Study: Structure of toxic tau tangles determines type of dementia, rate of progression

The distinct structures of toxic protein aggregates that form in degenerating brains determine which type of dementia will occur, which regions of brain will be afflicted, and how quickly the disease will spread, according to a study from the Peter O'Donnell Jr. Brain Institute.

The research helps explain the diversity of dementias linked to tau protein aggregation, which destroys brain cells of patients with Alzheimer's and other neurodegenerative syndromes. The study also has implications for earlier and more accurate diagnosis of various dementias through definition of the unique forms of tau associated with each.

"In addition to providing a framework to understand why we get different types of neurodegeneration, this work has enormous promise for the development of drugs to treat specific neurodegenerative diseases, and for how to accurately diagnose them. It says that a one-size-fits-all strategy for therapy may not work, and that we have to approach clinical trials and drug development with an awareness of which forms of tau we are targeting," said study author Dr. Marc Diamond, founding Director of the Center for Alzheimer's and Neurodegenerative Diseases at the O'Donnell Brain Institute at UT Southwestern Medical Center.

Researchers used special cell systems to replicate distinct tau aggregate conformations. These different forms of pathological tau were then inoculated into the brains of mice. Each created different pathological patterns, recapitulating the variation that occurs in diseases such as Alzheimer's, frontotemporal dementias, and traumatic encephalopathy. The different forms of tau caused pathology that spread at different rates through the brain, and affected very specific brain regions. This experiment demonstrated that the structure of pathological tau aggregates alone is sufficient to account for most if not all of the variation seen in human neurodegenerative diseases that are tied to this protein.

The finding, published in Neuron, could have a notable impact on widespread efforts at the O'Donnell Brain Institute and elsewhere to develop treatments that eliminate tau and other toxic proteins from the brains of dementia patients.

"The challenge for us now is to figure out how to rapidly and efficiently determine the forms of tau that are present in individual patients, and simultaneously to develop specific therapies. This work says that it should be possible to predict patterns of disease in patients and responses to therapy based on knowledge of tau aggregate structure," Dr. Diamond said.

Dr. Diamond's lab, at the forefront of many notable findings relating to tau, had previously determined that tau acts like a prion - an infectious protein that can self-replicate and spread like a virus through the brain. The lab has determined that tau protein in human brain can form many distinct strains, or self-replicating structures, and developed methods to reproduce them in the laboratory. This led Dr. Diamond's team to the latest study to test whether these strains might account for different forms of dementia.

To make this link, 18 distinct tau aggregate strains were replicated in the lab from human neurodegenerative disease brain samples, or were created from mouse models or other artificial sources. Researchers inoculated the strains into different brain regions of mice and found striking differences among them.

While some strains had far reaching and rapid effects, others replicated only in limited parts of the brain, or caused widespread disease but did so very slowly. This surprising result answered a fundamental question that has dogged the field of neurodegenerative disease: Why are brain regions vulnerable in certain cases, but not others, and why do some diseases progress more rapidly than others?

For instance, in Alzheimer's disease, problems begin in brain memory centers before spreading to other areas that control functions such as language. Conversely, due to initial degeneration of frontal and temporal brain regions in frontotemporal dementia, the memory centers are relatively spared, and patients often first show changes in personality and behavior.

This study implies that with knowledge of tau aggregate structure in patients, or possibly even in healthy individuals, it should be possible to predict the brain regions most vulnerable to degeneration, and the rate of disease progression.

The study was funded by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, National Institute on Aging, the Tau Consortium, and the Cure Alzheimer's Fund. At UT Southwestern the work was facilitated with help from the Neuro-Models Facility, Whole Brain Microscopy Facility, and the Moody Foundation Flow Cytometry Facility.

Article: Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo, Sarah K. Kaufman, David W. Sanders, Talitha L. Thomas, Allison J. Ruchinskas, Jaime Vaquer-Alicea, Apurwa M. Sharma, Timothy M. Miller, Marc I. Diamond, Neuron, doi: 10.1016/j.neuron.2016.09.055, published 27 October 2016.

How protein fragments associated with Alzheimer's could trigger Parkinson's

Alzheimer's and Parkinson's diseases are different neurodegenerative conditions that can sometimes affect the same person, which has led scientists to investigate possible links between the two. Now one team, reporting in the journal ACS Chemical Neuroscience, has identified how amyloid beta, the protein fragment strongly associated with Alzheimer's disease, can induce cellular changes that might lead to Parkinson's.

Scientists still don't fully understand what causes these neurodegenerative conditions, but their investigations have revealed some insights. For example, certain molecular changes have emerged as factors in the development of these disorders. One such change is the mutation of an enzyme called protein disulfide isomerase (PDI) that protects neurons. And some research has hinted that biomarkers related to one disease can spur molecular processes leading to others. Mahesh Narayan and colleagues wanted to see how a particular form of amyloid beta might trigger cellular changes that can induce Parkinson's disease.

In their lab, the researchers incubated certain amyloid beta fragments - referred to as Aβ (25-35) - with cells (known as SH-SY5Y) often used in Parkinson's research. This set off in the cells a cascade of molecular changes associated with Parkinson's, including chemical mutations to PDI and the formation of protein clumps known as Lewy bodies. The results could provide an explanation for how someone with Alzheimer's might also develop Parkinson's. The findings also could help researchers discover ways to prevent this from happening.

The authors acknowledge funding from the Alzheimer's Disease Research Foundation.

Article: An 11-mer Amyloid Beta Peptide Fragment Provokes Chemical Mutations and Parkinsonian Biomarker Aggregation in Dopaminergic Cells: A Novel Road Map for "Transfected" Parkinson's, Parijat Kabiraj, Jose Eduardo Marin, Armando Varela-Ramirez, and Mahesh Narayan, ACS Chemical Neuroscience, doi: 10.1021/acschemneuro.6b00159, published online 16 September 2016.

Dysfunction in neuronal transport mechanism linked to Alzheimer's disease

Findings confirm mutation-caused problem but also reveal a new therapeutic target.

Researchers at University of California San Diego School of Medicine have confirmed that mutation-caused dysfunction in a process cells use to transport molecules within the cell plays a previously suspected but underappreciated role in promoting the heritable form of Alzheimer's disease (AD), but also one that might be remedied with existing therapeutic enzyme inhibitors.

The findings published in Cell Reports.

"Our results further illuminate the complex processes involved in the degradation and decline of neurons, which is, of course, the essential characteristic and cause of AD," said the study's senior author Larry Goldstein, PhD, Distinguished Professor in the Departments of Neuroscience and Cellular and Molecular Medicine at UC San Diego School of Medicine and director of both the UC San Diego Stem Cell Program and Sanford Stem Cell Clinical Center at UC San Diego Health. "But beyond that, they point to a new target and therapy for a condition that currently has no proven treatment or cure."

Alzheimer's disease is a neurodegenerative disorder characterized by progressive memory loss and cognitive dysfunction. It affects more than 30 million people worldwide, including an estimated 5.4 million Americans. One in 10 persons over the age of 65 has AD; one in three over the age of 85. There are currently no treatments proven to cure or reduce the progression of AD.

Genetically, AD is divided into two groups: the much more common sporadic (sAD) form of the disease in which the underlying primary cause is not known and the rarer familial (fAD) form, produced by inherited genetic mutations. In both forms, the brains of AD patients feature accumulations of protein plaques and neurofibrillary tangles that lead to neuronal impairment and eventual cell death.

The prevailing "amyloid cascade hypothesis" posits that these plaques and tangles are comprised, respectively, of amyloid precursor protein (APP) fragments and tau proteins that fuel cellular stress, neurotoxicity, loss of function and cell death. There has been some evidence, however, of another disease-driver: defects in endocytic trafficking - the process by which cells package large, external molecules into vesicles or membrane-bound sacs for transport into the cell for a variety of reasons or uses.

But previous research focused on non-neuronal cells and did not examine the effects of normal expression levels of AD-related proteins, leaving it unclear to what degree decreased endocytosis and other molecular movement within cells played a causative role.

Goldstein and colleagues analyzed neurons created from induced pluripotent stem cells in which they generated PS1 and APP mutations characteristic of fAD using the emerging genome editing technologies CRISPR and TALEN. In this "disease-in-a-dish" approach, they found that the mutated neurons displayed altered distribution and trafficking of APP and internalized lipoproteins (proteins that combine with or transport fat and other lipids in blood plasma). Specifically, there were elevated levels of APP in the soma or cell body while levels were reduced in the neuronal axons.

In previous work, Goldstein's team had demonstrated that PS1 and APP mutations impaired the activity of specific cellular enzymes. In the latest work, they found that treating mutated fAD neurons with a beta-secretase inhibitor rescued both endocytosis and transcytosis (molecule movement within a cell) functions.

Co-authors of the study include: co-first authors Grace Woodruff and Sol M. Reyna, and Mariah Dunlap, Rik Van Der Kant, Julia A. Callender, Jessica E. Young, and Elizabeth A. Roberts, all at UC San Diego

Lawrence S.B. Goldstein has an equity interest in Human Longevity, Inc., a company that may potentially benefit from the research results. He also serves on the company's Scientific Advisory Board. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies.

Article: Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations, Grace Woodruff, Sol M. Reyna, Mariah Dunlap, Rik Van Der Kant, Julia A. Callender, Jessica E. Young, Elizabeth A. Roberts, Lawrence S.B. Goldstein, Cell Reports, doi: 10.1016/j.celrep.2016.09.034, published 11 October 2016.

Hippocampus: What is its Function?

When learning about the human brain, it's helpful to remember that even the most powerful computer in the world is no match for this part of the human body. With its billions of nerve cells, and the thousands and thousands of connections each nerve cell makes, the brain gives new meaning to the word "complex."

There is much that scientists have come to learn and understand about the human brain. A small structure within the brain called the hippocampus played a big part in how that knowledge was obtained.

Contents of this article:

1. What is the hippocampus?
2. Functions of the hippocampus
3. Diseases that affect the hippocampus
4. Current research

What is the hippocampus?

The hippocampus is a seahorse-shaped part of the brain, found in the inner folds of the bottom middle section of the brain known as the temporal lobe. The hippocampus is two parts of the brain as there is one on each side of the head.

The hippocampus is located in the temporal lobe of the brain.

The hippocampus is about 1/100th of the size of the outer layer of the brain, or cerebral cortex. It consists of three layers, with characteristic pyramid-shaped cells.

Humans have known about the hippocampus for more than 4 centuries, making it one of the most studied parts of the brain. Its main functions involve human learning and memory. The hippocampus has even helped researchers learn how memory works.

In the 1950s, after his severe epilepsy did not respond to any other treatment, a young man known for years as Patient HM went in for brain surgery. In keeping with the best knowledge of the day, the part of his brain where his epileptic seizures seemed to come from was removed. This included both of his hippocampi.

He recovered from the surgery in most ways, except he had very serious memory problems. He could recall memories from his early childhood, but he could not remember much from the years leading up to his surgery.

More importantly, he had lost the ability to create new memories. His epilepsy was under control and the rest of his intelligence was fine, but he could not remember new events or words. He would even forget who he was talking to if he turned his head. HM became an experimental subject for the rest of his life.

After his death in 2008, HM's identity was revealed as Henry Molaison. Thanks to the sacrifice of his memory and his willingness to participate in ongoing studies, researchers were able to greatly expand their understanding of memory, the brain, and brain disease. Molaison made a great contribution to science and was reportedly happy to know he was helping others.

Related areas of the brain

The hippocampus is part of the limbic system, which includes parts of the brain associated less with conscious thought and more with feeling and reacting.

Situated on the edge of the cortex, the limbic system includes the hypothalamus and the amygdala. These structures help control different bodily functions, such as the endocrine system and what is commonly known as the "fight or flight" reaction.

Functions of the hippocampus

The hippocampus is one of the few areas of the brain where new nerve cells are generated through adulthood.

The hippocampus helps humans process and retrieve two specific kinds of memories: declarative memories and spatial relationships.

Declarative memories are memories related to facts and events. Learning how to memorize speeches or lines in a play is a good example of declarative memories in action.

Spatial relationship memories involve pathways or routes, as when cab drivers learn routes through a city. Knowledge of brain functions has grown to the point where researchers can now say spatial relationship memories are stored in the right hippocampus.

As the story of HM shows, the hippocampus also plays another vital role in memory. It is where short-term memories are turned into long-term memories, which are then stored elsewhere in the brain.

While it was once thought that new nerve cells only grew in embryos or young children, research has now shown that nerve cells develop throughout adulthood. The hippocampus is one of the few places in the brain where the new nerve cells are generated.

What happens if the hippocampus is affected by illness or injury?

HM's story reveals what happens when both hippocampi are completely removed. Similar problems develop when one hippocampus is damaged by illnesses such as Alzheimer's disease, or hurt in an accident.

When the hippocampus is impaired, patients can't develop new long-term memories. They also can't remember some things that happened before the hippocampal damage, but do better with things that happened longer ago.

Transient global amnesia is a specific form of memory loss that develops suddenly, seemingly on its own, and then goes away fairly quickly. Most patients with transient global amnesia eventually regain their memories, but researchers are not entirely clear on what causes these events. It is possible that damage to the hippocampus is involved.

Since the hippocampus plays such an important role in helping humans get around, affected individuals can have trouble getting from one place to another if it is damaged. They may be able to draw a map of the neighborhood they lived in as children, but find going to a store in a new area difficult.

Some diseases physically change the hippocampus. Both Alzheimer's disease and depression reduce the size of the hippocampus.

In Alzheimer's disease, this link is so well-established that watching the volume of the hippocampus can be used to diagnose the progress of the disease.

The impact is just as significant with depression. Scientists have found that in depression, the hippocampus wastes away and shrinks. It can shrink by up to 20 percent, according to some researchers.

Diseases that affect the hippocampus

The hippocampus is a sensitive part of the brain. It can be adversely affected by many different conditions, including long-term exposure to high levels of stress.

Three diseases are known to interfere with the ability of the hippocampus to do its job:

• Alzheimer's disease
• Epilepsy
• Depression

The hippocampus is one of the areas that Alzheimer's disease, the leading cause of dementia and memory loss, attacks first. Patients begin to lose their short-term memories and may find it difficult to follow directions.

As the disease progresses, affected parts of the brain start to waste away. The hippocampus loses volume as the disease continues, and patients become less and less able to function.

Alzheimer's, epilepsy, and depression all interfere with the hippocampus.

There is a strong link between the hippocampus and epilepsy. As is revealed in the story of Patient HM, the hippocampus is where many epileptic seizures begin.

Between 50 and 75 percent of patients with epilepsy who have autopsies had damage to the hippocampus. As the researchers note, it is not clear whether epilepsy is the cause or the result of the hippocampus damage, however.

The hippocampus also loses volume in cases of severe depression. As with the damage seen by epileptic seizures, scientists are continuing to explore which came first: a smaller hippocampus or depression.

There is substantial evidence that stress has a negative impact on the hippocampus. Individuals with Cushing's disease show a number of symptoms linked to high levels of cortisol, a hormone produced when people are under stress. One of these symptoms is a reduction in the size of the hippocampus.

Current research

The hippocampus is the subject of significant new research.

One promising study is examining the effects of exercise on the hippocampus. The researchers are exploring the idea that exercise in old age may strengthen this structure's ability to generate new nerve cells. This would preserve and potentially improve memory.

In ongoing work at Johns Hopkins University, researchers are studying the links between the hippocampus, depression, and specific structures called chromosomes. The idea of adults being able to create new nerve cells was first examined in the 1990s and continues to generate new routes of inquiry.

Written by Danielle Dresden

Treatment approach used in cancer holds promise for Alzheimer's disease

New Alzheimer's treatment could be delivered as nasal spray.

Researchers have developed a novel treatment that could block the development of Alzheimer's disease using microscopic droplets of fat to carry drugs into the brain. This treatment approach, which is used to target drugs to cancer cells, has been successfully applied to Alzheimer's disease for the first time, restoring memory loss in mice.

The study, which was led by researchers at Lancaster University and funded by Alzheimer's Society, is published in the journal Nanomedicine: Nanotechnology, Biology and Medicine.

The treatment uses tiny droplets of fat, called nanoliposomes, which are coated in protein fragments that are able to stop amyloid protein accumulating into plaques, even at low concentrations. Amyloid plaques are the toxic clumps of protein that cause damage to cells in the brains of people with Alzheimer's disease.

Mice that were genetically altered to develop Alzheimer's disease were injected with the nanoliposomes for three weeks. Those which received the drug recovered their long-term memory and could recognise familiar objects after a 24-hour period. In comparison, mice which received a placebo injection had no memory of objects seen the day before.

Lead researcher, Professor David Allsop, commented: "Following results this summer, there is renewed optimism for antibody drugs - treatments that harness the body's immune system to target amyloid plaques. However if these prove successful, treatments will have to be administered in a clinic by an IV drip and could have some potentially harmful side effects.

"Using nanoliposomes offers an alternative way to inhibit the toxic build-up of amyloid plaques without activating an immune response in the brain. Our hope is that this could one day be administered by something as simple and non-invasive as a nasal spray, which patients could use in the comfort of their own home."

Nanoliposomes are already used to better target toxic chemotherapy drugs to cancer cells. Recent studies have also shown that the fat droplets can pass directly into the brain through the nose, opening up the possibility of using a nasal spray to administer treatments for brain diseases, such as Alzheimer's.

Commenting on the need for innovative approaches to dementia treatments, Dr Doug Brown, Director of Research and Development at Alzheimer's Society, said: "With no new dementia drugs in nearly 15 years, we're at a critical time for dementia research. It's absolutely vital we continue to sniff-out new approaches to getting drugs into the brain. While we wait in anticipation for the results of ongoing clinical trials, Alzheimer's Society will continue to fund innovative research to tackle dementia head-on."

"Nanotechnology is promising great benefits to people with many different types of cancer, and it's exciting that it could one day offer the same hope to people with the most common form of dementia."

There are 850,000 people in the UK living with dementia, and currently available drugs are only able to treat the symptoms of dementia, rather than slowing its progression. The research team at Lancaster University are now seeking investment from industry to take their novel treatment forward to be tested in people.

Article: Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer's Aβ peptide, Maria Gregori, Mark Taylor, Elisa Salvati, Francesca Re, Simona Mancini, Claudia Balducci, Gianluigi Forloni, Vanessa Zambelli, Silvia Sesana, Maria Michael, Christos Michail, Claire Tinker-Mill, Oleg Kolosov, Michael Scherer, Stephen Harris, Nigel J. Fullwood, Massimo Masserini, David Allsop, Nanomedicine: Nanotechnology, Biology and Medicine, doi: 10.1016/j.nano.2016.10.006, published online 19 October 2016.

Newly identified rare Alzheimer's disease gene mutation more common in Icelandic people

A rare variant in the TM2D3 gene linked to increased risk and earlier onset of Alzheimer's disease.

People with Icelandic heritage are more likely to carry a novel rare mutation in the TM2D3 gene, which leads to greater risk for Alzheimer's disease, based on a new study published October 14th, 2016 in PLOS Genetics by Johanna Jakobsdottir of the Icelandic Heart Association, Sven van der Lee of Erasmus University in Rotterdam, and colleagues.

Alzheimer's disease is the most common form of dementia, affecting about 30% of adults above the age of 85. While scientists have already identified many common genetic variants that contribute to the disease, rare mutations with significant effects in the population have been more difficult to discover, except in rather isolated families. To find such rare variations, a collaboration of Alzheimer's researchers throughout the U.S. and Europe performed an analysis covering more than 11,000 genes in 1,393 late-onset Alzheimer's disease patients. They identified a variant in the TM2D3 gene that is associated with both a higher risk and earlier age of onset of Alzheimer's disease.

Interestingly, the TM2D3 genetic variant is about 10 times more common in Icelanders compared to the European population in general. Nevertheless, the variant remains quite rare and is present in fewer than 1% of the Icelandic population, and the prevalence of Alzheimer's disease in Iceland is comparable to that seen elsewhere in the world. The researchers also performed experiments in a fruit fly model, in which human TM2D3 was substituted for an equivalent fly gene, demonstrating that the discovered variant interferes with the Notch signaling pathway. Other Notch signaling factors have previously been shown to participate in the generation of amyloid plaque brain pathology in Alzheimer's disease.

Jakobsdottir, van der Lee and colleagues have identified a rare genetic variant associated with Alzheimer's risk, and propose a possible function to explain its role in the disease. The TM2D3 gene has not previously been linked to Alzheimer's, and thus may have importance for understanding the mechanisms that contribute to the late-onset form of the disease.

Johanna adds "We have found a rare variant in the TM2D3 gene that correlates with risk of late-onset Alzheimer's disease and showed that it likely interferes with the Notch signaling pathway, which has relevance for Alzheimer's disease as other Notch signaling factors play a role in amyloid plaque pathology. However, we have not proven causality and further study is needed, including additional experiments in the fly, DNA sequencing to identify additional variants, and RNA sequencing to study effects on gene expression."

Article: Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease, Jakobsdottir J, van der Lee SJ, Bis JC, Chouraki V, Li-Kroeger D, Yamamoto S, et al., PLoS Genetics, doi:10.1371/journal.pgen.1006327, published 20 October 2016.

Sudden blood pressure drops associated with long-term dementia risk

Orthostatic hypotension - low blood pressure when suddenly standing up - is associated with a 15 percent increase in a person's long-term risk of dementia, including Alzheimer's disease, according to a twenty-four year study of more than 6,000 people published this week in PLOS Medicine by Arfan Ikram and Frank Wolters from Erasmus Medical Center, the Netherlands, and colleagues.

Orthostatic hypotension, which can trigger head rushes or dizzy spells upon standing, is known to cause transient cerebral hypoperfusion, or brief episodes of reduced blood flow to the brain. Previous studies have also shown that reduced blood flow in the brain, in the elderly, can contribute over time to brain dysfunction, but hadn't specifically looked at hypoperfusion caused by orthostatic hypotension. Between 1990 and 1992, Ikram and colleagues evaluated 6204 men and women without dementia or history of stroke in the Dutch population-based Rotterdam Study, with a mean age of 68.5. Those with a drop of more than 20mmHg in their systolic blood pressure or 10 mmHg in their diastolic pressure within 3 minutes of standing from a resting position were classified as having orthostatic hypotension. Then, they followed the participants until 2014, tracking the occurrence of dementia.

After a mean follow-up time of 15.3 years, 1176 (19 percent) of the participants in the study developed dementia, including Alzheimer's disease, vascular dementia, Parkinson's dementia, and other dementias. Orthostatic hypotension at baseline, which was present in 1152 participants (18.6 percent), was associated with a 15 percent relative increase (95 percent confidence interval 1.00-1.34, p=0.05) in all dementia types. The association was even more pronounced for those who didn't have a compensatory increase in heart rate along with the momentary drop in blood pressure, with a 39 percent increase in long-term dementia risk (95 percent confidence interval 1.04-1.85, p=0.03). Variability in systolic blood pressure upon standing, even without meeting the formal criteria for orthostatic hypotension, was associated with an 8 percent increased risk of dementia (95 percent confidence interval 1.00-1.17, p=0.02). The study was limited to a mostly Caucasian population, so the associations may not hold true for other ethnicities.

Although this association between orthostatic hypotension and dementia does not necessarily represent a direct causal role, one possible explanation for the findings, the authors say, is that "brief episodes of hypoperfusion, elicited by sudden blood pressure drops, may lead to hypoxia [lack of oxygen] with detrimental effects on brain tissue."

The Heart Brain Connection consortium is supported by the Netherlands Cardiovascular Research Initiative (CVON2012-06). The Rotterdam Study is sponsored by the Erasmus Medical Centre and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research (NWO), The Netherlands Organization for Health Research and Development (ZonMW), the Research Institute for Diseases in the Elderly (RIDE), The Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Further support was obtained from the Netherlands Consortium for Healthy Ageing and the Dutch Heart Foundation (2012T008). None of the funding organisations or sponsors were involved in study design, in collection, analysis, and interpretation of data, in writing of the report, or in the decision to submit the article for publication.

The authors have declared that no competing interests exist.

Article: Orthostatic Hypotension and the Long-Term Risk of Dementia: A Population-Based Stud, Wolters FJ, Mattace-Raso FUS, Koudstaal PJ, Hofman A, Ikram MA, Heart Brain Connection Collaborative Research Group, PLOS Medicine, doi:10.1371/journal.pmed.1002143, published 11 October 2016.

Action Points

• Note that this AHA statement suggests that mid-life hypertension may lead to late-life dementia, and treatment of hypertension should be recommended on that basis (among others).
• Be aware that, though the biological rationale for this statement is on firm-footing, the objective evidence of a hypertension-dementia causal link is lacking.

There is compelling evidence that chronic arterial hypertension in mid-life is associated with late-life dementia, including Alzheimer's disease, according to the authors of a scientific statement issued by the American Heart Association (AHA).

While review of the literature revealed insufficient data to make evidence-based recommendations, "judicious" and individualized control of hypertension is probably key, Costantino Iadecola, MD, director of the Brain and Mind Research Institute at Weill Cornell Medical College in New York City, and colleagues reported online in Hypertension.

"There is a strong rationale for treating hypertension, taking into account age, brain health, cardiovascular and cerebrovascular health, and other risk factors," Iadecola told MedPage Today. "Maintaining cerebrovascular health is critical for brain health. That is, we need healthy vessels for a healthy mind."

Given the prevalence of hypertension and the fact that effective drugs are so accessible, "treatment of hypertension may prove to be one of the best ways to prevent or delay dementia," the AHA statement authors wrote.

They acknowledged, however, that the question of whether treating hypertension prevents or reverses cognitive decline remains unanswered. While observational studies have demonstrated that cerebrovascular damage caused by hypertension is cumulative, evidence that antihypertensive treatment improves cognition is not conclusive.

Also, the cognitive impact of late-life hypertension isn't clear, as some evidence has suggested that "in very late life, aggressive treatment may be more problematic than helpful," they wrote.

Results from the Systolic Blood Pressure Intervention (SPRINT-MIND) trial, which is evaluating the role of treating high blood pressure relative to cognitive impairment, may address some of the knowledge gaps, the authors suggested.

Their literature review showed that hypertension may promote __alzheimer pathology by leading to ischemic damage of white matter critical for cognitive function.

Although there is "substantial evidence that hypertension leads to cognitive impairment, an effect attributed to oxidative stress-driven cerebrovascular dysfunction and damage, the underlying cellular and molecular mechanisms remain incompletely understood," the authors wrote.

"New discoveries in the cellular and molecular pathology of the cerebrovascular tree and associated cells, coupled with the use of new imaging tools, biomarkers, and genomic-proteomic approaches in clinical trials, offer the prospect to address these unanswered questions and to develop new treatments to mitigate the devastating impact of hypertension on cognitive health," they added.

In addition to a need for more understanding of the basic science aspects, there's also a need for more work in the form of randomized controlled trials to test whether interventions can prevent dementia. Barriers to that kind of information have included difficulties doing the needed decades-long longitudinal studies as well as a lack of uniform cognitive outcomes across studies. The complex relationship between hypertension and cerebrovascular risk factors has hampered treatment assessment, the researchers said.

But Iadecola noted that clinical trials that specifically address the role of hypertension in cognitive dysfunction across the entire life course -- from infancy to late life -- are urgently needed.

"Such an effort needs to be coupled to basic science investigations addressing why and how hypertension exerts such powerful deleterious effects on cognitive function and its overlap in Alzheimer's disease and other forms of late life dementia," he told MedPage Today.

There are a number of challenges clinicians currently face in treating hypertension, including individualizing blood pressure targets, he added. In an era of "precision medicine," these targets need to be established on a patient-by-patient basis, Iadecola said, noting that in the elderly, lowering blood pressure can be detrimental.

Establishing the best time to initiate treatment, particularly when a patient's blood pressure falls into the "prehypertension" range of 120 to 139 mm Hg systolic, also remains a concern: "There is evidence that elevations in blood pressure in the prehypertension range are also associated with increased demential risk," Iadecola said. "Whether treatment initiated in this blood pressure range is effective remains to be established."

In the absence of contraindications, starting treatment "as soon as blood pressure starts to inch up," may be worthwhile, he suggested.

Control of hypertension is likely to be a fundamental step in the effort to reduce the incidence of AD and other forms of dementia worldwide, Iadecola said.

Recent epidemiological data have shown that the incidence of dementia in the Framingham Heart Study has been falling at a rate of about 20% per decade and perhaps declining in some other Western countries too.

"Although the specific causes remain to be firmly established, many experts agree that treatment of hypertension may have had a major role in the decline," he said.

Results from the long-term randomized controlled Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial would seem to support this, he noted. Those results indicated that control of hypertension and other vascular risk factors as well as physical and mental activity and a healthy diet can prevent or improve cognitive decline in an at-risk population of elderly, Iadecola said.

Iadecola disclosed no conflicts of interest. Co-author David S. Knopman, MD, disclosed relationships with Lilly, TauRX, Biogen, Lundbeck Pharmaceuticals, and DianTU. No other study authors disclosed conflicts of interest.

• Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

last updated 10.14.2016

• Primary Source

  Hypertension

  Source Reference: Iadecola C, et al "Impact of hypertension on cognitive function: A Scientific Statement from the American Heart Association" Hypertension 2016; DOI: 10.1161/HYP.0000000000000053.

take posttest 0 comments

Although the nation's election focus has been on all things presidential, there are plenty of state ballot issues to think about, including many involving healthcare. MedPage Today has put together a sampling of the healthcare ballot issues voters will be considering in the upcoming election.

Tobacco, Marijuana Initiatives

Several states, including California, Colorado, Missouri, and North Dakota, have initiatives that ask voters to increase the state tobacco tax. California's Proposition 56 would increase that state's tobacco tax by $2, while Colorado's would go up by $1.75 under that state's initiative.

"We used to be ahead of the curve on this, and over the years we have drifted downward to the bottom half of the states" in terms of the size of the tobacco tax in California, Carla Kakutani, MD, chair of the legislative committee at the California Academy of Family Physicians (CAFP), said in a phone interview.

The academy is endorsing the proposal for two reasons: "Anything that can decrease smoking, we're in favor of; research has shown that if the cost of a cigarette pack is increased by 10%, you'll see a decrease in teen smoking by 7%," said Kakutani. In addition, the measure includes electronic cigarettes, "so that would make it at least somewhat more difficult for kids to get ahold of [those]."

In Colorado, the tobacco tax hasn't been raised since 2004, noted James Fenton, MD, a pulmonologist at National Jewish Health in Denver. "We realized that Colorado had one of the lowest tobacco taxes in the country – $0.84 a pack -- essentially a dollar below the national average [tax] for nontobacco-producing states," he said in a phone interview. And yet, "... [we have] found tobacco taxes to be an effective deterrent for smoking ... They are found to be the single most effective way to reduce tobacco use." Unlike California, however, Colorado's initiative applies only to tobacco products, not e-cigarettes or marijuana, Fenton added.

North Dakota's proposed tobacco tax would set up a tobacco trust fund to fund certain veterans' programs; the tobacco tax revenue would be split among the trust fund, the general state fund, and the state's community health fund.

Marijuana also appears on the ballot in several states, with three -- Arkansas, Florida, and North Dakota -- asking voters whether they want to legalize marijuana for medical use, or to expand the current medical marijuana law. "Arkansas actually has two competing medical marijuana initiatives on the November ballot: The Arkansas Medical Marijuana Act (restricts access to state-approved dispensaries) and the Medical Cannabis Act (patients who have received the necessary approval from physicians and the state can grow marijuana plants on their own)," the American Academy of Sleep Medicine (AASM) noted on its website. "Should both initiatives win approval, the one with the highest number of 'yes' votes will supersede the other."

In addition, voters in five states -- Arizona, California, Maine, Massachusetts, and Nevada -- are being asked to legalize marijuana for recreational use, according to the National Conference of State Legislatures' Ballot Measure Database.

Curbing the Cost of Rx Drugs

California will be considering a measure aimed at reducing the high cost of some prescription drugs. The measure, known as Proposition 61, would cap the prices paid by state-run health programs at no more than what the Department of Veterans Affairs pays for its drugs. The measure has wide support among state voters, including 77% of Democrats and 70% of Republicans, according to Politico. And it has been an expensive battle, with the measure's opponents spending more than $60 million to defeat the measure compared with $9.4 million in spending by proponents.

The CAFP has not taken a position on the bill. "It feels like we do not have enough information one way or another," said Kakutani. "We have been discussing where we should weigh in on drug pricing. I think 61 is well-intentioned but may have unintended consequences."

Medical Liability Reform

Arkansas' Issue 4 addresses malpractice lawsuits: it would limit attorney contingency fees in malpractice cases to 33%, and would have the state legislature enact a cap on non-economic damage awards in malpractice cases, noting that 'such a measure may never be smaller than $250,000.'"

Universal Healthcare

One state, Colorado, is asking its voters whether they want universal healthcare. The ballot measure, known as Amendment 69, would get rid of the state’s Affordable Care Act (ACA) exchanges and would replace most private insurance plans; however, it is not considered a single-payer plan and would not eliminate government programs such as Medicare, TriCare, or the Department of Veterans Affairs (VA) health system in the state — instead, it would act as supplemental insurance for people in those programs. People also would still be able to buy private insurance, although it is thought to be unlikely that they would want to pay to duplicate the new program’s benefits.

The program, known as ColoradoCare, would be supervised by a board of 21 people and would be financed through individual and employer taxes, totaling a 10% tax increase overall. Patients would be able to choose their own primary care physicians, and many deductibles and copays would be eliminated.

The measure's proponents argue that having a universal system would cut out insurance company overhead and therefore lower costs overall. But opponents are concerned about how the measure would affect providers. "Competition between health insurers plays a critical function in our state's healthcare system by helping to drive down costs," the Colorado Hospital Association wrote in a position paper opposing the amendment. "Working with multiple insurers provides hospitals with the negotiating power they need to ensure reimbursements are sufficient."

Physicians for a National Health Program (PNHP), an organization supporting single-payer healthcare, notes on its website that the proposal has many strengths, but that because some private and other public payers would still be in the system, “[the proposal] sacrifices much of the administrative savings that could be realized through a true single- payer reform because providers would have to maintain much of their current cost-tracking and billing apparatus in order to apportion costs among the multiple payers.” PNHP has not taken a position on the proposal.

Physician-Assisted Suicide

A measure on the ballot in Colorado would allow patients who have been diagnosed with a terminal illness -- defined as having less than 6 months to live -- to request a prescription from their doctor to hasten their death.

The law would require two physicians to confirm the prognosis, and to confirm that the patient has gotten information about other options. It would also require patients to undergo a mental health evaluation if either doctor believes the patient isn't mentally capable of making the decision, and it exempts from civil or criminal liability anyone who helps the patient access the medication or who is present when it is self-administered.

Jennifer Popik, JD, director of medical ethics at the National Right to Life Committee, which opposes the measure, noted that the Colorado legislature has rejected nearly identical bills this year and last year, arguing that they were too dangerous. "We agree that these assisted suicide laws pose too great a threat to vulnerable populations no matter what so-called 'safeguards' they might contain," she wrote in an email. "We join many typically politically unaligned groups opposing these measures, including disability rights groups, the American Medical Association, prolife and church groups, and others."

Although proponents claim that such a law would simply provide another medical option, "there is evidence from the state living with a nearly identical version of this law the longest -- Oregon -- that these laws have expanded far beyond those we think of as terminally ill -- including diabetics and those with HIV and hepatitis, because without treatment they could die within 6 months," she continued. "So many may be giving up unnecessarily on many more good years of life."

Compassion & Choices, an aid-in-dying organization, supports the measure. "End-of-life decisions are best left to dying people, consulting their families, their faith, and their doctors – not the government," Jessica Grennan, campaign manager of the Yes on Colorado End-of-Life Options effort, said in a press release posted on the organization's website. "This proposal takes government out of these personal decisions and allows patients to make their own choices about their life based on their health, their family's input, and their personal religious beliefs."

Biomedical Research

On the Montana ballot, Initiative 181 would establish a state Biomedical Research Authority "to oversee and review grant applications for the purpose of promoting the development of therapies and cures for brain diseases and injuries and mental illnesses, including Alzheimer's, Parkinson's, brain cancer, dementia, traumatic brain injury, and stroke." Grants would be funded by state general obligation bonds.

Safer Movie Sex

Proposition 60 on the California ballot would require the use of condoms during filming of sexual intercourse, and would require producers of adult films to "pay for performer vaccinations, testing, and medical examinations related to sexually transmitted infections." Producers also would have to post the condom requirement at film sites, and the initiative would impose liability on producers who fail to comply, as well as on agents "who knowingly refer performers to noncomplying producers."

Reproductive Rights

One issue notably missing from this year's state ballots is reproductive rights. Organizations on both sides of the abortion debate said they were not following any ballot issues on the topic this time around.

This article, originally posted on Oct. 6 at 06:00 ET, has been updated with new information.

last updated 10.05.2016

0 comments

Experimental drug shows promise in treating Alzheimer's disease

An experimental drug shows promise in treating Alzheimer's disease by preventing inflammation and removing abnormal protein clumps in the brain that are associated with the disease, suggests a study in mice presented at the ANESTHESIOLOGY® 2016 annual meeting.

A key characteristic of Alzheimer's disease is the development of abnormal protein clumps called amyloid plaques and tangled bundles of fibers in the brain. These changes cause inflammation in the brain and damage to the neurons. This progressive damage leads to memory loss, confusion and dementia. The new drug, known as NTRX-07, appears to decrease this inflammation in the brain, while preserving neurons and regenerative cells in the brain.

"This drug may reduce inflammation in the brain, which is linked to Alzheimer's disease," said lead researcher Mohamed Naguib, M.D., a physician anesthesiologist in the Department of General Anesthesiology at the Cleveland Clinic and professor of anesthesiology at the Cleveland Clinic Lerner College of Medicine. "NTRX-07 uses a different mechanism than many other Alzheimer's drugs currently available, as it targets the cause of the disease, not just the symptoms."

The authors discovered NTRX -07's memory-restoring abilities while studying the drug's potential to treat a complex, chronic pain condition called neuropathic pain. "Patients who have neuropathic pain have chronic neuroinflammation," said Dr. Naguib. "This is a compound that blunts that inflammation."

Researchers tested NTRX -07 on mice bred to have similar brain neurodegenerative issues as seen in Alzheimer's. They found that inflammation produced in response to the disease caused changes in the brain's microglia cells - immune cells that typically remove dangerous amyloid plaques (protein clumps) in the brain. As the amyloid plaques accumulated in the mice, the microglia (immune cells) were unable to remove them, leading to inflammation and damage to nerve cells, which caused decreased cognitive ability.

Microglia cells have receptors on the surface called CB2 receptors, which when activated can produce an anti-inflammatory response. NTRX -07 targets CB2 receptors, which leads to decreased inflammation and prevents damage to the brain tissue. The new drug improved removal of abnormal amyloid plaques and improved memory performance and other cognitive skills.

The drug also increased levels of a protein called SOX2, which has been shown to help new brain cells develop and protect the brain in people with Alzheimer's disease. The study found in mice treated with NTRX-07, the levels of SOX2 were restored to normal levels. In contrast, mice treated with a placebo showed decreased levels of SOX2, active inflammation in the brain, poor removal of amyloid plaques, and poor memory performance.

Joseph F. Foss, M.D., director, of clinical research for general anesthesiology at Cleveland Clinic, and Dr. Naguib are co-founders of NeuroTherapiaTM, a spin-off company created by Cleveland Clinic Innovations to develop NTRX -07. NeuroTherapiaTM recently received a $1.7 million investment from the Alzheimer's Drug Discovery Foundation to advance NTRX-07 toward human clinical trials. The company also has received $700,000 from the Alzheimer's Association to support the proposed Phase I human studies. They anticipate initiating the human clinical studies in 2017.

Alzheimer's disease: New analyses from Phase 3 studies showing clinical benefit of Tramiprosate

Results published in The Journal of the Prevention of Alzheimer's Disease (JPAD) describe analyses of Phase 3 data for the investigational amyloid-targeted drug, tramiprosate, in patients with Mild to Moderate Alzheimer's disease (AD). These efficacy analyses evaluated patient subgroups based on the number of e4 alleles of apolipoprotein E (APOE4), a major genetic risk factor in up to 65 percent of patients with AD.^1,2 The published results showed a gene-dose effect at the high dose of tramiprosate (150 mg, twice daily), with patients with two APOE4 alleles (APOE4/4 homozygotes) showing the largest clinical benefit, those with one APOE4 allele (APOE4 heterozygotes) showing an intermediate benefit, while APOE4 non-carriers showed no benefit from tramiprosate. The results published in JPAD are the first evidence from a large clinical trial to associate efficacy of an amyloid-targeted agent with APOE4 status in AD patients.

The manuscript, titled "Clinical Benefits of Tramiprosate in Alzheimer's Disease Are Associated with Higher Number of APOE4 Alleles: The 'APOE4 Gene-Dose Effect'," is featured in the advanced online publication of The Journal of the Prevention of Alzheimer's Disease (JPAD)³ with lead authors from Alzheon, Inc., a biopharmaceutical company focused on treatments for neurodegenerative and neuropsychiatric disorders. Based on the analyses in the publication, Alzheon is developing ALZ-801, an optimized oral prodrug of tramiprosate, and has refined the design of the pivotal clinical trial to evaluate ALZ-801 as a potential disease-modifying agent in symptomatic AD patients who are APOE4/4 homozygotes.

Anton P. Porsteinsson, MD, Professor of Psychiatry at the University of Rochester School of Medicine and Dentistry and Director of the Alzheimer's Disease Care, Research and Education Program at the University of Rochester in Rochester, NY, and an investigator in the North American Phase 3 clinical trial, commented: "The genetically‐defined population of APOE4 carriers has an 8‐12 fold increased risk of developing AD and has more rapidly progressive disease, usually becoming symptomatic a decade earlier than non‐carriers of the APOE4 genotype. These analyses with tramiprosate in the APOE4 subgroups are compelling, and suggest a meaningful clinical benefit, on top of the existing symptomatic AD treatments, in Alzheimer's patients who are in great need of new treatments. We can apply these insights about the therapeutic response of APOE4 carriers to refine patient selection and potentially improve the success rate of new Alzheimer's medicines."

The efficacy and safety analyses with tramiprosate published in JPAD reveal a therapeutic effect in patients who are carriers of APOE4 after segmenting them from the larger, non-genetically-defined study population in the Phase 3 clinical program, involving more than 2,000 AD patients in North America and Europe. In the overall Mild and Moderate AD study population with baseline MMSE of 16-26 (and any APOE genotype), the North American study did not demonstrate a significant benefit with either of two tramiprosate doses (100 mg BID and 150 mg BID), compared to placebo, during the 78-week study period.⁴ As a result, the European study was terminated before completion, and the results were not previously published.

"To our knowledge, this is the first time that the clinical benefits of an amyloid-targeted agent have been associated with the number of APOE4 alleles in Alzheimer's patients. This new insight shows how we can apply a precision medicine approach in AD and develop this drug for the right patients, namely patients with the APOE4 genotype, which carries the highest risk as well as the earliest onset and faster disease progression," said Martin Tolar, MD, PhD, Founder, President and CEO of Alzheon. "These newly-published findings form the basis for the design of our Phase 3 program, and further support our company's commitment to advance ALZ-801 into pivotal studies in APOE4/4 homozygous AD patients who represent up to 15% of AD patients¹. We are preparing to advance ALZ-801, a promising new treatment for Alzheimer's disease, into confirmatory clinical studies in 2017."

The observed gene-dose effects of tramiprosate in APOE4 carriers are consistent with the prevalence of amyloid pathology in AD patients. Amyloid imaging in AD clinical trials has shown the highest prevalence of positive amyloid scans in APOE4/4 homozygotes, and the lowest prevalence in APOE4 non-carriers.⁵ As one of the few orally-administered amyloid-targeted agents, tramiprosate blocks the aggregation of beta amyloid monomers into toxic oligomers, and was developed to show efficacy in patients with amyloid pathology and an accurate diagnosis of AD.

Efficacy Results in APOE4/4 Homozygous Patients from the JPAD Phase 3 Analyses

The published results showed the largest clinical benefit in the Alzheimer's APOE4/4 homozygous AD patients, who represent approximately 15 percent of patients in the study.³ APOE4/4 homozygous patients who received the high dose of tramiprosate showed efficacy benefit compared to placebo on both cognitive and functional measures in the Phase 3 analyses. The effects on the ADAS-cog cognitive outcome were significant at Week 65 (LS means difference from placebo: 3.47, nominal p = 0.007) and Week 78 (2.60, nominal p = 0.043), and corresponded to 66 percent and 40 percent benefit from tramiprosate compared to placebo. These effects were supported by functional benefits on the CDR-SB that showed a positive trend at Week 65 (LS means difference from placebo: 0.79, nominal p = 0.063) and were numerically in favor of tramiprosate at Week 78 (0.54, nominal p = 0.21).

"APOE4/4 homozygous AD patients are especially challenging since they are known to have the highest burden of amyloid pathology in cerebral cortex and blood vessels, which explains their susceptibility to ARIA-E with some amyloid-targeted treatments. In these new subgroup analyses, the high dose of tramiprosate showed promising clinical effects in APOE4/4 homozygous AD patients already receiving maximal standard of care, and this dose was not associated with any events of vasogenic edema," said Susan Abushakra, MD, Chief Medical Officer of Alzheon and lead author on the JPAD publication. "Replication of these findings in Alzheon's planned Phase 3 study would provide a meaningful therapeutic advance for AD patients with the APOE4/4 genotype, and we are now preparing to carry forward these results into the development of ALZ-801."

Safety Results from the JPAD Phase 3 Analyses

The safety profile of tramiprosate in 2,025 AD patients across the two studies was favorable and similar in the APOE4 carriers and non‐carriers. The main adverse events were gastrointestinal (nausea, vomiting and weight loss), which were mild or moderate in severity.

New ARIA-E safety analyses were reported in the JPAD publication. Brain magnetic resonance imaging (MRI) evaluations in 426 patients were conducted during the Phase 3 studies and did not reveal any events of vasogenic brain edema (ARIA-E or amyloid-related imaging abnormalities-edema) on either dose of tramiprosate. Vasogenic edema (or brain swelling) is a side effect observed in clinical studies with some injectable anti-amyloid antibodies, which requires MRI monitoring and can occasionally be serious.⁶

Article: Clinical Benefits of Tramiprosate in Alzheimer's Disease Are Associated with Higher Number of APOE4 Alleles: The 'APOE4 Gene-Dose Effect, S. Abushakra, A. Porsteinsson, B.Vellas, J. Cummings, S. Gauthier, J.A. Hey, A. Power, S. Hendrix, P. Wang, L. Shen, J. Sampalis, M. Tolar, The Journal of the Prevention of Alzheimer's Disease, doi: 10.14283/jpad.2016.115, published online 24 October 2016.

Risk of hospital admissions could be reduced with better general practice strategies

Hospital admission rates are 55 per cent higher in some areas than in others because of a greater prevalence of conditions such as diabetes, alcoholism, dementia and socioeconomic deprivation. According to published research, those admission rates could be reduced if GPs were better supported to provide more specialist care for chronic conditions and difficult-to-reach groups.

The study, carried out by the University of Bristol's School of Social and Community Medicine, measured how much admission rates varied between the 8,000 general practices in England during 2011/12, and included 1.8 million admissions.

This study focused on ambulatory care sensitive conditions (ACSCs) such as diabetes, alcoholism, asthma and dementia, where the provision of better care outside hospital, by GPs and other healthcare professionals, can potentially reduce the need for admission.

Overall, researchers found that admission rates in some practices were 55 per cent higher than others. Chronic conditions such as diabetes, schizophrenia and hypertension tended to be much more variable than acute conditions such as strokes and hip fractures, as were those that disproportionately affect deprived communities, such as alcoholism.

Dr John Busby, lead author of the study, published in The British Journal of General Practice, said: "Admission rates for some of the conditions in our study, including alcoholism, schizophrenia and diabetes, were over three times higher in some practices than others. Clearly, this raises important questions about why these differences exist and what can be done to standardise care around best practice.

"Existing mechanisms, such as the quality and outcomes framework and NICE guidelines, aim to ensure that patients receive a consistent quality of primary care across all practices in England. Our results suggest that these might not be working effectively and that new strategies are required."

Previous studies have looked at the variation in admission rates for some of these conditions. However, they have tended to focus on a small number of health conditions and have used different methodologies, making it almost impossible to draw comparisons across studies.

This latest study from Bristol applied the same methods to a broad range of conditions, enabling researchers to make more accurate comparisons and to identify which conditions the NHS could focus on in order to improve care.

"Substantial differences in admission rates among general practices could mean that some patients are receiving suboptimal care," added Dr Busby. "Our research suggests that differences in the way GP care is delivered across England could have an important impact on patient health. This could include sub-optimal management of chronic disease which puts patients at higher risk of hospital admission, but also overly-cautious referrals to hospital, or a lack of alternatives to treat patients in the community. Clearly this matters to patients as most would prefer not to be admitted to hospital if it can be avoided, but it is also extremely important to the NHS finances as unplanned hospital admissions are expensive and can disrupt other care."

Researchers now intend to explore why such large variations exist between practices for some conditions, and how those reasons might help improve care. A follow-up investigation is being carried out to assess how the characteristics of a general practice are related to admission rates. This includes factors such as the distance to the nearest A&E, how easy it is to see a GP, how often patients can see their preferred GPs, and how many hospital beds are available in the local area.

Dr Busby added: "Given the results of this study, it will be interesting to see if the importance of each of these factors differs by condition. The way in which primary care is delivered is evolving rapidly, it is important that these changes are informed by good-quality evidence."

The research was supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care West (CLAHRC West) at University Hospitals Bristol NHS Foundation Trust.

Article: Opportunities for primary care to reduce hospital admissions: a cross-sectional study of geographical variation, John Busby, Sarah Purdy and William Hollingworth, The British Journal of General Practice, doi: 10.3399/bjgp16X687949, published 25 October 2016.

Cell protein offers new hope in fighting the effects of aging

A protein found within the powerhouse of a cell could be the key to holding back the march of time, research by scientists at The University of Nottingham has shown.

The discovery could offer a new target for drugs that may help to slow the debilitating effects of aging on our bodies.

And their research, published in the academic journal Aging, could have special significance for combatting age-related decline and halting the progression of neurodegenerative conditions such as Alzheimer's and Parkinson's Disease.

The work, led by Dr Lisa Chakrabarti and PhD student Amelia Pollard in the University's School of Veterinary Medicine and Science, has centred on a family of proteins called carbonic anhydrase found within mitochondria - the cells' 'batteries' which convert the oxygen we breathe into the energy (ATP) needed to power our body.

Dr Chakrabarti said: "What's really exciting about this development is that we have been able to surmise that the function of this protein is playing a role in the aging process within the cell.

"This gives us a very promising start in working out how we can best target this protein within the mitochondria to slow the effects of aging in the body while limiting other unwanted side effects on the body. It could potentially offer a significant new avenue in both tackling degenerative illnesses and the general effects of aging on the body."

Using a specialist process called 2D gel electrophoresis, the scientists separated out all the proteins found within the mitochondria of brain cells and muscle cells from normal young brains and normal middle-aged brains and compared the two samples.

They found that the carbonic anhydrase was found in greater quantity and was more active in the samples of the middle-aged brain. Significantly, this increase was also reflected in samples from young brains suffering from early degeneration, suggesting that the increase is detrimental.

To establish whether this was indeed detrimental and not evidence of the body's attempt to guard against this degeneration - known as a protective effect - the scientists studied the effect of carbonic anhydrase on nematode worms.

They found that feeding carbonic anhydrase to the tiny c elegans worms - measuring around just one millimetre in length - reduced their life span.

As we age, our body's tissues and functions begin to diminish. Aging has been associated with a loss of muscle mass which begins around the age of 50 and becomes more pronounced in our 60s, leading to a reduction in strength and greater frailty.

Aging in the brain can cause the onset of cognitive impairment affecting memory, reasoning and multitasking and can lead to dementia. Other neurodegenerative diseases such as Alzheimer's and Parkinson's Disease can cause the early onset of cognitive decline.

The scientists are continuing their work to identify chemical compounds that may be successful in targeting carbonic anhydrase and to study what effect these potential inhibitors have on worms which have had their lives shortened by the protein.

The Nottingham study could be the first step to the development of a new type of drug that targets carbonic anhydrase in just the body's mitochondria to protect against aging and degeneration.

The three-year project was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) through its Doctoral Training Programme support for Amelia Pollard.

Article: Mitochondrial proteomic profiling reveals increased carbonic anhydrase II in aging and neurodegeneration, Amelia Pollard, Freya Shephard, James Freed, Susan Liddell, Lisa Chakrabarti, AGING, published online 10 October 2016.

Brain folding 'slackens' with age, study finds

The abundance of crevices and ridges in the outer layer of the human brain - commonly referred to as "folds" - make the organ instantly recognizable. Theory holds that the folding brain is a result of evolution, a way to condense the cerebral cortex and improve brain cell communication and functioning. Now, researchers have shed light on how folding occurs in the human brain and how it changes with age.

Researchers find that the cerebral cortex loses tension as we age, and this change is even more pronounced in patients with Alzheimer's disease.

The cerebral cortex is a critical part of the human brain. Composed of folded gray matter, the cerebral cortex is responsible for higher-level functions, such as consciousness, language, intelligence, and memory.

Only a handful of species - including humans, cats, dogs, and dolphins - have folds in the cerebral cortex.

Previous research has suggested that the way in which these folds arise follows a universal law across species, meaning that they all fold in the same way, irrespective of the shape and size of the cortex.

"However, it was yet to be determined whether this law also applies to the morphological diversity of different individuals in a single species, in particular with respect to factors, such as age, sex, and disease," note the study authors, led by Dr. Yujiang Wang of Newcastle University in the United Kingdom.

A 'simple universal law' for cortical folding in humans

To find out whether folding of the cerebral cortex is universal in humans, Dr. Wang and team used magnetic resonance imaging (MRI) to map the brain folds of more than 1,000 healthy adults.

The results - published in the Proceedings of the National Academy of Sciences - revealed that cortical brain folding in humans does follow a "simple universal law."

However, the team found that as we age, cortical folding changes. Specifically, the researchers found that tension on the inside of the cerebral cortex reduces.

"It would be similar to the skin," explains Dr. Wang. "As we age, the tension drops and the skin starts to slacken."

The researchers also identified gender differences in cortical folding; among men and women of the same age, the cerebral cortex of women showed slightly less folding.

Cortical folding differs in patients with Alzheimer's

On assessing cortical folding in the brains of patients with Alzheimer's disease, the team found that these patients showed more pronounced, earlier changes in cortical tension and folding than healthy adults.

Additionally, the mechanism by which cortical folding changes in patients with Alzheimer's disease differed to that of healthy men and women.

"More work is needed in this area but it does suggest that the effect Alzheimer's disease has on the folding of the brain is akin to premature aging of the cortex," says Dr. Wang. "The next step will be to see if there is a way to use the changes in folding as an early indicator of disease."

Overall, the researchers believe their study has provided some much-needed insight into the factors that influence cortical folding in the human brain.

"It has long been known that the size and thickness of the cortex changes with age but the existence of a general law for folding shows us how to combine these quantities into a single measure of folding that can then be compared between genders, age groups, and disease states."

Dr. Yujiang Wang

Read about a study that suggests nicotine has the potential to halt brain aging.

Written by Honor Whiteman

Stronger muscles lead to stronger brain

A study led by the University of Sydney in Australia has found that gradually increasing muscle strength through activities such as weightlifting improves cognitive function.

Stronger muscles reduce cognitive impairment in elderly patients.

The study was conducted in collaboration with the Centre for Healthy Brain Ageing (CHeBA) at the University of New South Wales and the University of Adelaide.

The results have been published in the Journal of American Geriatrics.

The trial involved a Study of Mental and Resistance Training (SMART) carried out on patients with mild cognitive impairment (MCI) between 55-68 years old. Patients with MCI have a higher risk of developing dementia and Alzheimer's disease.

The findings are particularly significant given the high incidence of dementia and Alzheimer's disease among the aging population. According to the 2016 World __alzheimer Report, 47 million people worldwide have dementia and this number is expected to triple by 2050.

In the United States, the figure predicted for people with Alzheimer's disease in 2050 is 13.8 million.

Due to the high cost of care for patients with dementia, the World Alzheimer Report recommends moving beyond specialist care. The report suggests a holistic approach that focuses on improving the quality of life for people living with the condition.

Seen in this context, a link between physical training and improving brain function might be a step in the right direction.

How a disciplined weightlifting schedule can improve cognition

The trial looked at progressive resistance training - such as weightlifting - and the functioning of the brain.

The study examined 100 older adults living with MCI. "Mild cognitive impairment" refers to older patients who have cognitive difficulties that are noticeable but not significant enough to interfere with their daily activities.

Eighty percent of patients diagnosed with MCI develop Alzheimer's disease after approximately 6 years.

For the trial, MCI patients were divided into four groups and assigned a range of activities. These included a combination of resistance exercise - including weightlifting - and placebo resistance in the form of seated stretching. Activities also included computerized cognitive training and its placebo equivalent.

The cognitive training and placebo activities did not yield cognitive improvements.

However, the study did demonstrate a proportional relation between improvement in brain function and improvement in muscle strength.

"What we found in this follow-up study is that the improvement in cognition function was related to their muscle strength gains. The stronger people became, the greater the benefit for their brain."

Lead author Dr. Yorgi Mavros

Previous studies have shown a positive link between physical exercise and cognitive function, but the SMART trial led by Dr. Mavros provides further information on the type, quality, and frequency of exercise needed to get the full cognitive benefits.

In the trial, participants did weightlifting sessions twice a week for 6 months, working to at least 80 percent of their peak strength. The weights were gradually increased as participants got stronger, all the while maintaining their peak strength at 80 percent.

"The more we can get people doing resistance training like weightlifting, the more likely we are to have a healthier aging population," says Dr. Mavros. "The key, however, is to make sure you are doing it frequently, at least twice a week, and at a high intensity so that you are maximizing your strength gains. This will give you the maximum benefit for your brain."

This is also the first time a study has shown a clear causal link between increasing muscle strength and improving brain function in patients over 55 years old who have MCI.

Exercise and cognitive function

It has been suggested that exercise indirectly helps prevent the onset of Alzheimer's disease and lowers the risk of cognitive impairment. Exercise helps with physiological processes such as glucoregulation and cardiovascular health. When these are sub-optimal, they increase the risk of cognitive impairment and Alzheimer's disease.

Exercise also improves other cognitive processes, such as selective attention, planning, organizing, and multitasking.

Some studies have also suggested a connection between an increase in the size of certain brain areas and exercise training.

With age, the hippocampus is known to reduce in size, which leads to cognitive impairment. However, aerobic exercise has shown an increase in the size of the anterior hippocampus by 2 percent, which can improve spatial memory.

Earlier this year, a team of researchers that included Dr. Mavros released a similar test where they noticed cognitive improvement after weightlifting.

Using functional magnetic resonance (fMRI), they analyzed changes in the brain after 6 months of progressive resistance training and computerized cognitive training in older adults. They found that progressive resistance training such as weightlifting "significantly improved global cognition."

Authors of this study pointed out that it remains unclear whether physical training in itself stops the degenerative effects of old age, or whether they boost some other mechanisms that support cognition.

Although muscle strength seems to be clearly connected with cognitive impairment, the mechanism behind it is still not entirely evident.

In the future, Mavros and team hope to uncover it by connecting the increases in brain size to muscle strength and cognitive improvement.

"The next step now is to determine if the increases in muscle strength are also related to increases in brain size that we saw. In addition, we want to find the underlying messenger that links muscle strength, brain growth, and cognitive performance, and determine the optimal way to prescribe exercise to maximize these effects."

Senior author Prof. Maria Fiatarone Singh, University of Sydney

Read about Alzheimer's disease and how close we are to finding a cure.

Written by Ana Sandoiu

Exercising while angry or emotionally stressed may place the heart at greater risk, suggested an observational study of more than 12,000 first MI patients asked about potential triggers.

Anger or emotional upset in the hour before onset was estimated as elevating the odds of MI 2.44-fold, with a similar 2.31-fold elevation from heavy exertion, in the case-crossover analysis; but the combination of the two further raised the odds to 3.05 fold (P<0.001 for interaction).

The associations didn't depend on age, smoking status, hypertension, baseline physical activity, or several other factors that could influence heart attack risk.

But self-recall bias was possible, and clinicians shouldn't stop recommending regular physical activity, which helps prevent risk long-term, the researchers cautioned in the Circulation paper.

"Taken together, these results from INTERHEART suggest that further research is needed to identify those most vulnerable to the effects of external triggers through risk stratification," they concluded.

Heart Risk in Cancer Survivors

Cardiovascular mortality is at least as big a risk for older breast cancer survivors as is death from recurrence, a population-based study showed in JAMA Cardiology.

The study of nearly a million women diagnosed with early-stage breast cancer in the Ontario Cancer registry and followed through administrative databases there showed:

• Breast cancer was the most common overall cause of death (at 49.9%), followed by death from cardiovascular causes (at 16.3%)
• For women age 66 or older, the 10-year risk of cardiovascular death approached that of breast cancer death (7.6% vs 11.9%)
• With prior cardiovascular disease, the two causes of death were equivalent for the first 5 years, after which cardiovascular causes jumped ahead (16.9% vs 14.6% at 10 years).
• For women 66 or older who survived breast cancer for at least 5 years, the two were equal to 10 years, after which cardiovascular disease exceeded breast cancer

"Cardiovascular death is an important competing risk for older women with early-stage breast cancer," the researchers concluded. "This finding mandates adequate attention to cardiovascular preventive therapy after diagnosis of breast cancer."

Antihypertensives and Mood Disorders

Calcium antagonists and beta blockers were associated with higher risk for severe depression and other mood disorders leading to hospitalization, while ACE inhibitors and angiotensin-receptor blockers (ARBs) were associated with lower risk, according to data from two large hospitals in the West of Scotland reported in Hypertension.

But thiazide diuretics were not linked to the severe mood disorder risk in the database of 111,936 patients ages 40 to 80 on no antihypertensive meds and 32,130 on chronic antihypertensive monotherapy with follow-up for 5 years.

"Mental health is an under-recognized area in hypertension clinic practice, and our study highlights the importance of reviewing mental health diagnoses and progression," the researchers concluded.

"Until validated, it is worthwhile remembering that antihypertensive drugs may have an impact on mental health. The neutral effect (or reduced risk) exerted by ACE inhibitor/ARB could lead to consideration of these drugs in certain subgroups of patients at risk of mood disorders."

Hypotension and Dementia

Orthostatic hypotension was associated with a small increase in dementia risk, according to an analysis of 6,204 participants in the population-based Rotterdam Study who were initially free of stroke or dementia reported in PLOS Medicine.

The adjusted hazard ratio of 1.15 had a P-value of borderline statistical significance, at 0.05, but was similar for both Alzheimer's disease and for vascular dementia over 15.3 years of follow-up. The effect was particularly seen among people without a compensatory increase in heart rate.

"These findings suggest that transient cerebral hypoperfusion plays a role in the aetiology of dementia and that further studies are warranted to investigate the effects of hypoperfusion and treatment of orthostatic hypotension on markers of neurodegenerative disease and cognition," the researchers concluded.

In Other News

Going right into combination therapy for newly-diagnosed pulmonary arterial hypertension might be associated with better long-term survival, post-hoc analysis of the randomized AMBITION trial suggested. See the full MedPage Today story here.

last updated 10.14.2016

0 comments

Alzheimer's protein changes shape to enter brain cells

One of the hallmarks of Alzheimer's disease is toxic plaques of a protein building block or peptide called amyloid beta that enters brain cells and destroys them. There is a big debate as to whether amyloid beta is toxic before or after it enters cells. Now, by showing that the peptide changes shape before it crosses the cell membrane, scientists step closer to an answer.

Amyloid beta forms into sheets before entering brain cells.
Image credit: Bieschke/WUSTL

Alzheimer's disease is a progressive, irreversible brain disorder that erodes memory and thinking skills, and eventually deprives people of their ability to lead an independent life.

Estimates suggest the disorder may rank third, just behind heart disease and cancer, as a cause of death for older Americans.

While the causes of Alzheimer's are still a mystery, scientists do know that brains of people with the disease begin to undergo complex, toxic changes, some of which begin 10 years or more before memory and thinking problems appear.

Two of these toxic changes are the formation of amyloid plaques and tangles of another protein called tau. At the same time, there is a gradual loss of healthy neurons that stop working, lose connections with each other, and die.

The new study, published in the Journal of Biological Chemistry, is the work of a team from the United States and Germany, led by Jan Bieschke, assistant professor of biomedical engineering at Washington University in St. Louis, MO.

Amyloid beta forms into sheets

The researchers found that before amyloid beta can be absorbed into the cell, it must form into long, flat sheets where the peptides stack onto each other - rather like a layer cake, as Prof. Bieschke explains:

Fast facts about Alzheimer's disease

• Experts suggest over 5 million Americans have the disease
• Most people with Alzheimer's have the late-onset form; symptoms appear in their mid-60s
• The early-onset form occurs at age 30-60 and represents less than 5 percent of all cases.

Learn more about Alzheimer's

"Somewhere on this aggregation pathway, this type of structural element is formed for the amyloid beta to get into the cell. There is a two-step process: amyloid beta can bind to the membrane and form aggregates while on the surface of the cell, then it gets taken up into the cell."

The finding helps to address a long-standing debate about whether amyloid beta is toxic before or after entering the cell.

Once inside the cell, toxic amyloid beta disrupts it by interfering with its mitochondria - the compartments that make energy for the cell.

The result is that the cell stops breathing and eventually dies.

Armed with the new information about beta sheets, the team now plans to follow what happens after amyloid beta crosses the cell membrane and proceeds to interfere with mitochondria.

One of the things they want to examine is the interaction between amyloid beta and the mitochondria membrane, and find out if it is similar to the interaction between the beta sheets and the membrane of the cell.

"Another question we will ask is: Can we manipulate the uptake or formation of these structures so they cannot enter the cell? This may be a therapeutic strategy to help future patients with Alzheimer's."

Prof. Jan Bieschke

Learn how toxic tau protein spreads through space between brain cells.

Written by Catharine Paddock PhD

Hormone therapy for prostate cancer may raise dementia risk

Men with prostate cancer who are treated with a form of hormone therapy may be at much higher risk of dementia, according to new research published in JAMA Oncology.

Men treated with ADT for prostate cancer may be at greater risk of dementia, say researchers.

The study found that men with prostate cancer who underwent androgen deprivation therapy (ADT) were almost twice as likely to be diagnosed with dementia in the 5 years after treatment than men who did not receive ADT.

Used since the 1940s, ADT is a treatment that reduces levels of androgens, which are male hormones - such as testosterone and dihydrotestosterone (DHT) - that can stimulate the growth of prostate cancer cells.

According to the American Cancer Society, ADT may be used for prostate cancer if the cancer is no longer treatable with surgery or radiation, if the cancer returns following surgery or radiation, or before or alongside radiation in order to boost treatment efficacy.

Lead study author Dr. Kevin T. Nead, of the Department of Radiation Oncology at the Perelman School of Medicine at the University of Pennsylvania, and colleagues note that each year, more than half a million men in the United States are treated with ADT.

While ADT has shown significant benefits for prostate cancer survival, some studies have shown the treatment may have negative implications for cognitive function.

Last year, for example, another study by the same research team uncovered a link between ADT and Alzheimer's disease - the most common form of dementia.

The new study builds on those results, suggesting that ADT may have even broader implications for cognitive functioning.

Dementia risk doubled for men treated with ADT

The researchers came to their latest findings by using a "text processing" tool to analyze the medical records of 9,272 men of an average age of 67 who were treated for prostate cancer between 1994-2013. Of these, 1,826 were treated with ADT.

The team assessed dementia incidence among the men in the 5 years after treatment, including incidence of Alzheimer's disease, vascular dementia, and frontotemporal dementia.

Compared with men who were not treated with ADT, those who did receive the treatment were more than twice as likely to be diagnosed with dementia over 5 years; ADT-treated men had an absolute dementia risk of 7.9 percent, compared with 3.5 percent for men not treated with ADT.

The team found that regardless of age, the risk of dementia with ADT was still doubled.

Among men aged 70 and older, the absolute risk of developing dementia was 13.7 percent for those treated with ADT, compared with 6.6 percent for those who did not receive the treatment. For men younger than 70, men treated with ADT had a 2.3 percent risk of dementia, compared with 1 percent for those not treated with the therapy.

While the study was not designed to pinpoint the mechanisms by which ADT might raise dementia risk, the authors point to previous studies that suggest testosterone protects brain cells. As such, reducing levels of this hormone with ADT may eliminate some of the ways in which the brain staves off dementia.

"Low testosterone and androgen deprivation therapy have also been shown to increase cardiometabolic disease, which is an independent risk factor for dementia by impacting neurovascular function," Dr. Nead told Medical News Today. "Through these mechanisms, androgen deprivation therapy may globally decrease neurovascular function, thereby increasing the risk of dementia."

'Doctors should talk to patients about possible cognitive risks of ADT'

Given that Dr. Nead and colleagues have now produced two studies suggesting a link between ADT and dementia, they say further research into the cognitive effects of this cancer therapy is warranted.

"As the population of older, long-term cancer survivors continues to rise, the health issues that cancer therapies can leave in their wake will become increasingly important.

Further studies are needed to investigate the association between this therapy and dementias, given the significant patient and health system impacts if there are higher rates among the large group of patients undergoing ADT today."

Dr. Kevin T. Nead

MNT asked Dr. Nead whether healthcare providers should warn prostate cancer patients about the possible cognitive risks of ADT.

"All men should have a detailed discussion with their doctors regarding the risks and benefits of ADT. Based on the body of literature that now exists, it would be reasonable to counsel patients regarding potential cognitive risks as this has been shown in multiple retrospective and prospective studies," he replied.

"We would, however, not recommend specific changes to clinical practice based on this study alone, given that androgen deprivation therapy is a life-extending treatment in some men with prostate cancer."

Read about a study that suggests high blood pressure can increase the risk of dementia.

Written by Honor Whiteman

Untangling a cause of memory loss in neurodegenerative diseases

NIH-funded mouse study identifies a possible therapeutic target for a family of disorders.

Tauopathies are a group of neurodegenerative disorders, including Alzheimer's disease that are characterized by the deposition of aggregates of the tau protein inside brain cells. A new study reveals that the cutting of tau by an enzyme called caspase-2 may play a critical role in the disordered brain circuit function that occurs in these diseases. Of interest, the culprit tau fragment identified in this study is actually resistant to forming aggregates, and it causes a disturbance in memory function in animal models before brain cell loss occurs.

In mice genetically engineered to mimic aspects of human tauopathy disorders, the researchers restored some of the learning and memory deficits by blocking caspase-2 activity, which suggests that some of the cognitive loss seen in tauopathies might be reversible. The study was funded by the National Institutes of Health's National Institute of Neurological Disorders and Stroke (NINDS) and published in the journal Nature Medicine.

"The results of this exciting study suggest that the cognitive loss that occurs in tauopathy may be reversed by blocking the function of caspase-2," said Roderick A. Corriveau, Ph.D., a program director at NINDS. "This motivates further investigation of caspase-2 as a novel therapeutic target for dementia."

Using a mouse model of tauopathy that produces a mutated form of human tau protein, researchers correlated memory deficits with the presence of a fragment of the tau protein. The tau fragment, which is produced when caspase-2 cuts the full-length tau protein at a specific location, was also found at higher levels in the brains of Alzheimer's disease patients compared to healthy individuals of the same age.

While the standard hallmark of tauopathies is the appearance in brain tissue of large tangles of abnormal tau protein, it has recently become less clear whether the tangles of tau are actually causing cognitive decline.

"In the past, many studies focused on the accumulation of tangles and their connection to memory loss," said Karen H. Ashe, M.D., Ph.D., professor of neurology at the University of Minnesota and senior author of this study, "but the more we learn, the less likely it seems that they are the cause of disease symptoms. The pathological fragment of tau that we have identified resists forming tangles and can instead move freely throughout the cell. Therefore, we decided to look for other mechanisms that could affect synaptic function."

To do this, Dr. Ashe's group used fluorescent labeling to track and compare the behavior of normal and mutated tau in cultured neurons from the rat hippocampus, the brain region most associated with learning and memory. Unlike normal tau, both mutated tau and the short fragment produced when caspase-2 cuts tau were primarily found within structures called dendritic spines, where neurons receive inputs from neighboring cells. The overabundance of mutated tau, including the caspase-2-produced fragment, caused disruptions in synaptic function in the spines. The impact on synapses was specific, with no observed effects on the overall structure or survival of the neurons.

"It appears that abnormally processed tau is disrupting the ability of neurons to properly respond to the signals that they receive, producing memory deficits independent of tangle formation," said Dr. Ashe. "Because this effect is occurring without cell death or a loss of synapses, we have a better chance of intervening in the process and hopefully reversing symptoms of the disease."

Dr. Ashe and her team are now planning additional experiments to uncover the mechanisms by which abnormally processed mutant tau produces memory deficits.

The study was supported by the NIH (NS63214 and NS79374) with additional funding provided by the T. and P. Grossman Family Foundation, B. Grossman, and K. Moe.

Article: Caspase-2 cleavage of tau reversibly impairs memory, Xiaohui Zhao, Linda A Kotilinek, Benjamin Smith, Chris Hlynialuk, Kathleen Zahs, Martin Ramsden, James Cleary & Karen H Ashe, Nature Medicine, doi:10.1038/nm.4199, published 10 October 2016.