Alzheimer's disease is a 'double-prion disorder,' study shows

by University of California, San Francisco

AB42 Cells - infected with amyloid beta prions. Credit: Prusiner lab / UCSF Institute for Neurodegenerative Diseases

Two proteins central to the pathology of Alzheimer's disease act as prions—misshapen proteins that spread through tissue like an infection by forcing normal proteins to adopt the same misfolded shape—according to new UC San Francisco research.

05 may 2019--Using novel laboratory tests, the researchers were able to detect and measure specific, self-propagating prion forms of the proteins amyloid beta (A-β) and tau in postmortem brain tissue of 75 Alzheimer's patients. In a striking finding, higher levels of these prions in human brain samples were strongly associated with early-onset forms of the disease and younger age at death.

Alzheimer's disease is currently defined based on the presence of toxic protein aggregations in the brain known as amyloid plaques and tau tangles, accompanied by cognitive decline and dementia. But attempts to treat the disease by clearing out these inert proteins have been unsuccessful. The new evidence that active A-β and tau prions could be driving the disease—published May 1, 2019 in Science Translational Medicine—could lead researchers to explore new therapies that focus on prions directly.

"I believe this shows beyond a shadow of a doubt that amyloid beta and tau are both prions, and that Alzheimer's disease is a double-prion disorder in which these two rogue proteins together destroy the brain," said Stanley Prusiner, MD, the study's senior author and director of the UCSF Institute for Neurodegenerative Diseases, part of the UCSF Weill Institute for Neurosciences. "The fact that prion levels also appear linked to patient longevity should change how we think about the way forward for developing treatments for the disease. We need a sea change in Alzheimer's disease research, and that is what this paper does. This paper might catalyze a major change in AD research."

What are Prions?

Prions are misfolded versions of a protein that can spread like an infection by forcing normal copies of that protein into the same self-propagating, misfolded shape. The original prion protein, PrP, was identified by Prusiner in the 1980s as the cause of Creutzfeldt Jakob Disease (CJD) and spongiform bovine encephalopathy, also known as Mad Cow Disease, which spread through consumption of meat and bone meal tainted with PrP prions. This was the first time a disease had been shown to infect people not by an infestation of an organism such as a bacterium or a virus, but through an infectious protein, and Prusiner received a Nobel Prize for that discovery in 1997.

Prusiner and colleagues have long suspected that PrP was not the only protein capable of acting as a self-propagating prion, and that distinct types of prion could be responsible for other neurodegenerative diseases caused by the progressive toxic buildup of misfolded proteins. For example, Alzheimer's disease is defined by A-β plaques and tau tangles that gradually spread destruction through the brain. Over the past decade, laboratory studies at UCSF and elsewhere have begun to show that amyloid plaques and tau tangles from diseased brains can infect healthy brain tissue much like PrP, but considerably more slowly.

The scientists’ new cellular assays could assess the presence of prion-like amyloid beta (top row), alpha-synuclein (middle row), or tau proteins (bottom row) in human kidney cells, as indicated by the bright orange spots. Credit: A. Aoyagi et al., Science Translational Medicine (2019)

Many scientists have been reluctant to accept that A-β and tau are self-propagating prions—instead referring to their spread as "prion-like"—because unlike PrP prions, they were not thought to be infectious except in highly controlled laboratory studies. However, recent reports have documented rare cases of patients treated with growth hormone derived from human brain tissue, or given transplants of the brain's protective dura mater, who went on to develop A-β plaques in middle age, long before they should be seen in anyone without a genetic disorder. Prusiner contends that these findings argue that both Aß and tau are prions even though they propagate more slowly than highly aggressive PrP prions.

In response to these debates, Prusiner likes to quote from a 1969 lecture by neuroscientist Bernard Katz: "There is a type of scientist who, if given the choice, would rather use his colleague's toothbrush than his terminology!"

Laboratory Bioassays Reveal Aß and Tau Prions in Human Postmortem Brain Samples

In the new study, the researchers combined two recently developed laboratory tests to rapidly measure prions in human tissue samples: a new A-β detection system developed in the Prusiner lab and a tau prion assay previously developed by Marc Diamond, Ph.D., a former UCSF faculty member who is now director of the Center for Alzheimer's and Neurodegenerative Diseases at UT Southwestern Medical Center.

Unlike earlier animal models that could take months to reveal the slow spread of A-β and/or tau prions, these cell-based assays measure infectious prion levels in just three days, enabling the researchers to effectively quantify for the first time the levels of both tau and A-β prions in processed extracts from post-mortem brain samples. In the new study, they applied the technique to autopsied brain tissue from over 100 individuals who had died of Alzheimer's disease and other forms of neurodegeneration, which was collected from repositories in the United States, Europe, and Australia.

In assays comparing the samples from Alzheimer's patients with those who died of other diseases, prion activity corresponded exactly with the distinctive protein pathology that has been established in each disease: in 75 Alzheimer's disease brains, both A-β and tau prion activity was elevated; in 11 samples from patients with cerebral amyloid angiopathy (CAA), only A-β prions were seen; and in 10 tau-linked frontotemporal lobar degeneration (FTLD) samples, only tau prions were detected. Another recently developed bioassay for alpha-synuclein prions only found these infectious particles in the seven samples from patients with the synuclein-linked degenerative disorder multiple system atrophy (MSA).

"These assays are a game-changer," said co-author and protein chemist William DeGrado, Ph.D., a professor of pharmaceutical chemistry and member of the UCSF Cardiovascular Research Institute, who contributed to the design and analysis of the current study. "Previously Alzheimer's research has been stuck looking at collateral damage in the form of misfolded, dead proteins that form plaques and tangles. Now it turns out that it is prion activity that correlates with disease, rather than the amount of plaques and tangles at the time of autopsy. So if we are going to succeed in developing effective therapies and diagnostics, we need to target the active prion forms, rather than the large amount of protein in plaques and tangles."

A-β and Tau Prion Activity Linked to Alzheimer's Patients' Longevity

The most remarkable finding of the new study may be the discovery that the self-propagating prion forms of tau and A-β are most infectious in the brains of Alzheimer's patients who died at a young age from inherited, genetically driven forms of the disease, but much less prevalent in patients who died at a more advanced age.

In particular, when compared to measurements of overall tau buildup—which is known to increase with age in Alzheimer's brains—the researchers found a remarkable exponential decline in the relative abundance of the prion forms of tau with age. When the researchers plotted their data, they saw an extremely strong correlation between tau prions and patients' age at death: relative to overall tau levels, the quantity of tau prions in the brain of a patient who died at age 40 were on average 32 times higher than in a patient who died at 90.

"I still remember where I was sitting and what time of day it was when I first saw this data over a year ago," said co-author and leading neurodegeneration researcher William Seeley, MD, a professor of neurology at the UCSF Memory and Aging Center who directs the UCSF Neurodegenerative Disease Brain Bank, which provided tissue used in the study. "I've very rarely, if ever, seen this kind of correlation in human biological data. Now the job is to find out what the correlation means."

The research raises a number of questions that will need to be addressed by future studies, including whether differences in prion infectivity could explain the long-standing mystery of why Alzheimer's progresses at such different rates in different patients. Other open questions resulting from the research include whether higher prion levels in brain samples from younger patients are linked to the early onset of the disease or how quickly it progressed, and whether lower prion levels in older brains reflect less "infective" prion variants or instead some ability of these patients' brains to dispose of misfolded proteins.

The evidence that prion forms of A-β and tau play a specific role in Alzheimer's disease—one that cannot be captured by simply counting amyloid plaques and tau tangles in patient brains—also raises questions on current approaches to Alzheimer's diagnosis, clinical trial design, and drug discovery, say the authors, who hope their novel assays will spur renewed interest in developing therapies to target the now-measurable prion proteins.

"We have recently seen many seemingly promising Alzheimer's therapies fail in clinical trials, leading some to speculate that we have been targeting the wrong proteins," said Carlo Condello, Ph.D., one of the study's lead authors. "But what if we just haven't been designing drugs against the distinctive prion forms of these proteins that actually cause disease? Now that we can effectively measure the prion forms of A-β and tau, there's hope that we can develop drugs that either prevent them from forming or spreading, or help the brain clear them before they cause damage."

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More information: A. Aoyagi el al., "Aβ and tau prion-like activities decline with longevity in the Alzheimer's disease human brain," Science Translational Medicine (2019). stm.sciencemag.org/lookup/doi/ … scitranslmed.aat8462

Journal information: Science Translational Medicine 

Provided by University of California, San Francisco 

Suicidal thoughts? Therapy-oriented website can help

by University of Washington

Mental health researchers behind the website nowmattersnow.org have demonstrated that the site could be beneficial in decreasing suicidal thoughts.Researchers asked more than 3,000 website visitors how they felt before they got to the site compared to a few minutes on the website. Nearly one-third were significantly less suicidal, and the intensity of their negative emotions had also decreased. Results were published in the Journal of Medical Internet Research, an open-access publication.

04 may 2019--Lead author Ursula Whiteside, a clinical psychologist at the University of Washington School of Medicine, said the results offer hope for people struggling to cope. The site exposes visitors to dialectical behavioral therapy (DBT), a form of psychotherapy that combines behavioral science and Buddhist principles on mindfulness and acceptance. It was developed by UW psychology professor Marsha Linehan.

"We set out to build a free resource based not only in science but also with the voices and stories of people who had experienced suicidal thoughts," Whiteside said. "We wanted clinicians to feel empowered to help those who are struggling."

The home page presents a panel of video-linked images of individuals with relatable experiences on suicide and negative emotions and resources to explore DBT skills.

The site was launched in 2014 on Sept. 10, World Suicide Prevention Day, and had more than 250,000 unique visitors as of December 2018. Site funding came from the National Institute of Mental Health and the American Foundation of Suicide Prevention.

Whiteside said she wanted any research she and her colleagues were doing to be accessible right away since the public has little access to DBT therapy.

The survey of users was conducted from March 5, 2015, and Dec. 3, 2017. Of the 3,670 unique survey responses, 514 (14% of survey sample) identified as men ages 36 to 64; 460 (13%) identified as mental health professionals and 308 (8%) as other healthcare professionals, with 40 (1%) identifying as both.

Users were asked to rate their suicidal thoughts or negative feelings on a scale of 1-5 (5 being the most suicidal or negative). More than 70% of survey respondents recalled having some suicidal thoughts when they arrived at the website. Of those who reported suicidal thoughts (2,644) at baseline, 29% reported a reduction of one point or more in suicidal thoughts during the site visit. The vast majority, 63%, experienced no change, and 8% rated suicidal thoughts 1 or more points worse. Of those who reported worse scores after the visit, 2% were more than one point worse 1% (N = 21) were 3 or 4 points worse.

Researchers found that significant reductions in suicidal thoughts and negative emotions were consistent across subgroups, including middle-aged men, who represent 38% of all suicides. However, reductions for middle- age men were not as large as that of the rest of the sample; therefore the website could be more tailored toward men, researchers wrote.

Co-author Julie Richards, with Kaiser Permanente Washington Health Research Institute, said the website gives healthcare providers a resource for their patients.

"The vast majority of people who die by suicide never receive specialized mental health care," she said.

Researchers noted that nearly half of all people who die by suicide in the United States see some type of healthcare provider in the month before their death. They said newly released screening and care guidelines have the potential to increase the number of suicidal patients detected in healthcare settings. Unfortunately, they said, most providers—particularly those in primary-care settings, where the majority of patients are seen before death by suicide—have no relevant training and lack immediate resources to support patients.

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More information: www.nowmattersnow.org

Journal information: Journal of Medical Intern

The body according to Leonardo da Vinci

by Max Planck Society

Glimpse into the left side of a human skull, about 1651. Credit: Royal Collection Trust / Her Majesty Queen Elizabeth II 2013

In an age of modern anatomy atlases and freely available online body-browsers, Leonardo da Vinci's drawings of organs and body parts done with quill, ink and red chalk may strike us as aesthetically pleasing, yet antiquated. Nevertheless, almost everyone in Germany carries a reproduction of his famous Vitruvian Man with them – on their health insurance card. Alessandro Nova, Director at the Kunsthistorisches Institut in Florenz, on the other hand, explores Leonardo's work in the light of the scientific knowledge it generates.

02 may 2019--Anyone who examines Leonardo da Vinci's anatomical drawings will probably first ask themselves to what extent the detailed studies correlate to today's state of medical knowledge. The depictions seem all too familiar, hardly deviating from the way we see things today.

Yet it is important to note that Leonardo was a pioneer in this area and wasn't able to refer to anything even approximating such graphic visualizations of the inner workings of the human body. Medical-historical research has already extensively compared the knowledge that Leonardo garnered in his day with that of today's anatomical information, just as his specific morphological and physiological discoveries have long been fully appreciated. The extensive inventory of drawings has also been philologically classified and sub-divided into anatomical units such as skeletal system, musculature, nervous system and circulatory system, as well as into today's established systems, which had not yet been identified in Leonardo's day. In short, it can be said that the anatomical studies have since been well researched.

But perhaps it was just that that motivated Alessandro Nova, Director at the Kunsthistorisches Institut in Florenz since 2006, to take a fresh look at the drawings, not so much by examining their results, but by pursuing the question of what role the process of drawing, the genuine artistic act, played in the generation of scientific knowledge.

Veiled in the shadow of ignorance

Giorgio Vasari (1511 to 1574), who paid tribute to numerous Renaissance artists with comprehensive biographies, also turned his attention to Leonardo's anatomical studies and shed light on his association with the physician and anatomy professor Marcantonio della Torre (1481 to 1511). According to Vasari, "he was one of the first that began to illustrate the problems of medicine with the doctrine of Galen, and to throw true light on anatomy, which up to that time had been veiled in the thick and gross shadow of ignorance. And in this he found marvelous aid in the brain, work and hand of Leonardo, who made a sketchbook with drawings in red chalk retouched in pen and ink: the bodies that he dissected with his own hand were drawn with the greatest diligence."

Less is more: In drawing the female organs and vascular system, Leonardo left out the stomach and intestine. Credit: Royal Collection Trust / Her Majesty Queen Elizabeth II 2013

Leonardo was at the height of his anatomical research when he met della Torre in Pavia around 1510. The artist had turned his attention to anatomy as early as 1487 in Milan – something that would occupy him for the rest of his life. In the beginning, his investigations into traditional medical knowledge played an important role, at least as far as he was able to tap into such information. After all, it must be borne in mind that Leonardo was self-taught in this area, and could read neither Latin nor Greek. In his day, he was considered to be a man without a classical education, which made it much more difficult for him to gain access to the academic world.

This was especially the case with the work of Galen of Pergamon (129 to 199 A.D.), whose doctrines went unchallenged back then. It has been proven that Leonardo's library contained a copy of Johannes de Ketham's Fasciculus Medicinae, whose illustrations could at least visually con-vey Galen's teachings before an Italian edition was published in 1495. When Leonardo carried out his first corpse dissections, his goal was to understand and verify the centuries-old views of the Greek anatomist and physician; however, his meticulous autopsies brought him increasingly into conflict with this handed-down knowledge. A challenging situation arose, which from then on would also be reflected in Leonardo's drawings. The contradictions he encountered spurred him on to create his own illustrated work that could record his observations and that was ultimately intended to convey no less than a new understanding of the human body.

Virtuosity with chalk, pen and silverpoint

Leonardo's encounter with della Torre twenty years later was an important experience for both of them. Leonardo benefited from the exchange with a scientist who had a command of the terminology and rules of the field. Della Torre, on the other hand, was able to make good use of the artist's extraordinary skills as a draftsman. "However, it would be incorrect to reduce Leonardo's role to that of an artist who simply placed his eye and hand at della Torre's disposal," says Alessandro Nova, whose research picks up here. For, although none of Leonardo's contemporaries was as adept at drawing with a pen and silverpoint or with black and red chalk as Leonardo was, his anatomical works are anything but an exact mimetic recording of the reality that would have presented itself to anyone who took a close look at the dissected corpses. "Their graphic clarity stems, rather, from an enormous intellectual capacity that previously systematized and grasped that which he observed," emphasizes Nova. "I call this a 'manipulation of the visual data' or the 'constructed view'. Leonardo masterfully interwove various techniques with each other, such as the assembling of sever-al views to form a new image, the magnification, separation or dismantling of details, and the simplification or fragmentation of physicality to the benefit of a transparent figure."

Leonardo's drawing of the female organs, for instance, which he completed shortly before his encounter with della Torre, is an ingenious construction that, although it would never be found in reality, nevertheless conveys an image of the morphology and functioning of the female body in a precision that had not existed until then. Leonardo gave due consideration to the graphic figurative modes: while he drew the uterus as transparent, he depicted the windpipe three-dimensionally and fully formed. In contrast, he rendered the heart in a sectional view, and the digestive organs, like the stomach and intestine, he left out completely in favor of a clearer arrangement. This example clearly shows – and this holds true for most of Leonardo's anatomical drawings – that they are stylized representations and that it is their high degree of abstraction that ensures their compelling readability to this day.

In the sketch that shows the brachial plexus and muscle strength, for the sake of clarity, Leonardo refrained from showing the surrounding bones. Credit: Royal Collection Trust / Her Majesty Queen Elizabeth II 2013

Clarity through the art of omission

In order to illustrate the musculature of the foot and lower leg, Leonardo also made use of the art of omission and simply extracted the entire skeleton, as this would have obscured the structure and organization of the muscles and tendons. By disassembling the spine into its individual parts, he graphically illustrated their structure, which would otherwise have had to be explained at great length. To this end, he enlarged certain bones disproportionately to emphasize their particular functionality; with others, he considered it necessary to show them from various perspectives to facilitate understanding from all sides. "Leonardo himself explained: 'Through this tersest way of drawing from various perspectives, one provides full and true knowledge of them,'" says Alessandro Nova, quoting the artist and scholar.

This methodical understanding can already be seen in Leonardo's early anatomical drawings, like the skull studies from 1489. Only the combination of depictions from different perspectives, for example the orthogonal projection and the top view, can provide the viewer with a comprehensive and informative image of the inner workings of the skull. The drawing is thus not a portrayal of the skull, but a symbol that can't be seen in this form in reality. Furthermore, Nova can convincingly attest to the model-like character of such an assembly by comparing Leonardo's sectional drawings of the central structure of a domed church: "He adapted the methods of depiction that he was familiar with from his work as an artist for his anatomical studies."

In the company of quartered corpses

Incidentally, in a new preface to his anatomy treatise in 1509, Leonardo listed what he considered to be the necessary requirements for modern anatomical drawings. "In the process, he explicitly points out that it requires much more than expert draftsmanship," says Nova with a grin, in light of Leonardo's apparent foresight, and goes on to quote Leonardo's words: "But though possessed of an interest in the subject, you may perhaps be deterred by natural repugnance, or if this does not restrain you, then perhaps by the fear of passing the night hours in the company of these corpses, quartered and flayed, and horrible to behold. And if this does not deter you, then perhaps you may lack the skill in drawing essential for such representation, and even if you possess this skill it may not be combined with a knowledge of perspective, while if it is so combined you may not be versed in the methods of geometrical demonstration, or the methods of estimating the forces and power of the muscles; or you may perhaps be found wanting in patience so that you will not be diligent."

The perspectival studies of the anatomy of the foot and the transparent depiction of the lower leg and foot musculature bear witness to da Vinci’s extraordinary talent as a draftsman. Credit: Royal Collection Trust / Her Majesty Queen Elizabeth II 2013

Drawing is a cognitive act for Leonardo

Leonardo thus deliberately edited his drawings and constantly worked on improving the forms of representation. As a natural scientist, he penetrated the surface of the body, delving into the interior while dissecting it. As an artist, through the medium of diagrams, he again returned to the body as a whole, which he pieced together anew from the information he considered important. His drawing features a density of information that could never have been gleaned from a single autopsy. Only several dissections finally generated the "data" that flowed into a collective representation and yielded the overall image. As a result, by pondering over the way to arrive at the best depiction, Leonardo simultaneously attained a deeper understanding of the object. "As such, for him, drawing is not a reproductive, but a cognitive act," explains Hana Gründler, who is working with Alessandro Nova on this project. "In his drawings, Leonardo doesn't simply represent "fixed" knowledge. It is rather the act of drawing itself that sets free renewed reflec-tions about what is being drawn. This, in turn, leads to a modified view of the research object." Gründler continues: "The processuality in the acquisition and generation of knowledge also becomes visible in the numerous correc-tions and improvements that have been identified in the drawings."

New observations versus ancient knowledge

Of course, Leonardo's research began with nature studies, which are what gave him cause time and again to un-dertake the complex efforts required for performing autopsies, whether in Milan, Florence or Rome. Through empirical studies, he succeeded in revising traditional scientific representations, and a brief look at the illustrations in Ketham's book is all it takes to appreciate the progress in Leonardo's drawings, which denote a new epoch in the history of the depiction of the human body. "However, on occasion, he didn't completely break with tradition," stresses Nova, citing the studies in which Leonardo and della Torre turned their attention to the heart and its ventricles. While, on the one hand, they made the pioneering discovery that the heart's system included four – and not just two – ventricles, on the other hand, Leonardo's drawings of this, which recorded their discovery, depicted the heart's septum as porous and permeable for blood, which he could not have observed on an exposed heart. "He could only have taken the hypothetical existence of these pores between the ventricles from the literature of the times. The precision of new observations here still collides with the fictions of conventional knowledge as it was imparted in Galen's teachings," con-cludes Nova.

A mere footnote in the history of medicine

Although the drawings are at the heart of Nova's research, they can't be fully understood and analyzed without the accompanying texts that Leonardo added in his famous mirror writing. Text and image form an inseparable whole. From a very early stage, Leonardo planned to publish the results of his dis-sections in a richly illustrated work with the title De figura umana – "of course, it's a pity that, as with so many of the projects in his life, he was ultimately unable to bring this undertaking to completion," Nova finds. This is why there is only the occasional reference to Leonardo in today's history of science and medicine. Only the written elucidations make it possible to explain functional correlations and communicate the primary morphological observation from a physiological perspective.

Does agony and suffering characterize dying? The tranquil death of a 100-year-old man inspired Leonardo to create this memento mori, while, for his anatomical treatise, he acknowledged the discovery of the four ventricles extensively in the famous mirror writing. Credit: Royal Collection Trust / Her Majesty Queen Elizabeth II 2013

Findings drawn up in dialog form

To this end, over the decades, Leonardo even altered the concept of his treatise. While, in 1489, he assumed there would be a tight, balanced synthesis of words and images, in which, however, the drawings would ultimately have predominated, he decided, starting in 1509, to draw up the results in dialog form, which was standard for many written works during the Italian Renaissance, and which could better express doubts, opinions and unresolved issues. Leonardo came to recognize that one could limit oneself to the medium of drawing only "if it were possible to observe all of the things that are depicted in these drawings in a single figure. But it is better to render and describe."

"In the end, it was another physician who profited from Leonardo's achievements," says Alessandro Nova. "It was Flemish anatomist Andreas Vesalius who, in 1543, was the first to publish an illustrated anatomical work based on dissections of the body: the compendium De humani corporis fabrica. But it is believed that he may have known Leonardo's drawings."

The anatomical subject matter and the comprehensive accompanying texts go beyond what an art historian usually deals with, making an interdisciplinary approach virtually inescapable. In 2008, a conference was held in Florence that brought together physi-cians and science historians, philologists and linguists, and last but not least, art historians. The results were published in 2011 in a collection of essays entitled Leonardo da Vinci's Anatomical World. Language, Context and 'Disegno'. In this publication, Leonardo's language is examined and light shed upon the philosophical and literary works that he dealt with and that influenced his texts. It may come as a surprise that, up until that point, and despite the immense body of literature about the life and work of Leonardo, no one had ever turned their attention to the books and treatises written by della Torre, even though he was, for a short time, working in such close collaboration with Leonardo.

The search for the seat of the soul

As the study of the human body was far more than an empirical-scientific project for Leonardo, the metaphysical aspects can't be overlooked. "While I thought I was learning how to live, I have been learning how to die," he once philosophized, and it comes as no surprise that the search for the seat of the intellect, the soul and the emotions repeatedly accompanies his anatomical studies. The encounter with a 100-year-old man in Florence around 1507/1508 with whom Leonardo spoke shortly before the man's death and whose body he then dissected induced him to look for traces of dying in the specific anatomy of the deceased. Since, in those days, the process of dying was particularly associated with agony and suffering, the tranquil passing away of the old man had strongly impressed Leonardo.

In the meantime, Alessandro Nova has also begun to turn to other scientific areas in his exploration of Leonardo's drawings. To this end, he invited young scholar Rodolfo Maffeis to join him in conducting research into Leonardo's studies concerning light and astronomy. In contrast to the anatomical drawings, the astronomical sketches haven't been historically-philologically examined, meaning that they must first be classified and embedded in the knowledge context of the time. Moreover, 2011 and 2013 saw two further conferences devoted to Leonardo's optical studies and to his concept of nature. "When it comes to optics, we also encounter the typical triad: appropriation of traditional knowledge, contraposition of his own experiments and observations, and recording of the results in texts, sketches and drawings," says Nova, reporting on the first results. As with anatomy, optics preoccupied Leonardo his entire life, so that it isn't far afield to interpret his meticulous scientific studies as a permanent subtext to his artistic accomplishments.

Or did they even constitute the main text? The further exploration of the interrelationship between art and science, which, in the past, were very closely tied to each other, could offer vital impulses to research into Leonardo da Vinci. Thanks to Alessandro Nova, this interrelationship has finally found a bastion at the Kunsthistorisches Institut in Florenz.

Provided by Max Planck Society 

When is Alzheimer's not Alzheimer's? Researchers characterize a different form of dementia

by NIH/National Institute on Aging

Credit: CC0 Public Domain

A recently recognized brain disorder that mimics clinical features of Alzheimer's disease has for the first time been defined with recommended diagnostic criteria and other guidelines for advancing and catalyzing future research. Scientists from several National Institutes of Health-funded institutions, in collaboration with international peers, described the newly-named pathway to dementia, Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE, in a report published on April 30, 2019, in the journal Brain.

01 may 2019--"While we've certainly been making advances in Alzheimer's disease research—such as new biomarker and genetic discoveries—we are still at times asking, 'When is Alzheimer's disease not Alzheimer's disease in older adults?'" said Richard J. Hodes, M.D., director of the National Institute on Aging (NIA), part of the NIH. "The guidance provided in this report, including the definition of LATE, is a crucial step toward increasing awareness and advancing research for both this disease and Alzheimer's as well."

Alzheimer's is the most common form of dementia, which is the loss of cognitive functions—thinking, remembering, and reasoning—and every-day behavioral abilities. In the past, Alzheimer's and dementia were often considered to be the same. Now there is rising appreciation that a variety of diseases and disease processes contribute to dementia. Each of these diseases appear differently when a brain sample is examined at autopsy. However, it has been increasingly clear that in advanced age, a large number of people had symptoms of dementia without the telltale signs in their brain at autopsy. Emerging research seems to indicate that the protein TDP-43—though not a stand-alone explanation— contributes to that phenomenon.

What is TDP-43?

TDP-43 (transactive response DNA binding protein of 43 kDa) is a protein that normally helps to regulate gene expression in the brain and other tissues. Prior studies found that unusually misfolded TDP-43 has a causative role in most cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. However, these are relatively uncommon diseases. A significant new development seen in recent research is that misfolded TDP-43 protein is very common in older adults. Roughly 25 percent of individuals over 85 years of age have enough misfolded TDP-43 protein to affect their memory and/or thinking abilities.

TDP-43 pathology is also commonly associated with hippocampal sclerosis, the severe shrinkage of the hippocampal region of the brain—the part of the brain that deals with learning and memory. Hippocampal sclerosis and its clinical symptoms of cognitive impairment can be very similar to the effects of Alzheimer's.

"Recent research and clinical trials in Alzheimer's disease have taught us two things: First, not all of the people we thought had Alzheimer's have it; second, it is very important to understand the other contributors to dementia," said Nina Silverberg, Ph.D., director of the Alzheimer's Disease Centers Program at NIA. In the past many people who enrolled in clinical trials likely were not positive for amyloid. "Noting the trend in research implicating TDP-43 as a possible Alzheimer's mimic, a group of experts convened a workshop to provide a starting point for further research that will advance our understanding of another contributor to late life brain changes," Silverberg explained. In addition to U.S. scientists, experts included researchers from Australia, Austria, Sweden, Japan, and the United Kingdom with expertise in clinical diagnosis, neuropathology, genetics, neuropsychology and brain imaging.

Supported by NIA, the workshop was held Oct. 17 and 18, 2018, in Atlanta, and co-chaired by Dr. Silverberg and Peter Nelson, M.D., Ph.D., from the University of Kentucky, Lexington, the lead author on the paper. As published in the report, outcomes included classification guidelines for diagnosis and staging of LATE as well as recommendations for future research directions.

LATE: A new research priority

The authors wrote that LATE is an under-recognized condition with a very large impact on public health. They emphasized that the "oldest-old" are at greatest risk and importantly, they believe that the public health impact of LATE is at least as large as Alzheimer's in this group.

The clinical and neurocognitive features of LATE affect multiple areas of cognition, ultimately impairing activities of daily life. Additionally, based on existing research, the authors suggested that LATE progresses more gradually than Alzheimer's. However, LATE combined with Alzheimer's—which is common for these two highly prevalent brain diseases—appears to cause a more rapid decline than either would alone.

"It is important to note that the disease itself is not new. LATE has been there all along, but we hope this report will enable more rapid advancement in research to help us better understand the causes and open new opportunities for treatment," said Dr. Silverberg.

LATE and TDP-43 also were featured as emerging scientific topics at the recent Alzheimer's Disease-Related Dementias Summit 2019, at which presenters foreshadowed research priorities covered in the Brain report.

Laying groundwork for LATE

A key recommendation was for routine autopsy evaluation and classification of LATE. The researchers suggest the autopsy diagnosis be in three stages, according to where in the brain TDP-43 is detected:

• Stage 1: amygdala only
• Stage 2: amygdala and hippocampus
• Stage 3: amygdala, hippocampus and middle frontal gyrus

Additional recommendations include highlighting the great need for the development of biomarkers, further pathological studies, and the generation of new animal models. Suggestions were provided for possible strategies to help guide future therapeutic interventions, including the importance of removing subjects with LATE from other clinical trials, which could significantly improve the chances of successful Alzheimer's breakthroughs. The researchers also discussed the importance of more epidemiological, clinical, neuroimaging and genetic studies to better characterize LATE, and the need for research in diverse populations.

"It can't be emphasized enough that this research wouldn't have gotten this far—and can't go further—without those who are willing to donate brain tissue after death," said Dr. Hodes. "We are grateful for organ donors and their families, as well as all clinical trial participants, who truly are crucial to furthering discoveries that can lead to treatments and cures."

More information: Nelson PT, et al. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain (2019). DOI: 10.1093/brain/awz099

Journal information: Brain 

Provided by NIH/National Institute on Aging

Study shows older men feel 'excluded, overlooked and cut-off'

by University of Bristol

Credit: CC0 Public Domain

With increasing numbers of older men experiencing loneliness, a new report published April 29 calls for a better understanding of how to tackle the growing public health challenge.

29 april 2019--A two-year study, led by the University of Bristol in collaboration with Age UK, highlights the issues faced by older men, many of whom describe feeling socially excluded, overlooked, cut-off and feeling 'left out of things'—all of which have a range of negative impacts on day-to-day life.

These feelings were triggered by a variety of life events, including loss of a partner, retirement or relocation.

To combat the problem, researchers at the University are calling for changes to the focus of adult social care services – urging for greater priority to be given to the running of groups rather than focusing primarily on care and support for individuals. There should also be more inclusive, tailored groups for older men in marginalised groups.

It follows a report from Age UK which shows the number of over 50s suffering from loneliness is set to reach two million by 2025/6 due to a rising number of older people. This compares to around 1.4 million in 2016/7 – a 49 per cent increase in 10 years.

Unfortunately, older men who live alone are more likely to be socially isolated than their female counterparts, having less regular contact with family and friends, and this can exacerbate feelings of loneliness.

The circumstances and experiences that increase the risk of loneliness and isolation appears to rise with age, and among those with long-term health problems and/or disability.

To date, little research has been undertaken into older men's experiences of loneliness and isolation. Researchers at the University of Bristol interviewed 111 men, aged between 65 and 95 and living in the West and South West of England, to identify new ways in which social care and voluntary services could help alleviate the problem.

There was generally a reluctance to speak to others and seek help, often due to a perception that people wouldn't be interested, or the potential stigma attached to loneliness. Men with adult children avoided speaking to their children as they didn't want to worry them, or it was not in keeping with their role as the father-type figurehead.

The report highlights the 'critical role' voluntary and independent services play in promoting social wellbeing and loneliness. However, those involved in leading and running these groups say funding cuts are placing a strain on resources and insufficient staff numbers.

A key finding, which researchers hope will influence policy makers, was that men valued mixed-age groups which mirror social interactions in everyday life, as opposed to groups specifically targeting older people. Equally, men valued groups that facilitated emotional and social ties with other men.

Dr. Paul Willis, from the University of Bristol's School for Policy Studies, led the research. He said: "For a growing number of people, particularly those in later life, loneliness can define their lives and have a significant impact on their wellbeing.

"Because loneliness occurs when people's ability to engage with others is inhibited, helping people cope with and overcome these feelings is vital.

"Our research has shown the importance of groups and networks in older men's lives, especially those run by voluntary and third sector organisations. Support for such groups needs to be given greater priority by local authorities, both in terms of support from social workers and long-term funding."

The project focused on older men from seldom-heard groups, including men who were single or living alone in rural and urban areas, men who were carers for loved ones, men living with hearing loss, and gay men who were single or living alone.

While loneliness and isolation impacted negatively on men's lives across the groups, there were important differences identified. For example, men with hearing loss were often isolated from family and friends in social gatherings and events because of their hearing loss and challenges in keeping up with conversations around them in noisy environments, such as pubs.

For older gay men, experiences of loneliness and isolation were entangled with earlier life-experiences of being reluctant to come out to others in fear of social censure or hostility from family or work colleagues.

For male carers, the companionship of the person they cared for routinely inhibited feelings of loneliness however the caring experience isolated them from others, such as diminished time spent with friends.

There are clear reasons behind the high numbers of lonely older people, according to Age UK. The risk of being lonely is dramatically higher among older people who have financial difficulties, are in poor health or have a disability, are carers or have recently been bereaved.

Loneliness occurs when people do not have someone to open up to and their ability to have meaningful conversations and interactions is inhibited.

Caroline Abrahams, Charity Director at Age UK, said: "This study helps further our understanding about how older men experience loneliness and how best to help.

"Loneliness is a problem among many older people, especially for those who are in poor health or have a disability, who are carers for loved ones, who have been bereaved, have financial difficulties or who don't have family and friends nearby.

"This study highlights specific issues and challenges for men, who can find it difficult to talk about feeling lonely.

"As more older men live longer we need to appreciate that the numbers who are chronically lonely are likely to increase too—unless we act which we can and we must do. The study also gives service providers, like Age UK, useful tips on how to help older men overcome loneliness, and things to consider when engaging with those from seldom-heard groups."

Based on this new research, Age UK has produced good practice guidance for service providers, tips for older men themselves and information for families or friends who are worried that an older man close to them might be lonely.

More information: Addressing older men's experiences of loneliness and social isolation in later life. www.bristol.ac.uk/policybristo … licy-briefings/omam/

Provided by University of Bristol 

Pain during sex? Incontinence or constipation? You might benefit from pelvic floor physiotherapy

by Claudia Brown, The Conversation

"How did I not know this was a pelvic floor issue? Why didn't my doctor send me here sooner? Do you have other patients with problems like mine?"

28 april 2019--As a physiotherapist, I hear these questions again and again, from people of all ages and genders, who are struggling with issues related to the urinary system, sexual function and the lower digestive tract.

Adrian is one example. A 35 year-old active cyclist and successful professional, he has a nagging pain in the private parts that just won't go away. It is interfering with his sporting activities and ruining his sex life. Pressure from the bicycle seat, the ambitious effort to cycle 100 kilometres in record time, and the stress from a crazy week at work have all resulted in pelvic floor muscle tension and chronic pelvic pain.

Then there's Lisa, a 63 year-old woman who is ready to become involved in a new relationship. In her search for a companion, she explores online dating and begins to realize that sex may be involved sooner than later. She worries that she may not be ready, physically, not having had sex for quite a few years, and wonders what she could do to improve her vaginal comfort and physical confidence.

These patients, and many others, did not know that a physiotherapist could help them. In my role as a clinician and as course co-ordinator for pelvic floor rehabilitation at McGill University's School of Physical and Occupational Therapy, I see a huge lack of awareness of the impact that physiotherapy can have on the lives of people suffering these very personal conditions.

From pain during sexual intercourse to urinary incontinence after surgery for prostate cancer, to anal incontinence after pregnancy, physiotherapy can help.

Pain during sexual intercourse

Up to 20 per cent of women have pain during sexual intercourse. This is a surprising statistic, especially when it predominantly includes active women in their twenties and thirties, who may believe that there is something psychologically wrong with them when all of the gynaecological tests come up negative.

Vestibulodynia, an invisible hypersensitivity at the entrance to the vagina, is considered the most common cause of sexual pain in pre-menopausal women. It can be treated in physiotherapy.

The pelvic floor muscles span the private area under the pelvis. They are responsible not only for helping to control the passage of urine, stool and gas, but also for allowing comfort and pleasure during sex.

These muscles also support the pelvic organs and help with balance and stability. It is important to be able to contract and to relax these muscles. Pelvic floor exercises train the muscles for the desired result, and are sometimes referred to as "targeted" Kegels.

In pelvic floor physiotherapy, patients learn exercises, and they may receive manual treatments, biofeedback and/or electrical stimulation. Biofeedback displays pelvic floor activity on a computer screen, making it easier to contract and relax muscles that are usually hidden from view. Electrical stimulation causes a pain-free muscle contraction, with the goal of improving the ability to contract and relax naturally.

Research supports the use of physiotherapy in the treatment of a variety of pelvic disorders. A team approach is ideal, and, depending upon the condition, may involve collaboration with general practitioners, urologists, gynaecologists, sex therapists and others.

Prostate, pregnancy and potty

After surgery for prostate cancer, up to 40 per cent of men experience problems with urinary incontinence. Pelvic floor physiotherapy teaches men different strategies to control leakage. Men can even consult prior to surgery, in order to prepare.

Women experience an array of pelvic floor issues during and after pregnancy. It is important to mention that many women who have had a third or fourth degree tear during delivery will experience issues with anal incontinence later in life.

Some countries systematically refer these patients for preventative physiotherapy and some centres in Canada are now beginning to follow suit.

More than 40 per cent of women also have issues with bladder control. Patients with stress urinary incontinence and those with an overactive bladder can experience significant improvement in physiotherapy.

Physiotherapy is considered first-line intervention for both types of incontinence by the International Continence Society, the Canadian Urological Association and the European Association of Urology.

Constipation is another issue that may be caused by the inability to relax the muscles of the pelvic floor and anal sphincter at the appropriate time. Physiotherapists can work to improve "defecation dynamics" and provide suggestions for lifestyle changes.

In children, constipation may lead to soiling or overflow incontinence. Children may also be seen for urinary disorders.

A co-ordinated physiotherapy plan

The internet has been instrumental in enabling patients to learn about embarrassing or taboo subjects in the privacy of their own homes, and has led many to seek out physiotherapy as a viable treatment option for pelvic conditions.

Patients consulting for pelvic floor issues learn how the bladder functions, how the pelvic floor muscles can be involved in constipation, what causes the muscles to be such culprits in pelvic pain and how new brain research supports a bio-psycho-social approach for the management of their problems. They find an ally in the physiotherapist, who supports them and directs them towards the improvement of their condition.

A step-by-step coordinated physiotherapy plan is a key element in the interdisciplinary management of patients with disorders related to the pelvic floor.

Provided by The Conversation 

Doctors face a dilemma when seeking mental health assistance for themselves

by Ellen Goldbaum, University at Buffalo

Credit: CC0 Public Domain

It's no secret that physicians have stressful jobs. Figuring out how to mitigate and deal with that stress can be a key part of a successful medical career. But while individual physicians seek and find help for their mental health issues privately, the prevailing public perception among physicians is that it just isn't done.

26 april 2019--Sourav Sengupta, a University at Buffalo faculty member, knows all about it. An assistant professor of psychiatry and pediatrics in the Jacobs School of Medicine and Biomedical Sciences at UB, who also treats patients, he reached a point a few years back where he knew that escalating professional and personal demands were impacting his effectiveness.

Last month, JAMA Network online published his essay, "Rebuilding more of me," about how he worked through his issues with the help of a therapist. He wasn't sure how it would be received, but in the few weeks since its publication, he has received personal email messages from dozens of physicians from across the U.S. who reached out to share perspectives and their experiences.

Since publication, Altmetric rated the essay in the top 5% of publications; it has been viewed more than 6,500 times and downloaded more than 500 times. Sengupta has received emails from physicians at every career stage, who tell him it was a relief to read it, to know that others have also gone through this and have succeeded.

'I am an attending physician in the field from which I seek support'

The essay describes the difficulty Sengupta felt in figuring out how to access the help he needed. "I am an attending physician in the field from which I need support," he wrote. "Many of the best clinicians and treatment setting are not options. I know them too well."

Once he found a psychotherapist he could work with confidentially, who wasn't a colleague, he began to open up. Sengupta wrote: "His willingness to acknowledge that clinical work is stressful and can become toxic establishes a life raft upon which I can hoist myself, build new strategies, and shape a different perspective."

That struggle is behind Sengupta now and he was ready to move on. Besides occasionally discussing his experience with others who might be going through something similar, he didn't consider sharing it more widely.

He changed his mind this past winter, when the Jacobs School held an event on National Physician Suicide Awareness Day. Faculty members who direct UB residencies decided to screen a provocative documentary called "Do No Harm: Exposing the Hippocratic Hoax." The movie and a panel discussion that followed took on the issue of physician mental health and suicide. Alarming statistics were discussed, for example, that among physicians ages 25 to 39, suicide accounts for 26% of deaths compared to 11% in the same age group in the general population.

The event struck a chord. More than 200 of UB's 800-plus medical residents and fellows attended. As Sengupta listened to the discussion that followed the screening, he realized he needed to share his story.

"One of the most distressing themes in the discussion afterwards was how scared or resistant or hesitant the trainees were about seeking any therapeutic support," he recalled. "I had the chance to share a little of my experience and a number of residents wondered aloud if it might be helpful for more attendings and medical education leaders to open up a bit more about these kinds of things.

"I wrote the essay for a very particular reason," he said. "There were hundreds of trainees in the room but the vibe around seeking support was quite negative. It wasn't that people thought physicians shouldn't get help, but that there were lots of factors that would probably keep them from seeking help, such as stigma, having enough time, concern for how it might impact their careers.

"I wrote the essay in the hope that I could convey to other physicians what actually happens when you work with a therapist, that it's a collaborative process that can lead to really positive outcomes."

Sengupta, who directs UB's child and adolescent psychiatry fellowship program, also has a close-up view of the difficulties that students and especially medical residents undergo.

"I do see them struggling sometimes," said Sengupta. "Medicine is such a challenging field to be in in this day and age. Trainees are such a critical part of the system and at the same time, they probably need far more support than they are getting. It can be a tough system to work in. You can lose track of what brought you into the field."

Self-stigmatization

Among the factors contributing to physicians' reluctance to seek help are the traits that led them to medicine in the first place, Sengupta said.

"Who is the type of person that ends up wanting to be a physician and then succeeding?" Sengupta asked. "We are pretty intelligent and we're hard-working but we are probably not talking about the struggles we're having. We're internalizers."

At the same time, the nature of medical training itself also contributes. "The training values toughness and grit and perseverance. That shouldn't be to the exclusion of getting help and support but somehow it can be translated into that. Taking care of oneself can seem to represent weakness or incompetence. Sometimes it's the message that is given or sometimes it's a message that trainees perceive.

"Doctors are supposed to be larger than life figures, take in everything, be wise and be helpful," he continued. "We do a really good job of stigmatizing ourselves. When really, getting support when needed could help us get back on track to finding meaning in helping others."

He knows, however, that the challenges to changing the culture are significant. For one thing, he said, trying to find someone who can help is complicated and sensitive. "How interesting would it be if we created some sort of way for physicians who are struggling to communicate with each other… a support group of sorts?"

In the essay, he describes how he shared his experience with his trainees; it came up in the context of a broader conversation about self-care. Afterward, he noticed a change in the way they interacted with him. "I sense a subtle shift in the way some of them approach me. A bit more willing to discuss challenges and vulnerabilities. More open to reflection and self-improvement. A few clinicians even ask for help in finding therapists for themselves, allowing me to transform my process of seeking help into a way to help others."

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More information: Sourav Sengupta. Rebuilding More of Me, JAMA (2019). DOI: 10.1001/jama.2019.2137

Journal information: Journal of the American Medical Association 

Provided by University at Buffalo