Different biological variants discovered in Alzheimer's disease
by Amsterdam University Medical Center
Credit: Pixabay/CC0 Public Domain
Dutch scientists have discovered five biological variants of Alzheimer's disease, which may require different treatments. As a result, previously tested drugs may incorrectly appear to be ineffective or only minimally effective. This is the conclusion of researcher Betty Tijms and colleagues from Alzheimer Center Amsterdam, Amsterdam UMC and Maastricht University. Their study is published in Nature Aging.
29 jan 2029--In those with Alzheimer's disease, theamyloidand tau proteins clump in the brain. In addition to these clumps, otherbiological processessuch as inflammation and nerve cell growth are also involved. Using new techniques, the researchers have been able to measure these other processes in thecerebrospinal fluidof patients with amyloid and tau clumps.
Betty Tijms and Pieter Jelle Visser examined 1,058 proteins in the cerebrospinal fluid of 419 people with Alzheimer's disease. They found that there are five biological variants within this group. The first variant is characterized by increased amyloid production. In a second type, the blood-brain barrier is disrupted, and there is reduced amyloid production and less nerve cell growth.
Furthermore, the variants differ in the degree of protein synthesis, the functioning of the immune system, and the functioning of the organ that produces cerebrospinal fluid. Patients with different Alzheimer's variants also showed differences in other aspects of the disease. For example, the researchers found a faster course of the disease in certain subgroups.
The findings are of great importance for drug research. They could mean that a certain drug might only work in one variant of Alzheimer's disease. For example, medication that inhibits amyloid production may work in the variant with increased amyloid production, but may be harmful in the variant with decreased amyloid production. It is also possible that patients with one variant would have a higher risk of side effects, while that risk would be much lower with other variants.
The next step for the research team is to show that the Alzheimer's variants do indeed react differently to medicines, in order to treat all patients with appropriate medicines in the future.
More information: Cerebrospinal fluid proteomics in Alzheimer's disease patients reveals five molecular subtypes with distinct genetic risk profiles, Nature Aging (2024). DOI: 10.1038/s43587-023-00550-7 , www.nature.com/articles/s43587-023-00550-7
Tuesday, September 19, 2023
Exercise-induced hormone irisin may reduce Alzheimer's disease plaque and tangle pathology in the brain
Researchers who previously developed the first 3D human cell culture models of Alzheimer's disease (AD) that displays two major hallmarks of the condition—the generation of amyloid beta deposits followed by tau tangles—have now used their model to investigate whether the exercise-induced muscle hormone irisin affects amyloid beta pathology.
19 set 2023--As reported in the journalNeuron, the Massachusetts General Hospital (MGH)–led team has uncovered promising results suggesting that irisin-based therapies might help combat AD.
Physical exercise has been shown to reduce amyloid beta deposits in various mouse models of AD, but the mechanisms involved have remained a mystery.
Exercise increases circulating levels of the muscle-derived hormone irisin, which regulates glucose and lipid metabolism in fat tissue and increases energy expenditure by accelerating the browning of white fat tissue.
Studies have revealed that irisin is present in human and mouse brains and that its levels are reduced in patients with AD and in mouse models of the condition.
To test whether irisin plays a causal role in the link between exercise and reduced amyloid beta, Se Hoon Choi, Ph.D. and Eun Hee Kim, Ph.D., of the Genetics and Aging Research Unit at MGH, along with additional research colleagues applied the hormone to their 3D cell culture model of AD.
"First, we found that irisin treatment led to a remarkable reduction of amyloid beta pathology," says Choi. "Second, we showed this effect of irisin was attributable to increased neprilysin activity owing to increased levels of neprilysin secreted from cells in the brain called astrocytes."
Neprilysin is an amyloid beta–degrading enzyme that has been found to be elevated in the brains of mice with AD that were exposed to exercise or other conditions leading to reduced amyloid beta.
The researchers uncovered even more details about the mechanisms behind irisin's link to reduced amyloid beta levels. For example, they identified integrin αV/β5 as the receptor that irisin binds to on astrocytes to trigger the cells to increase neprilysin levels.
Furthermore, they discovered that irisin's binding to this receptor causes reduced signaling of pathways involving two key proteins: extracellular signal-regulated kinase (ERK) and signal activator of transcription 3 (STAT3). Reduced ERK-STAT3 signaling was critical for irisin-induced enhancement of neprilysin.
Previous studies have shown that in mice, irisin injected into the blood stream can make its way into the brain, making it potentially useful as a therapeutic.
"Our findings indicate that irisin is a major mediator of exercise-induced increases in neprilysin levels leading to reduced amyloid beta burden, suggesting a new target pathway for therapies aimed at the prevention and treatment of Alzheimer's disease," says Rudolph Tanzi, Ph.D., a senior author of the study and director of the Genetics and Aging Research Unit.
Additional co-authors include Hyeonwoo Kim, Mark P. Jedrychowski, Grisilda Bakiasi, Joseph Park, Jane Kruskop, Younjung Choi, Sang Su Kwak, Luisa Quinti, Doo Yeon Kim, Christiane D. Wrann, and Bruce M. Spiegelman.
Epidemiological studies have shown that women are twice as likely as men to develop Alzheimer's disease (AD), but the cause of this phenomenon has been unclear.
09 mar 2022--Now, however, a study led by Prof. Keqiang Ye from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences provides a clear answer to this mystery that has puzzled mankind for decades.
Their findings were published in Nature on March 2.
Integrating their previous studies, Prof. Ye's team has established the theory that the C/EBPβ/AEP pathway is the core factor driving the pathogenesis of neurodegenerative diseases.
"Based on this theory, our team searched for female hormones that are dramatically changed during menopause and tested which hormone selectively activates the C/EBPβ/AEP pathway," said Prof. Ye.
Prof. Ye's team identified follicle-stimulating hormone (FSH) as the major pathogenic factor.
"During menopause, the serum concentration of FSH strongly increases, binding to the cognate FSH receptor on neurons and activating the C/EBPβ/AEP pathway. This results in Aβ and Tau pathologies, leading to the development of AD," said Dr. Zaidi Mone, co-corresponding author of the study and a tenured professor at the Mount Sinai School of Medicine in New York.
The researchers employed different methods to demonstrate this finding. Using ovariectomized mice, they used anti-FSH antibody treatment to block FSH and inactivate the C/EBPβ/AEP pathway. They also deleted FSH receptor (FSHR) expression in neurons to abolish the binding of FSH to FSHR in the hippocampus. Both of these methods alleviated pathology and cognitive dysfunction. In addition, knockdown of C/EBPβ in the AD mice model decreased AD pathologies.
Besides working with female mice, the researchers also injected FSH into male mice and discovered that FSH promoted AD pathologies.
All these findings suggest that increased FSH after menopause binds to FSHR in neurons and activates the C/EBPβ/AEP pathway, which plays an important role in triggering AD pathology.
In the near future, the team will focus on dissecting the relationship between specific risk genes such as ApoE4 and FSH to explore why female ApoE4 carriers are more vulnerable to developing AD.
"Our findings demonstrate that the C/EBPβ/AEP signaling pathway acts as a core factor in these age-dependent diseases, which may help disclose how a variety of risk factors mediate neurodegenerative diseases via activating this pathway," said Dr. Seong Su Kang from Emory University.
In addition, Prof. Ye's team is extending this theory to numerous age-dependent chronic diseases such as diabetes, atherosclerosis, cancer, and aging.
An MRI scan of the hippocampus, the brain’s memory center, in an older person with no signs of cognitive decline (left) and a person of similar age with mild Alzheimer’s (right) has been analyzed with a new technique that shows where healthy brain cells have been lost (dark areas). New research from Washington University School of Medicine in St. Louis shows that this novel MRI approach can identify brain cell damage in people at early stages of Alzheimer’s, before tissue shrinkage is visible on traditional MRI scans. Credit: Satya Kothapalli/School of Medicine
Alzheimer's disease usually is diagnosed based on symptoms, such as when a person shows signs of memory loss and difficulty thinking. Up until now, MRI brain scans haven't proven useful for early diagnosis in clinical practice. Such scans can reveal signs of brain shrinkage due to Alzheimer's, but the signs only become unmistakable late in the course of the disease, long after the brain is significantly damaged and most people have been diagnosed via other means.
09 mar 2022--But new research from Washington University School of Medicine in St. Louis shows that a mathematical analysis of data obtained with a novel MRI approach can identifybraincell damage in people at early stages of Alzheimer's, before tissue shrinkage is visible on traditional MRI scans and before cognitive symptoms arise.
"This could be a new way to use MRI to diagnose people with Alzheimer's before they develop symptoms," said senior author Dmitriy Yablonskiy, Ph.D., a professor of radiology at the university's Mallinckrodt Institute of Radiology. "The technique takes only six minutes to acquire data and can be implemented on MRI scanners that are already used worldwide for patient diagnostics and clinical trials."
Published in the Journal of Alzheimer's Disease, the study relies on a new quantitative Gradient Echo (qGRE) MRI technique developed in the Yablonskiy lab to show brain areas that are no longer functioning due to a loss of healthy neurons.
"Using this technique in patients with Alzheimer's disease, we discovered brain areas that look normal on traditional MRI but look dark on qGRE images, which we attribute to significant neurodegeneration," said Satya V. V. N. Kothapalli, Ph.D., a staff scientist in radiology and the first author of the study. "We call them 'dark matter.'"
While traditional MRI is capable of showing where damaged areas of the brain have decreased in volume, the qGRE technique goes a step further, detecting the loss of neurons that precedes brain shrinkage and cognitive decline.
Alzheimer's disease develops slowly over the course of two decades or more before symptoms arise. First the brain protein amyloid beta accumulates into plaques in the brain, then another brain protein—tau—coalesces into tangles and neurons begin to die. Finally, tissue atrophy becomes visible on MRI brain scans, and cognitive symptoms arise. People at early stages of the disease can be identified via amyloid-PET brain scans or by testing for amyloid in the blood or the cerebrospinal fluid that surrounds the brain and spinal cord, but such tests do not provide information on neuronal damage.
The study involved 70 people ages 60 to 90 who were recruited through the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC). Participants completed extensive clinical and cognitive testing to assess their level of cognitive impairment. The participant group included people with no cognitive impairment as well as those with very mild, mild or moderate impairments.
Each participant underwent either a PET brain scan or a spinal tap to gauge the amount of amyloid plaques in his or her brain. They also underwent MRI brain scans.
Researchers applied the qGRE MRI technique to scan the hippocampus, the brain's memory center and one of the earliest affected brain regions in Alzheimer's. Results showed the hippocampus often contained a viable tissue section with relatively preserved neurons and a dark matter dead zone virtually devoid of healthy neurons.
These dark matter areas were present in people who tested positive for amyloid but were not yet experiencing symptoms, and they grew larger as the disease progressed. Compared with traditional MRI measures of brain atrophy, biomarkers for dark matter correlated much better with individual cognitive scores for very mild to moderate dementia.
The study builds on and corroborates findings from Alzheimer's research that took place at Washington University more than two decades ago when Alzheimer's was formally diagnosed only through autopsy.
In 2001, John C. Morris, MD, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and director of the Knight ADRC, led a study that examined the brain tissue of deceased Alzheimer's patients and found that damaged brain regions had begun to lose healthy neurons well before the disease caused a significant loss of brain volume in these areas.
Then, in the early 2000s, Tammie L. S. Benzinger, MD, Ph.D., a professor of radiology and of neurosurgery, and the Knight ADRC's director of imaging studies, was among the pioneers at the Mallinckrodt Institute of Radiology to use PET brain scans targeted against amyloid beta as a tool for detecting Alzheimer's.
In the current study, also co-authored by Morris and Benzinger, researchers documented the same relationship between neuronal loss and Alzheimer's symptoms using the non-invasive qGRE MRI technique in living patients.
Working with co-author Richard Perrin, MD, Ph.D., an associate professor of pathology and immunology, the research team also confirmed this relationship under the microscope by examining brain tissues that were donated after the death of a study participant. The postmortem examination showed that the neuronal loss in the hippocampus actually exceeds loss of tissue volume and that these changes are well reflected in MRI measures of dark matter.
Yablonskiy and colleagues are among the many researchers now pursuing a low-cost, easily accessible test for Alzheimer's as an alternative to the expensive PET brain scans and invasive spinal taps now used in research settings to assess the presence and progression of the disease.
Such a test, especially one that can identify people at very early stages of disease, would provide a huge boost to Alzheimer's research, drastically slashing the cost and the time necessary to screen patients for clinical trials, thus spurring the development of new treatments.
While Alzheimer's researchers continue to pursue drug treatments for the disease, most agree that successful treatment will hinge on early detection and on finding ways to head off brain damage before later stages of Alzheimer's.
While PET scans and spinal taps continue to play important roles in Alzheimer's research, both have limitations that prevent their widespread use as a screening tool for early signs of the disease.
PET brain scans are still the gold standard for detecting signs of Alzheimer's, but the machines are expensive and seldom available for routine patient diagnosis, much less widespread clinical screening. PET scans also require the injection of a radioactive tracer for brain imaging.
As Alzheimer's progresses, it can be detected by testing for tau proteins in cerebrospinal fluid, but sampling requires a spinal tap that may be too invasive for use as a general screening tool, especially for people who have no symptoms.
Another promising option for Alzheimer's screening—also under development at Washington University—is a noninvasive, relatively inexpensive blood test that has proven to be highly accurate in detecting early signs of Alzheimer's disease. A commercial version of the blood test recently became available to doctors in the United States and Europe, but it is not yet covered by health insurance.
While each testing approach has its own strengths and weaknesses, the qGRE MRI technique may be poised for early adoption since it is based on MRI technology that is widely available worldwide, is noninvasive and can be carried out without the use of radioactive tracers.
"Our qGRE test offers great potential as an early diagnostic tool for the preclinical stage of Alzheimer's disease, thus providing a large window for therapeutic intervention," Yablonskiy said. "It also has great potential as a noninvasive MRI technique available in a conventional clinical setting for the widespread screening that is necessary to get people with early Alzheimer's into clinical drug trials."
More information: Satya V.V.N. Kothapalli et al, Quantitative Gradient Echo MRI Identifies Dark Matter as a New Imaging Biomarker of Neurodegeneration that Precedes Tisssue Atrophy in Early Alzheimer's Disease, Journal of Alzheimer's Disease (2021). DOI: 10.3233/JAD-210503
Journal information: Journal of Alzheimer's Disease
Tuesday, August 03, 2021
A new online tool to improve Alzheimer's clinical trials recruitment
by National Institute on Aging
The newly launched Outreach Pro, a tool for Alzheimer’s researchers who need to create and customize recruitment resources such as websites, handouts, videos, and social media posts. Credit: NIH National Institute on Aging
The National Institute on Aging (NIA), part of the National Institutes of Health (NIH), has launched a new online research tool to help increase participation by traditionally underrepresented populations in clinical trials on Alzheimer's disease and related dementias. Unveiled at the Alzheimer's Association International Conference (AAIC), Outreach Pro enables those involved with leading clinical research to create and customize participant recruitment communications such as websites, handouts, videos, and social media posts.
03 aug 2021--"We are facing a critical and growing need for people living with Alzheimer's and related dementias, as well as those at higher risk, and healthy people, to participate in clinical trials," said NIA Director Richard J. Hodes M.D. "That need is especially acute for frequently underrepresented groups such as Black and Hispanic Americans, which is why Outreach Pro includes an emphasis on helping clinical trial researchers connect with these and other important communities."
Outreach Pro is an integral part of NIA's efforts to implement the National Strategy for Recruitment and Participation in Alzheimer's and Related Dementias Clinical Research. Released in 2018, the national strategy was developed in collaboration with the Alzheimer's Association with input from government, private sector, academic, and industry stakeholders, as well as from individuals, caregivers, and study participants. The overarching goal is to engage broader segments of the public, including underrepresented populations, to participate in Alzheimer's and related dementias clinical research.
"It is critical that clinical trials have appropriate representation to ensure we have a complete understanding of how well different therapies or approaches to dementia care work in different populations," said Holly Massett, Ph.D., NIA senior advisor on clinical research recruitment and engagement, who oversees the implementation of the national strategy. "Outreach Pro was designed to provide well-tested and culturally appropriate outreach materials that resonate with diverse populations and encourage them to participate in clinical trials."
To use Outreach Pro, researchers and clinicians first select desired templates with one of three communication goals in mind: 1) to educate about Alzheimer's, related dementias, and/or brain health; 2) to increase awareness and interest in Alzheimer's and related dementias clinical trials; or, 3) to provide information about a specific Alzheimer's or related dementias clinical trial currently enrolling participants. Each template can then be tailored using a central library of messages, headlines, photos, and text that have been extensively tested among individuals representing diverse and underserved populations.
Outreach Pro's current library of content includes materials specifically designed for a range of audiences, including Black Americans and Hispanics/Latinos. Initially, the materials will be available in English and Spanish, and there are plans underway to add Asian American and Pacific Islander resources and languages by fall 2021. Materials for American Indian and Alaska Native communities will be developed and added in 2022.
NIA developed Outreach Pro and its content systematically by using literature reviews, environmental scans, listening sessions with stakeholders, focus groups, national surveys, and user testing. The NIA team created tool features in a culturally responsive way, so that all stages of content development reflect the culture and languages of the communities for whom the materials are designed. NIA plans to add content and scale up the tool's capabilities based on feedback and performance measurement.
Outreach Pro expands NIA's resources dedicated to recruitment diversity. For example, in 2020, NIA funded four exploratory Alzheimer's Disease Research Centers that will broaden research initiatives with underrepresented groups, including Black Americans, Native Americans, and those in rural communities. In 2019, NIA launched the Alzheimer's and Dementia Outreach, Recruitment, and Engagement (ADORE) Resources. The ADORE repository offers the research community resources to support recruitment and retention of volunteers into clinical trials and studies.
In total, NIA is supporting 270 Alzheimer's and related dementias clinical trials, including those focused on lifestyle and caregiving interventions. Late-stage trials often include thousands of participants, requiring even more volunteers to help researchers meet recruitment goals for diversity.
Alzheimer’s disease is characterized by progressive memory loss, spatial disorientation and many other cognitive and behavioural disorders that ultimately lead to a state of total dependence. Credit: Shutterstock
16 jun 2021--Alzheimer's disease is characterized by progressive memory loss, spatial disorientation and many other cognitive and behavioral disorders that ultimately lead to a state of total dependence.
As researchers who study Alzheimer's biomarkers—objective biological measures used to identify the disease, measure its progression and determine the effectiveness of treatments—we're very interested in the discovery of new treatments for this disease.
Aducanumab, which will be marketed under the name Aduhelm, was jointly developed by Biogen and Eisai. It is a monoclonal antibody administered by injection that binds to brain aggregates of amyloid and allows our bodies to dispose of them. The treatment is based on the idea that amyloid, a small protein that accumulates in the brains of people with Alzheimer's disease, is at the origin of a cascade of events that leads to the disease.
Questionable results
The FDA approval is based on two 18-month clinical trials that were conducted with aducanumab. One showed a slowing of the progression of cognitive impairment by about 22 percent in people who received the high-dose treatment. The other showed no difference between those who were given aducanumab and those given the placebo.
Typically, regulatory authorities require two Phase 3 trials with positive results to approve a drug. Biogen and Eisai terminated both trials after an independent panel of experts concluded that based on preliminary results, aducanumab was unlikely to be effective in slowing the cognitive decline of the disease despite showing some effectiveness in reducing brain amyloid levels.
In addition, aducanumab has been associated with cerebral edema in 40 percent of those treated. Edema is a fluid mass that produces pressure in the skull and requires medical monitoring or surgery.
After further review of the results from the two clinical trials, Biogen and Eisai announced in October 2019 that aducanumab administered in high doses showed efficacy on cognitive symptoms in patients with early Alzheimer's. This way of analyzing the results was strongly criticized by the scientific community, including some of the investigators who had participated in the clinical trials.
Neurons with amyloid plaques. Credit: Shutterstock
Amyloid may have little influence
The amyloid cascade, the idea behind how aducanumab works, is the subject ofgreat controversy in the scientific community. This hypothesis has dominated for nearly 30 years and guided the search for treatments that aim to remove amyloid from the brain. Yet every clinical trial using this approach has failed, representing dozens of products and hundreds of billions of dollars in investment.
More and more, we are realizing that the problems with Alzheimer's may not involve amyloid either directly or solely. For example, a person who is genetically predisposed to accumulate amyloid may develop Alzheimer's earlier, but may not progress more rapidly than a person who is not predisposed. This means that amyloid may have little influence on disease progression.
Even advocates of the amyloid hypothesis have become more measured about its possible influence, proposing that it may only have an indirect impact on brain dysfunction in Alzheimer's disease. This would occur through a process of brain inflammation, which is one of the possible causes of neuronal death in this disease.
So how can one explain the FDA's decision, which runs contrary to the recommendation of its own expert panel and is based on evidence that shows that amyloid only makes a small contribution to the progression of the disease?
Aducanumab reduced the amount of amyloid accumulated in the brain by nearly two-thirds in treated individuals. While this is a dramatic result, their symptoms persisted, meaning that amyloid is not a good biomarker of the disease.
The discovery and validation of reliable biomarkers to detect diseases and assess the efficacy of treatments only comes about after a long and rigorous process. The use of amyloid has never really gone through this process, yet the FDA approved a treatment based on this. Bypassing this process sets a risky precedent.
No curative treatment targeting Alzheimer's symptoms has emerged since the first treatments came to market in 1997. Aducanumab is the first approved treatment aimed at slowing the progression of the disease. The surprise and excitement generated by the first success in a journey that has included hundreds of failed clinical trials may explain why the FDA granted the drug conditional approval.
The approval also satisfies the financial interests of Biogen, Eisai and its investors. The most modest estimates put annual revenues from the sale of aducanumab at more than US$50 billion. Expectation of new revenue for Eisai and Biogen pushed the stock values of these companies up by 75 percent and 40 percent respectively the day the announcement was made.
New evidence collected after the launch of aducanumab will be critical to the future of the amyloid hypothesis and our understanding of Alzheimer's disease. With such a complex disease, it is likely that we will need to develop multiple approaches to stop its progression, much like triple therapy for HIV/AIDS. That's why we must not interrupt research on biomarkers and new therapeutic approaches.
Friday, June 22, 2018
Deep brain stimulation showing promise for patients with mild Alzheimer's disease over 65
Dr. Andres Lozano of Krembil Neuroscience Centre at Toronto Western says 'we are encouraged by these findings.' Credit: The Globe and MailAn age group analysis of data from the ADvance trial has shown that participants over the age of 65 continue to derive the most benefit from Deep Brain Stimulation of the fornix (DBS-f), as observed in the data from the phase 2 findings (12—24 months) of the Phase II trial.
22 jun 2018--The findings, published today in the Journal of Alzheimer's Disease, by a team of researchers led by Dr. Andres Lozano at Toronto Western Hospital's (TW) Krembil Neuroscience Centre (KNC), are the potential beginnings of a patient profile for DBS-f treatment for Alzheimer's disease. The neurology and psychology aspects of the trial in Toronto were led by TW neurologist Dr. Peter Tang-wai and neuropsychologist Dr. Mary-Pat McAndrews respectively.
To further explore the benefits for this demographic, the research team is soon launching a Phase III, multi-centre international trial that will study the effects of DBS-f in 140 patients over age 65.
"We are encouraged by these findings as they continue to help us identify who will benefit most from DBS to treat Alzheimer's disease and learn more about this illness," says Dr. Andres Lozano, neurosurgeon and the principal investigator of the study. "With so few treatments available and the incidence of Alzheimer's only expected to increase, we really need to fully explore all treatments that seem to be of benefit to patients."
These latest results were captured from the second year of data of the ADvance trial whose first-year data was published in 2016. In that trial, forty-two patients with mild Alzheimer's disease were enrolled in a randomized, double-blind multicentre phase II clinical trial and implanted with DBS electrodes directed at the fornix—a bundle of nerve fibres in the brain that carry signals from the hippocampus—and followed for a total of two years.
In the first 12 months of the trial, to better measure the impact of electrical stimulation in the brain, patients were randomly assigned to either the "on" or "off" stimulation group after their procedure and monitored. Once this phase of follow up was complete, all patients then had their electrodes turned on, and were followed for another 12 months.
In the second 12-month phase, researchers noted similar observations they had seen in the first phase: that, although there were no differences overall in cognitive outcomes between study participants who had their device turned on right after surgery and those who had it turned on after 12 months, those 65 years of age and older appeared to experience a slower progression of Alzheimer's than those under that age, regardless of when their device was turned on.
"The next phase of our research will help determine whether this observed benefit is something we continue to see in this age group," says Lozano who is also University Professor and Chairman, Department of Neurosurgery, University of Toronto. "If it does, this could potentially give us a treatment for mild, late-onset Alzheimer's disease."
Provided by University Health Network
Sunday, October 30, 2016
High blood pressure can impair cognitive function, pose risk for Alzheimer's
High blood pressure in middle age can lead to impaired cognition and is a potential risk factor for Alzheimer's disease, according to a statement from the American Heart Association co-authored by Loyola Medicine neurologist José Biller, MD.
30 OCT 2016--Dr. Biller is a member of the multidisciplinary panel of experts that wrote the statement, published in the heart association journal Hypertension. Dr. Biller is chair of the department of neurology of Loyola University Chicago Stritch School of Medicine. The panel is chaired by Constantino Iadecola, MD, of Weill Cornell Medicine and co-chaired by Kristine Yaffe, MD, of the University of California San Francisco.
Dementia affects an estimated 30 to 40 million people worldwide, and the number is expected to triple by 2050 due to an aging population and other factors.
An estimated 80 million people in the United States have hypertension, and the brain is among the organs most affected. Except for age, hypertension is the most important risk factor for vascular problems in the brain that lead to stroke and dementia.
There is consistent evidence that chronic high blood pressure during middle age (40 to 64) is associated with altered cognitive function in both middle age and late life (65 to 84). Cognitive abilities that are affected include memory, speed of processing and executive function (ability to organize thoughts, manage time, make decisions, etc.)
The effect of high blood pressure in late life is less clear. Some studies suggest it's harmful, while other research suggests it may improve cognition. This highlights "the complexities of recommending uniform levels of blood pressure across the life course," the expert panel wrote.
Observational studies have demonstrated that high blood pressure causes atherosclerosis (hardening of the arteries) and other damage to the brain's blood vessels, leading to reduced blood flow to brain cells. But evidence from clinical trials that treating blood pressure improves cognition is not conclusive.
After carefully reviewing available studies, the panel concluded there are not enough data to make evidence-based recommendations. However, judicious treatment of high blood pressure, taking into account goals of care and the patient's individual characteristics, "seems justified to safeguard vascular health and, as a consequence, brain health," the panel concluded.
The paper is titled, "Impact of hypertension on cognitive function: a scientific statement from the AmericanHeart Association."
More information: Costantino Iadecola et al, Impact of Hypertension on Cognitive Function: A Scientific Statement From the American Heart Association, Hypertension (2016). DOI: 10.1161/HYP.0000000000000053
Provided by Loyola University Health System
Tuesday, September 27, 2016
Multimodal everyday training and brain stimulation can help with memory problems
"By taking the correct steps, it is possible to delay or alleviate the early clinical symptoms of Alzheimer's such as forgetfulness," stresses Peter Dal-Bianco, Alzheimer's expert at MedUni Vienna's Department of Neurology, speaking on the occasion of World Alzheimer's Day on 21 September. A recent study from Finland and Sweden confirms the findings of MedUni Vienna researchers. For example, it was found that "multimodal everyday training" has a beneficial effect upon cognitive abilities such as planning and implementing projects.
27 sept 2016--In the so-called FINGER study (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability), 1,260 people aged between 60 and 77, who were already forgetful, were divided into two groups. Over a period of 24 months, one group of 631 people received regular physical exercise to fit in with their everyday lives, comprising walks with simultaneous conversation, balance and memory training on a computer, social activities, a healthy diet and monitoring of their cardiovascular status. Dal-Bianco says, "The result was a significant improvement in cognitive abilities in terms of processing speed and executive functions in the active group, as compared to the control group." The control group consisted of 629 people.
This is also corroborated by research results obtained at MedUni Vienna: "For example: inactive people have an 80 percent higher Alzheimer's risk than people who are physically active. Other factors that can accelerate the clinical onset of dementia include being overweight, diabetes mellitus, high blood pressure and smoking," says Dal-Bianco, in summary.
Currently, there are more than 30 million Alzheimer's sufferers worldwide. According to forecasts, this figure will have reached 63 million by 2030 and around 114 million by 2050. Currently 120,000 people are affected in Austria and by 2050 this is expected to be around 280,000.
Dal-Bianco: "The neurodegenerative tissue changes in the brain happen slowly and start approximately 30 years before the first clinical symptoms of dementia appear. And so, if we take the correct steps at an early stage and we also demonstrate scientifically that they work, many people would be able to delay the clinical onset of the disease so that they die from old age before they have to experience it."
The Department of Neurology at MedUni Vienna currently uses brain stimulation with ultrasound waves (currently as part of an ongoing clinical trial) – as well as drug therapy – to treat early-stage Alzheimer's. These waves are thought to supply energy to the brain tissue. This is thought to promote regeneration of structures in the nervous system: "This should improve brain performance," explains Dal-Bianco.
And another study into the early diagnosis of neurodegenerative diseases, such as Alzheimer's, is currently being conducted at MedUni Vienna, together with Gerhard Garhöfer of the Department of Clinical Pharmacology: This involves increasing the activity of the neurons in the retina of the eye by means of photo stimulation. If these neurons stop being able to transmit adequate signals for the nutrients and blood supply they require, this can be an indication of the development of Alzheimer's. The MedUni Vienna researchers hope that this study will provide another possible method for early detection of Alzheimer's.
Provided by Medical University of Vienna
Wednesday, July 27, 2016
Two in ten Alzheimer's cases may be misdiagnosed
Alzheimer's disease is often misdiagnosed, possibly causing undue stress for those who don't have the disease but are told they do, and delays in treatment for others, two new studies reveal.
27 july 2016--Although no cure or effective treatment for Alzheimer's disease exists, a correct diagnosis is essential because some drugs can delay its progress and help preserve quality of life for as long as possible. An early diagnosis also gives patients time to plan for their end-of-life care, experts say.
"There are drugs that are beneficial for at least a short amount of time that can be given at a very early stage and possibly boost memory," said Dean Hartley, director of science initiatives, medical and scientific relations at the Alzheimer's Association.
"Planning your care and finances is extremely important," he said. "With a correct diagnosis people can also be put into a clinical trial to see if new drugs will work."
The diagnosis of Alzheimer's disease is made based on symptoms. No blood test or imaging test is currently available to diagnose the disease with 100 percent accuracy, which is why misdiagnoses occur. In addition, Alzheimer's is a much more complex disease than once thought, making a correct diagnosis even harder. However, progress is being made in finding better ways to diagnose the disease, Hartley said.
In the first study, a team of researchers from the Mayo Clinic in Jacksonville, Fla., led by Melissa Murray, found that men may be misdiagnosed more often.
One reason may be that men in the study seemed to develop Alzheimer's at a younger age than women and had a more aggressive form of the disease. Men tended to develop Alzheimer's in their 60s, while women developed it in their 70s, 80s and 90s, said Murray, an assistant professor of neuroscience.
Men also seemed to have Alzheimer's in different areas of the brain than women. This may account for the misdiagnosis among men, because their symptoms can be different than those of women, Murray said. She said men's symptoms may be behavioral, or there may be language difficulty or motor problems instead of the memory problems usually associated with Alzheimer's.
"Age and sex interact," Murray said.
This study included information from the State of Florida brain bank. The researchers examined more than 1,600 brains of people who had Alzheimer's. The people had ranged in age from 37 to 102.
Diagnosis is important so people can take care of financial planning and end-of-life wishes, Murray suggested.
In the second study, researchers from the Keenan Research Center for Biomedical Science at St. Michael's Hospital in Toronto, Canada, looked at inconsistencies between clinical and autopsy diagnoses in more than 1,000 people listed in the National Alzheimer's Coordinating Center database.
"Even with all the latest diagnostic methods, the discrepancy between the clinical diagnosis of Alzheimer's disease and the pathological diagnosis is about 20 percent," said senior researcher adjunct scientist Dr. David Munoz.
Munoz and his colleagues found that 78 percent of the patients had a correct diagnosis in the clinic, which was later confirmed in an autopsy of the brain. However, nearly 11 percent of those diagnosed with Alzheimer's in the clinic didn't have the disease. And, another nearly 11 percent who weren't diagnosed with Alzheimer's actually had the disease.
Those falsely diagnosed with Alzheimer's had other conditions that accounted for their symptoms, including Lewy body dementia, brain atrophy and other types of dementia, the researchers found.
People whose Alzheimer's diagnosis was missed also may have had other types of dementia, such as Parkinson's disease dementia, vascular dementia or Lewy body dementia, the study authors reported.
The results of both studies were scheduled for presentation July 26 at the Alzheimer's Association International Conference, in Toronto. Findings from meetings are generally considered preliminary until published in a peer-reviewed journal.
Earlier distinction between Alzheimer's disease and frontotemporal dementia
In the white matter of the brain in particular, large differences can be measured between the brains of people with Alzheimer's disease and those with the behavioural variant frontotemporal dementia. Neuropsychologist Christiane Möller used advanced image analysis techniques on MRI brain scans from dementia patients in an early stage of the disease. She will defend her doctoral research on 1 May at the VU University Medical Centre. Her research was funded by the NWO's National Initiative Brain & Cognition.
09 may 2015--Alzheimer's disease and the behavioural variant of frontotemporal dementia (FTD) are the two most commonly occurring types of dementia at a young age. Medical specialists still find it difficult to make a distinction between the two types of disease at an early stage of the illness. Using existing imaging techniques the difference is often not visible to the naked eye on scans.
Möller used advanced analysis methods that can measure brain damage not yet visible to the human eye. "At a group level the diseases were found to exhibit large differences in the white matter of the brain in particular. In frontotemporal dementia there is a lot of damage to the white matter of the brain in the foremost parts of the brain, whereas in the brains of people with Alzheimer's disease no damage could be measured compared with FTD. A combination of different analysis methods made the distinction even clearer still."
The aim of the research was to detect changes in the brain as early as possible and to determine if there were differences in the brain between the two types of dementia. "For drug development in particular, a good diagnosis is a prerequisite", says Möller. The VU University Medical Center carried out the study together with Leiden University Medical Center and the Erasmus Medical Center in Rotterdam. This research falls under the programme 'Brain & Cognition: societal innovation' and is funded by the National Initiative Brain & Cognition, a unit of NWO.
In the Netherlands there are already about 250,000 people who suffer from dementia and it is expected that by 2040 this number will have increased to half a million people. Knowledge about the cause of dementia makes it possible to develop very specific therapies so that the disease can be cured.
Provided by Netherlands Organisation for Scientific Research (NWO)
Friday, December 05, 2014
Study links running to lower Alzheimer's death risk
Higher fruit intake, cholesterol-lowering drugs also associated with reduced risk
05 dec 2014—Running more than 15 miles a week may reduce the risk of dying from Alzheimer's disease, new research suggests.
Walking can help, too, if the amount of energy expended is equivalent to running more than 15 miles weekly, the study found.
"Exercise seems to prevent the shrinkage [in the brain] that occurs with age," said study researcher Paul Williams, a staff scientist at Lawrence Berkeley Laboratory in Berkeley, Calif. And preserving brain volume may be why vigorous exercise helps reduce the risk of Alzheimer's death, according to Williams.
Williams' study also found that taking cholesterol-lowering drugs known as statins was linked to reduced risk of death from Alzheimer's disease, as did eating three or more pieces of fruit daily.
However, this study was only able to find associations between all of these factors and the risk of death from Alzheimer's disease. The study wasn't designed to prove whether or not running, walking, eating fruit or taking statins caused a decreased risk of Alzheimer's disease.
The study was published online recently in the Journal of Alzheimer's Disease.
About 5 million Americans age 65 and older have Alzheimer's disease, which causes problems with memory, thinking and behavior, according to the Alzheimer's Association.
The study included more than 153,000 runners and walkers who have been participating in the National Runners' and Walkers' Health Studies. Men and women were recruited for the studies beginning in the early 1990s.
Williams followed them for an average of almost 12 years and tracked the number who died of Alzheimer's disease. Over the follow-up, there were 175 deaths from Alzheimer's disease.
In the study, those who ran more than 15.3 miles weekly had a 40 percent risk reduction in death from Alzheimer's. Running between 7.7 and 15.3 miles was linked with a 25 percent risk reduction, but Williams said that finding wasn't statistically significant.
The amount of running needed to lower risk substantially is about double the current exercise recommendations from the U.S. Centers for Disease Control and Prevention. The CDC exercise guidelines are equivalent to running 4.6 to 7.7 miles a week, according to Williams.
Walking to expend energy equivalent to a 15.3-mile run was also linked with risk reduction, Williams found. However, walkers have to walk about 50 percent further, walk briskly (equivalent to running a 12-minute mile) and put in more exercise time, according to Williams.
When looking at diet, the study found that those who ate three or more pieces of fruit a day had a 60 percent lower risk of death from Alzheimer's, compared to those who ate less than a piece of fruit daily. Williams said he doesn't know if this is due to just the fruit, or if the fruit is a sign of other healthy habits, such as an overall healthy diet.
Those who took statins, which have been linked with lower Alzheimer's disease risk in other studies, had a lower risk of death from Alzheimer's by 40 percent, Williams found.
Future study is needed, he said.
The findings about running and a reduced risk of Alzheimer's death echo some previous studies, said Heather Snyder, director of medical and scientific operations for the Alzheimer's Association.
One of the strengths of the new research, she said, is the large numbers. However, because the participants are exercisers, they are not representative of the general population, many of whom don't exercise, she said.
Bilingualism delays Alzheimer manifestation by more than four years
A new study at Ghent University has established that the symptoms of Alzheimer disease (AD) manifest themselves about four to five years later in bilinguals as opposed to monolinguals. In bilinguals, the disease onset was estimated at the age of 77, while in monolinguals, this was at the age of 73.
02 dec 2014--Between March 2013 and May 2014, 69 monolingual and 65 bilingual Belgian patients suffering from probable Alzheimer's disease (AD) participated in the study. Psychologists Evy Woumans, Michaël Stevens, and Wouter Duyck, together with neurologists Patrick Santens, Anne Sieben, and Jan Versijpt determined the age of AD manifestation and AD diagnosis for both language groups.
Later manifestation and diagnosis
Results showed that the age of AD manifestation was 71.5 in monolinguals and 76.1 in bilinguals. A similar difference was found for the age of AD diagnosis; for monolinguals this was 72.5 and for bilinguals it was 77.3. Analyses controlled for other confounding factors, such as education, profession, and socioeconomic status, which actually had a negative effect.
The protective effect of bilingualism
These findings confirm previous research suggesting that bilingualism can slow down cognitive ageing and contribute to cognitive reserve. It seems that constantly and actively controlling two languages is like a workout for the brain. It challenges our grey cells and keeps them from degenerating.
More information: Woumans, E., Santens, P., Sieben, A., Versijpt, J., Stevens, M., & Duyck, W. (in press). "Bilingualism delays clinical manifestation of Alzheimer's disease." Language and Cognition. users.ugent.be/~wduyck/article… vensDuyckInPress.pdf
Provided by Ghent University
Sunday, October 26, 2014
New insight on why people with Down syndrome invariably develop Alzheimer's disease
Amyloid plaques are found in the brains of people with Down syndrome and Alzheimer's disease. Credit: Juan Gartner
26 oct 2014--A new study by researchers at Sanford-Burnham Medical Research Institute reveals the process that leads to changes in the brains of individuals with Down syndrome—the same changes that cause dementia in Alzheimer's patients. The findings, published in Cell Reports, have important implications for the development of treatments that can prevent damage in neuronal connectivity and brain function in Down syndrome and other neurodevelopmental and neurodegenerative conditions, including Alzheimer's disease.
Down syndrome is characterized by an extra copy of chromosome 21 and is the most common chromosome abnormality in humans. It occurs in about one per 700 babies in the United States, and is associated with a mild to moderate intellectual disability. Down syndrome is also associated with an increased risk of developing Alzheimer's disease. By the age of 40, nearly 100 percent of all individuals with Down syndrome develop the changes in the brain associated with Alzheimer's disease, and approximately 25 percent of people with Down syndrome show signs of Alzheimer's-type dementia by the age of 35, and 75 percent by age 65. As the life expectancy for people with Down syndrome has increased dramatically in recent years—from 25 in 1983 to 60 today—research aimed to understand the cause of conditions that affect their quality of life are essential.
"Our goal is to understand how the extra copy of chromosome 21 and its genes cause individuals with Down syndrome to have a greatly increased risk of developing dementia," said Huaxi Hu, Ph.D., professor in the Degenerative Diseases Program at Sanford-Burnham and senior author of the paper. "Our new study reveals how a protein called sorting nexin 27 (SNX27) regulates the generation of beta-amyloid—the main component of the detrimental amyloid plaques found in the brains of people with Down syndrome and Alzheimer's. The findings are important because they explain how beta-amyloid levels are managed in these individuals."
Beta-Amyloid, Plaques and Dementia
Xu's team found that SNX27 regulates beta-amyloid generation. Beta-amyloid is a sticky protein that's toxic to neurons. The combination of beta-amyloid and dead neurons form clumps in the brain called plaques. Brain plaques are a pathological hallmark of Alzheimer's disease and are implicated in the cause of the symptoms of dementia.
"We found that SNX27 reduces beta-amyloid generation through interactions with gamma-secretase—an enzyme that cleaves the beta-amyloid precursor protein to produce beta-amyloid," said Xin Wang, Ph.D., a postdoctoral fellow in Xu's lab and first author of the publication. "When SNX27 interacts with gamma-secretase, the enzyme becomes disabled and cannot produce beta-amyloid. Lower levels of SNX27 lead to increased levels of functional gamma-secretase that in turn lead to increased levels of beta-amyloid."
SNX27's Role in Brain Function
Previously, Xu and colleagues found that SNX27 deficient mice shared some characteristics with Down syndrome, and that humans with Down syndrome have significantly lower levels of SNX27. In the brain, SNX27 maintains certain receptors on the cell surface—receptors that are necessary for neurons to fire properly. When levels of SNX27 are reduced, neuron activity is impaired, causing problems with learning and memory. Importantly, the research team found that by adding new copies of the SNX27 gene to the brains of Down syndrome mice, they could repair the memory deficit in the mice.
The researchers went on to reveal how lower levels of SNX27 in Down syndrome are the result of an extra copy of an RNA molecule encoded by chromosome 21 called miRNA-155. miRNA-155 is a small piece of genetic material that doesn't code for protein, but instead influences the production of SNX27.
With the current study, researchers can piece the entire process together—the extra copy of chromosome 21 causes elevated levels of miRNA-155 that in turn lead to reduced levels of SNX27. Reduced levels of SNX27 lead to an increase in the amount of active gamma-secretase causing an increase in the production of beta-amyloid and the plaques observed in affected individuals.
"We have defined a rather complex mechanism that explains how SNX27 levels indirectly lead to beta-amyloid," said Xu. "While there may be many factors that contribute to Alzheimer's characteristics in Down syndrome, our study supports an approach of inhibiting gamma-secretase as a means to prevent the amyloid plaques in the brain found in Down syndrome and Alzheimer's."
"Our next step is to develop and implement a screening test to identify molecules that can reduce the levels of miRNA-155 and hence restore the level of SNX27, and find molecules that can enhance the interaction between SNX27 and gamma-secretase. We are working with the Conrad Prebys Center for Chemical Genomics at Sanford-Burnham to achieve this," added Xu.
Provided by Sanford-Burnham Medical Research Institute
Wednesday, September 17, 2014
World Alzheimer Report 2014 reveals persuasive evidence for dementia risk reduction
The World Alzheimer Report 2014 'Dementia and Risk Reduction: An analysis of protective and modifiable factors', released today, calls for dementia to be integrated into both global and national public health programmes alongside other major non communicable diseases (NCDs).
17 sept 2014--Alzheimer's Disease International (ADI) commissioned a team of researchers, led by Professor Martin Prince from King's College London, to produce the report. ADI is publishing this report, in conjunction with World Alzheimer's Day (21 September) and as a part of World Alzheimer's Month, an international campaign to raise awareness and challenge stigma.
The report reveals that control of diabetes and high blood pressure as well as measures to encourage smoking cessation and to reduce cardiovascular risk, have the potential to reduce the risk of dementia even in late-life. The report found that diabetes can increase the risk of dementia by 50%. Obesity and lack of physical activity are important risk factors for diabetes and hypertension, and should, therefore, also be targeted.
While cardiovascular health is improving in many high income countries, many low and middle income countries show a recent pattern of increasing exposure to cardiovascular risk factors, with rising rates of diabetes, heart disease and stroke.
Smoking cessation is strongly linked in the report with a reduction in dementia risk. For example, studies of dementia incidence among people aged 65 years and over show that ex-smokers have a similar risk to those who have never smoked, while those who continue to smoke are at much higher risk.
Furthermore, the study revealed that those who have had better educational opportunities have a lower risk of dementia in late-life. Evidence suggests that education has no impact on the brain changes that lead to dementia, but reduces their impact on intellectual functioning.
The evidence in the report suggest that if we enter old age with better developed, healthier brains we are likely to live longer, happier and more independent lives, with a much reduced chance of developing dementia. Brain health promotion is important across the life span, but particularly in mid-life, as changes in the brain can begin decades before symptoms appear.
The study also urges NCD programs to be more inclusive of older people, with the message that it's never too late to make a change, as the future course of the global dementia epidemic is likely to depend crucially upon the success or failure of efforts to improve global public health, across the population. Combining efforts to tackle the increasing global burden of NCDs will be strategically important, efficient and cost effective. Leading a healthier lifestyle is a positive step towards preventing a range of long-term diseases, including cancer, heart disease, stroke and diabetes.
However, survey data released by Bupa* has shown that many people are unclear about the causes and actions they can take to potentially reduce their risk of dementia. Just over a sixth (17%) of people realised that social interaction with friends and family could impact on the risk. Only a quarter (25%) identified being overweight as a possible factor, and only one in five (23%) said physical activity could affect the risk of developing dementia and losing their memories. The survey also revealed that over two thirds (68%) of people surveyed around the world are concerned about getting dementia in later life.
Professor Martin Prince, from King's College London's Institute of Psychiatry, Psychology & Neuroscience and author of the report, commented: "There is already evidence from several studies that the incidence of dementia may be falling in high income countries, linked to improvements in education and cardiovascular health. We need to do all we can to accentuate these trends. With a global cost of over US$ 600 billion, the stakes could hardly be higher."
Marc Wortmann, Executive Director, Alzheimer's Disease International said: "From a public health perspective, it is important to note that most of the risk factors for dementia overlap with those for the other major non communicable diseases(NCDs). In high income countries, there is an increased focus on healthier lifestyles, but this is not always the case with lower and middle income countries. By 2050, we estimate that 71% of people living with dementia will live in these regions, so implementing effective public health campaigns may help to reduce the global risk."
Professor Graham Stokes, Global Director of Dementia Care, Bupa, said: "While age and genetics are part of the disease's risk factors, not smoking, eating more healthily, getting some exercise, and having a good education, coupled with challenging your brain to ensure it is kept active, can all play a part in minimising your chances of developing dementia. People who already have dementia, or signs of it, can also do these things, which may help to slow the progression of the disease."
