Incorporating community volunteers into the health care system shows promise in reducing health care usage by older adults and shifting health care from hospitals to primary care, according to new research in CMAJ (Canadian Medical Association Journal).
13 may 2019--"We found thatolder adultswho took part in the Health TAPESTRY program changed the way in which they usedhealth careservices," says lead author Dr. Lisa Dolovich, Department of Family Medicine, McMaster University, Hamilton, Ontario. "Encouragingly, participants had more visits to primary care with fewer [emergency department] and hospital admissions compared to those not in the program."
The Health TAPESTRY (Health Teams Advancing Patient Experience: Strengthening Quality) project combines new elements, such as using trained volunteers and electronic software, with the current health system, to support optimal aging in adults aged 70 years or older. While results from the randomized controlled trial did not affect the primary goal of the study, which was to help older adults to reach their health goals, there were other positive effects between the intervention and control groups. For example, there was an increase of 81 minutes of weekly walking time in the intervention group compared with a 120-minute decrease in the control group, and the intervention group reported higher overall levels of physical activity. The volunteers gave primary health care teams information that the health providers might not have otherwise known.
"These findings suggest that Health TAPESTRY has the potential to improve the way primary care is delivered in Canada by shifting care of individuals away from hospitals to the community and to a more proactive and preventative team-based model of care," says coauthor Dr. David Price, chair, Department of Family Medicine, McMaster University.
In a related commentary, Dr. Susan Smith, Royal College of Surgeons in Ireland, Dublin, Ireland, writes, "The results of this study suggest that the Health TAPESTRY intervention may contribute to improvements in patient care for older, community-dwelling adults. Further exploration of this model of care is warranted given the challenge for all health systems in shifting from single-condition care pathways to approaches that seek to address multimorbidity."
Does hormone therapy for prostate cancer raise dementia risk?
by Steven Reinberg, Healthday Reporter
When men with prostate cancer have to take drugs that block the testosterone fueling their tumors, they can suffer a host of side effects that include impotence, bone loss, heart trouble and obesity.
12 may 2019--But new research uncovers yet another possible downside to the treatment: These men may be at greater risk fordementia.
For any type of dementia, that risk increased 17%; for Alzheimer's disease, it increased 23%, the researchers said.
Common side effects of so-called androgen-deprivation therapy include hot flashes, unstable mood, trouble sleeping, headaches, high blood sugar, allergic reactions and impotence.
"Androgen-deprivation therapy may not only cause physical changes —such as osteoporosis, cardiovascular disease or obesity—but may also cause changes in cognition," said researcher Dr. Karl Tully, a research fellow at Brigham and Women's Hospital in Boston.
But Tully cautioned that this study cannot prove that such hormone therapy caused dementia, only that the two are associated.
The investigators also found that men on this type of therapy had a 10% greater risk of seeking psychiatric services.
The risk for dementia increased as the length of therapy increased, the researchers noted. Men on androgen-deprivation therapy for six months had a 25% increased risk for any kind of dementia and a 37% increased risk for Alzheimer's, the findings showed.
Being on hormone therapy longer than six months increased the risk for dementia and using mental health services even more, Tully said.
For the study, Tully and his colleagues collected data on more than 100,400 men enrolled in Medicare. The men were diagnosed with prostate cancer between January 1992 and December 2009.
Given these findings, "physicians should be telling their patients about that risk and should probably perform regular screening," Tully said.
One urologist, however, doesn't think patients need to be told about this tenuous association.
"I don't think it's a fair discussion to have," said Dr. Elizabeth Kavaler, a urology specialist at Lenox Hill Hospital in New York City.
In this population, the increase in dementia may not be from hormone therapy at all, Kavaler said. As people live longer, the odds of developing dementia naturally increase.
Moreover, many of these patients probably had other medical conditions that might increase their risk for dementia and Alzheimer's, Kavaler added.
"Earlier generations were all worried about cancer—we're worried about dementia," she said.
In addition, patients with prostate cancer may not have a good option whether to start hormone therapy or not, she noted.
"We really don't have a choice. Androgen-deprivation therapy is what can be offered to men with recurring or advanced prostate cancer. It's a matter of treating a deadly disease versus the risk of developing a non-life-threatening condition," Kavaler said.
"How do you ask somebody to choose between losing your mind or not treating their high-risk disease," she said. "It's a hard position to put a patient in. I wouldn't even bring it up."
The findings were scheduled to be presented Sunday at the American Urological Association annual meeting, in Chicago. Research presented at meetings should be viewed as preliminary until published in a peer-reviewed journal.
More information: Karl Tully, M.D., research fellow, Brigham and Women's Hospital, Boston; Elizabeth Kavaler, M.D., urology specialist, Lenox Hill Hospital, New York City; May 5, 2019, presentation, American Urological Association, Chicago
Physician suicide is an urgent problem with rates higher than suicide rates in the general public, with potential for extensive impact on health care systems.
07 may 2019--A "Five things to know about ..." practice article in CMAJ (Canadian Medical Association Journal) provides an overview of this serious issue.
Five things about physician suicide:
As the only means of death more common in physicians than nonphysicians, suicide is an occupational hazard for physicians.
Firearms, overdose and blunt force trauma are the most common means, with benzodiazepines, barbiturates and antipsychotics being the most commonly used drugs.
Increased suicidal ideation begins as early as in medical school, with nearly 1 in 4 students surveyed reporting suicidal ideation within the last 12 months.
Complaints to regulatory bodies are associated with higher rates of suicidal ideation.
Suicidal physicians face unique barriers to care, including concerns regarding confidentiality, and fears of stigmatization and discrimination from peers, employers and licensing bodies.
Prevalence of common mental disorders by living arrangement. Credit: Jacob et al., 2019
Living alone is positively associated with common mental disorders, regardless of age and sex, according to a study published May 1, 2019 in the open-access journal PLOS ONE by Louis Jacob from University of Versailles Saint-Quentin-en-Yvelines, France, and colleagues.
06 may 2019--The proportion of people living alone has increased in recent years due to population aging, decreasing marriage rates and lowering fertility. Previous studies have investigated the link between living alone and mental disorders but have generally been conducted in elderly populations and are not generalizable toyounger adults.
In the new study, researchers used data on 20,500 individuals aged 16-64 living in England who participated in the 1993, 2000, or 2007 National Psychiatric Morbidity Surveys. Whether a person had a common mental disorder (CMD) was assessed using the Clinical Interview Schedule-Revised (CIS-R), a questionnaire focusing on neurotic symptoms during the previous week. In addition to the number of people living in a household, data was available on factors including weight and height, alcohol dependence, drug use, social support, and loneliness.
The prevalence of people living alone in 1993, 2000, and 2007 was 8.8%, 9.8%, and 10.7%. In those years, the rates of CMD was 14.1%, 16.3%, and 16.4%. In all years, all ages, and both men and women, there was a positive association between living alone and CMD (1993 odds ratio 1.69; 2000 OR 1.63; 2007 OR 1.88). In different subgroups of people, living alone increased a person's risk for CMD by 1.39 to 2.43 times. Overall, loneliness explained 84% of the living alone-CMD association. The authors suggest that interventions which tackle loneliness might also aid the mental wellbeing of individuals living alone.
Jacob summarizes: "Living alone is positively associated with common mental disorders in the general population in England."
More information: Jacob L, Haro JM, Koyanagi A (2019) Relationship between living alone and common mental disorders in the 1993, 2000 and 2007 National Psychiatric Morbidity Surveys. PLoS ONE 14(5): e0215182. doi.org/10.1371/journal.pone.0215182
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-propagatingprionforms of the proteins amyloid beta (A-β) and tau in postmortembraintissue 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."
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
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 theJournal of Medical Internet Research, an open-access publication.
04 may 2019--Lead author Ursula Whiteside, aclinical psychologistat 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.
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
Wednesday, May 01, 2019
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
