are much more common in people with young-onset Alzheimer’s than in those with late-onset Alzheimer’s.

The findings underscore the need to consider Alzheimer’s in midlife when these symptoms occur with cognitive or thinking problems, and may improve diagnosis and the quality of life for affected individuals.

“If you get cognitive impairment at age 55, people are not thinking about Alzheimer’s disease,” says Carmela Tartaglia, an associate professor in the Tanz Centre for Research in Neurodegenerative Diseases in the Temerty Faculty of Medicine and the senior author of the study published earlier this year in the journal GeroScience. “The fact that people get Alzheimer’s disease before age 65 is less well known, so many people have considerable delay in diagnosis, often up to five years.”

This delay can have dire consequences. “Many patients have gone through several doctors, psychiatrists or other specialists, and medications,” says Tartaglia, who also cares for patients in the Memory Clinic in University Health Network. “They've been told that they’re having a midlife crisis, are depressed or anxious, or are going through menopause. They may experience significant anxiety about losing their memory. Some people have even lost their jobs.”

The delay in diagnosis is not surprising, given that mental illness symptoms are common in people with Alzheimer’s – more than 80 per cent of people develop at least one mental illness symptom, such as depression, anxiety or apathy, as the disease progresses.

In the study, the researchers – including �鶹��Ƶ master’s student Melisa Gumus, the study’s first author – determined the prevalence and severity of mental illness symptoms over a four-year period in 126 people diagnosed with young-onset Alzheimer’s and 505 people with late-onset Alzheimer’s. When examining questionnaires about mental illness symptoms completed by caregivers, the researchers included people who were taking medications to treat mental illness symptoms as having mental illness symptoms, even if the person no longer exhibited symptoms. This novel approach provides the clearest picture of prevalence.

The study showed that depression and anxiety are much more common in young-onset patients, both at the start of and throughout the four years. For example, at the start of the study, 64 per cent of people with young-onset Alzheimer’s had depression and 33 per cent had anxiety, while 41 per cent with late-onset Alzheimer’s had depression and 17 per cent had anxiety. There was no significant difference between the two groups in the prevalence of other mental illness symptoms or in the severity of any symptoms.

While the study didn't explore why depression and anxiety are more common in young-onset patients, in addition to possible differences in disease processes, there are psychosocial differences such as heavy responsibilities for raising children, earning income or caring for elderly parents that may play a role.

“Our hope is that the findings help patients get diagnosed earlier,” says Tartaglia. “If, for example, a patient is 55 years old and has a new onset of depression or anxiety that is not situational, consider this as the beginning of neurodegenerative disease.” While there is no cure to stop the progression of Alzheimer’s, an accurate diagnosis allows people to take steps early. People at the early stages of the disease may be eligible to participate in clinical trials to slow the progression of Alzheimer’s or reduce specific symptoms. As well, people may be able to modify their work, apply for disability benefits or make other changes to improve their quality of life.

'Not all disease is the same': �鶹��Ƶ study highlights protein variability in neurodegenerative diseases

Christopher.Sorensen — Tue, 03 Dec 2019 13:46:37 +0000

'Not all disease is the same': �鶹��Ƶ study highlights protein variability in neurodegenerative diseases

Christopher.Sorensen Tue, 12/03/2019 - 08:46

Cutline

“If you’re developing therapies for Parkinson’s disease, and you’re targeting this alpha-synuclein aggregate pathology, it’s likely that one therapy may not fit all,” says �鶹��Ƶ Assistant Professor Joel Watts (photo by Gabrielle Giroday)

Gabrielle Giroday

Topic

Breaking Research

Tanz Centre for Research in Neurodegenerative Diseases

Biochemistry

Faculty of Medicine

Global

Research and Innovation

A new University of Toronto study sheds light on how protein strains vary in the brains of those affected by progressive neurodegenerative diseases like Parkinson’s, suggesting the need for patient-specific medicines.

Their research findings, published in the journal Nature Neuroscience, have important implications for people who are affected by progressive neurodegenerative diseases, and those trying to develop drugs to help them.

“It’s very evident in these diseases that there’s patient-to-patient variability. This provides a potential explanation of why,” says Joel Watts, an assistant professor in the Faculty of Medicine’s department of biochemistry and a principal investigator at the Tanz Centre for Research in Neurodegenerative Diseases.

“I think it also really gets to the concept of patient-specific medicine that might be necessary. This research also suggests a way of how that could be done.”

The research looked at the behaviour of different strains of the protein known as alpha-synuclein in the brains of mice. Alpha-synuclein is the principal pathological hallmark of Parkinson’s disease, and the research looked at whether different strains of the protein could lead to the manifestation of different diseases.

For the research, Watts and his team created two different strains of alpha-synuclein that were structurally different in test tubes. They then introduced them into mice and watched what happened.

The differing structures of the artificial strains led to different results, he says.

“What we found was that they caused two completely different types of diseases,” he says. “The mice took different amounts of time to show symptoms of diseases [and] the symptoms of the disease were different for the two. The pathological markers of disease – these protein aggregates – were found in different brain regions. That’s exactly what you see in human disease.”

Watts says the findings illuminate the complexity of the disease.

They also demonstrate the need for patient-specific medicine, he says.

“The lesson from the research is that if you’re developing therapies for Parkinson’s disease, and you’re targeting this alpha-synuclein aggregate pathology, it’s likely that one therapy may not fit all. If there are differences, you may need to have patient-specific therapies,” he says.

Watts has a background looking at prion diseases like mad cow disease.

He used his experience to inform his latest research, though he notes that, unlike prion diseases, neurodegenerative diseases such as Parkinson’s or Alzheimer’s are not infectious.

“Prion diseases are not all the same. They are sometimes transmissible from animals to humans and, in rare cases, humans to humans. There are different varieties and they’re caused by different strains of prions,” says Watts.

He also points to the flu, which requires people to get new flu shots every year due to varying strains.

“The same thing happens in neurodegenerative diseases. Instead of having changes in the viral DNA, you have changes in structure of these protein aggregates – these clumps of proteins that are pathological and found in the brains of people with diseases like Parkinson’s and Alzheimer’s,” he says.

Ultimately, the goal of Watts’s research is to develop testing paradigms for drugs that better reflect the complexity and variability of humans.

“Not all disease is the same and there is variability – and this could be explained by having different strains of alpha-synuclein,” says Watts. “We may need to consider patient-specific medicine when designing therapies or clinical trials to better classify patients into groups based on the type of strain they have.”

The study received support from the Canadian Institutes of Health Research, the Royal Society and European Research Council, among others.

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