Some of the Latest Aging-Related Research at Penn
Evidence of Alzheimer's in Patients with Lewy Body Disease Tracks with Course of Dementia
Retrospective Penn Study could help guide design of trials for emerging therapies
PHILADELPHIA – Patients who had a diagnosis of Parkinson’s disease (PD) with dementia (PDD) or dementia with Lewy bodies (DLB) and had higher levels of Alzheimer’s disease (AD) pathology in their donated post-mortem brains also had more severe symptoms of these Lewy body diseases (LBD) during their lives, compared to those whose brains had less AD pathology, according to research from the Perelman School of Medicine at the University of Pennsylvania. In particular, the degree of abnormal tau protein aggregations, indicative of AD, most strongly matched the clinical course of the LBD patients who showed evidence of dementia prior to their deaths, the team reports in The Lancet Neurology First Online, ahead of the January print edition.
The team used post-mortem brain tissue donated by 213 patients with LBD and associated dementia, which was confirmed during autopsies to have alpha-synuclein pathology. They paired the tissue analysis with the patients’ detailed medical records. This unique study combined data from eight academic memory or movement disorder centers, including the Penn Alzheimer’s Disease Core Center (ADCC) and the Udall Center for Parkinson’s Disease Research.
LBD is a family of related brain disorders made up of the clinical syndromes of PD, without or with dementia or DLB. LBD is associated with clumps of misshapened alpha-synuclein proteins. On the other hand, AD pathology is made up of clusters of the protein beta-amyloid called plaques and twisted strands of the protein tau, called tangles. Patients with LBD may have varying amounts of AD pathology, in addition to alpha-synuclein pathology.
Treatments directed at tau and amyloid-beta proteins are currently being tested in patients with Alzheimer’s disease. This study could help in selecting appropriate patients for trials of emerging therapies targeting these proteins singly or in combination with emerging therapies targeting alpha-synuclein protein in LBD.
The study, led by David Irwin, MD, an assistant professor of Neurology at Penn and an attending cognitive neurologist in the Penn Frontotemporal Degeneration Center and the Center for Neurodegenerative Disease Research, suggests that Lewy body pathology is the primary driver of disease seen in the patients; whereas, AD pathology has an impact on the overall course of disease.
“We are excited with the results of this collaborative study that points to tau as a major correlate of dementia since therapies targeting tau in AD are advancing and they could be as relevant to AD as to LBD with co-occurring AD-like tau pathology.” Irwin said. “In addition, clinical trials for other synuclein-related brain disorders may be improved by taking into account biomarkers of AD pathology.”
“This study is important for many reasons, not the least of which it illustrates the power of research that harnesses the resources of all of these collaborating centers,” said senior author John Q. Trojanowski, MD, PhD, director of the Penn ADCC and Udall Center and a professor of Pathology and Laboratory Medicine.
None of the LBD patients had a clinical diagnosis of AD, but their post-mortem brain tissue revealed varying amounts of AD neuropathology. Post-mortem analysis of five brain regions per patient showed that they fell into one of four categories of AD pathology: 23 percent negligible or no AD, 26 percent had low-level, 21 percent intermediate, and 30 percent had high-level.
Increasing severity of AD pathology correlated with a shortened time from motor symptoms to the onset of dementia and death, with the most significant trends seen in the intermediate- and high-level AD groups compared to the low-level and no AD groups. Tau pathology, in particular, was the strongest predictor of a shorter time to dementia and death. AD pathology was also higher in patients who were older at the time of onset of motor symptoms and dementia.
“We found that patients with a higher burden of Alzheimer’s pathology also had a higher burden of alpha-synuclein pathology in their brain,” Irwin said. “From this, we inferred a potential synergism between the deleterious processes in AD and DLB.” Trojanowski added there is experimental evidence for synergies between these pathologies in animal models.
The team also found that two relevant genetic variants in sequences of the patients’ DNA samples correlated with the amount of AD pathology. The frequency of a genetic variant in a gene coding for a protein involved in cholesterol metabolism (APOE, the most common risk factor for AD) was more frequent in patients who were in the intermediate or high AD pathology group compared to those in the low-level or no AD group. Interestingly, a variation in the gene for the protein GBA (a risk factor for LBD) was more frequent in patients without significant AD pathology. This gene is associated with LBD overall but not the subgroup with AD pathology.
In the brain, the enzyme GBA normally aids in the breakdown of worn out and misshapened proteins, such as alpha-synuclein. Together these findings suggest that genetic risk factors could influence the amount of AD pathology in LBD. Further understanding of the relationships between genetic risk factors and AD and alpha-synuclein pathology will help improve treatments for these disorders.
In the near future, using both post-mortem brain tissue and imaging in living patients, researchers in the Udall Center and ADCC will study how declines in cognitive ability relate to AD pathology in LBD. They hope this collaborative approach will help improve the diagnosis of these co-occurring indicators as early as possible in living patients.
This study was funded by the National Institutes of Health (K23 NS088341, P50 NS053488, P30 AG010124, P50 AG005133, P30 AG028383,P30 AG008017, P50 NS062684, P50 AG005136, P50 NS062684, R01 NS48595, U01 AG006781, R01 NS065070), as well as the Veterans Affairs Geriatric Research Education and the Clinical Center at the VA Puget Sound Health Care System.
Other coauthors are Murray Grossman, Daniel Weintraub, Howard I. Hurtig, John E Duda, Sharon X. Xie, Edward B. Lee, Vivianna M. Van Deerlin, Oscar L. Lopez, Julia K. Kofler, Peter T. Nelson, Gregory A. Jicha, Randy Woltjer, Joseph F. Quinn, Jeffery Kaye, James B. Leverenz, Debby Tsuang, Katelan Longfellow, Dora Yearout, Walter Kukull, C. Dirk Keene, Thomas J. Montine, and Cyrus P. Zabetian.
More Human-like Model of Alzheimer's Better Mirrors Tangles in the Brain
Penn Study Describing Improved Animal Model Sheds Light on Pathways of Alzheimer's and other Tauopathies
Tangled up brain fibrils made up of a rogue protein known as tau are the hallmark of Alzheimer’s disease (AD) that likely hold the key to treatments, making them of great interest to researchers. Mimicking the formation and spread of these tangles in animal models with greater accuracy allows scientists to better investigate new therapies to stop or slow their spread.
A new animal model developed at Penn Medicine using tau tangles isolated from the brains of Alzheimer’s patients rather than synthetic tau tangles paints a closer picture of the tau pathology in the AD brain, researchers from the Center for Neurodegenerative Disease Research(CNDR) at the Perelman School of Medicine at the University of Pennsylvania reported in the print issue of the Journal of Experimental Medicine. Seeding normal, wildtype mice with the highly potent Alzheimer’s brain-tau (AD-tau) protein induced damaging tangles in their brains for study, mirroring a more realistic progression of tau tangles seen in AD patients’ brains.
Importantly, the mice used in the experiment were non-transgenic, meaning they did not overexpress tau protein. Past animal studies, including research from Penn Medicine, using synthetic tau fibrils provided an explanation for the progression of Alzheimer’s and other related tauopathies by implicating the cell-to-cell transmission of pathological tau. However, this phenomenon was only demonstrated in models overexpressing tau. But increased tau expression is not a cause of Alzheimer’s or other conditions involving misshapened tau protein.
“Alzheimer’s patients don’t generally overexpress tau or harbor tau mutations, so it was important to develop a model that can recreate the pathology in a setting that more closely resembles what’s happening in patients,” said senior author Virginia M.-Y. Lee, PhD, MBA, CNDR director and a professor of Pathology and Laboratory Medicine. “This model will open up many new directions and opportunities for not just Alzheimer’s, but also for other pathological tau disorders, such as corticobasal degeneration [CBD] and progressive supranuclear palsy [PSP], conditions which cause Parkinson-like symptoms, but CBD and PSP also are associated with cognitive impairments that mimic Alzheimer’s.”
Normal tau keeps nerve cells functioning properly, but pathological tau can cause the protein to go rogue, or misfold, triggering the formation of protein clumps known as neurofibrillary tangles, which are tightly linked to AD. It has been shown to move from cell to cell to form tangles in the brain, first in the areas that make memories, and then outward to areas associated with remembering.
Synthetic tau tangles have been used in transgenic mice to pattern this spread by Penn and others in the field, but until now, it couldn’t produce enough misshapened tau protein in normal mice to fully support this hypothesis.
This is the first time, to the authors’ knowledge, researchers have shown abundant amounts of tau tangles convincingly induced in multiple brain regions within a few months after inoculation of AD-tau. This observation provides the strongest support thus far for the physiological relevance of cell-to-cell transmission of pathological tau in human tauopathies, the authors said.
“This relevant mouse model will allow us to better study the architecture of tau and its physiological consequence in mechanistic and therapeutic investigations,” Lee said, “but it also provides an experimental paradigm to examine how other factors, such as amyloid plaques, another hallmark of AD, contribute to the spreading, and how tau spreads in other diseases, like CBD and PSP, among other important questions that need to be answered.”
Penn co-authors include Jing L. Guo, Sneha Narasimhan, Lakshmi Changolkar, Zhuohao He, Anna Stieber, Bin Zhang, Ronald J. Gathagan, Michiyo Iba, Jennifer D. McBride, and John Q. Trojanowski.
This work was funded by the National Institutes of Health (AG10124 and AG17586), CurePSP, the Woods Foundation, and the BrightFocus Foundation (A2014005F).
Rhythm experience and Africana culture trial (REACT!): A culturally salient intervention to promote neurocognitive health, mood, and well-being in older African Americans
Abstract: The Rhythm Experience and Africana Culture Trial (REACT!) is a multi-site randomized controlled intervention study designed to examine the efficacy of using African Dance as a form of moderate-intensity physical activity to improve cognitive function in older African Americans. African Americans are almost two times more likely than Caucasians to experience cognitive impairment in late adulthood. This increased risk may be attributed to lower level and quality of education, lower socioeconomic status, and higher prevalence of vascular diseases, type 2 diabetes, hypertension, and obesity, all of which are recognized as risk factors for dementia. Fortunately, interventions targeting cardiovascular health (i.e., physical activity) are associated with improved neurocognitive function and a reduced risk for dementia, so African Americans may be particularly suited for interventions targeting cardiovascular health and cognitive function. Here, we describe a randomized intervention protocol for increasing physical activity in older (65–75 years) African Americans. Participants (n = 80) at two study locations will be randomized into one of two groups. The treatment group will participate in African Dance three times per week for six months and the control group will receive educational training on Africana history and culture, as well as information about health behaviors, three times per week for six months. If successful, the REACT! study may transform community interventions and serve as a platform and model for testing other populations, age groups, and health outcomes, potentially identifying novel and creative methods for reducing or eliminating health disparities.
Antipsychotic Drugs Linked to Increased Mortality Among Parkinson's Disease Patients
At least half of Parkinson’s disease patients experience psychosis at some point during the course of their illness, and physicians commonly prescribe antipsychotic drugs, such as quetiapine, to treat the condition. However, a new study by researchers at the Perelman School of Medicine at the University of Pennsylvania, the University of Michigan Medical School, and the Philadelphia and Ann Arbor Veterans Affairs (VA) Medical Centers and suggests that these drugs may do significantly more harm in a subset of patients.
The researchers’ analysis of about 15,000 patient records in a VA database found that Parkinson’s patients who began using antipsychotic drugs were more than twice as likely to die during the following six months, compared to a matched set of Parkinson’s patients who did not use such drugs.
“I think that antipsychotic drugs should not be prescribed to Parkinson’s patients without careful consideration,” said first author Daniel Weintraub, MD, who is an associate professor of Psychiatry and Neurology at Penn Medicine and a fellow in Penn’s Institute on Aging. Senior author Helen C. Kales, MD, professor of Psychiatry at University of Michigan and a Research Investigator at the VA Center for Clinical Management Research added, “Treatment with antipsychotics should be reserved for those cases where the benefits exceed the risks.”
These findings are not the first to link antipsychotic drugs to increased mortality. Studies dating back to the early 2000s, including a number from Dr. Kales’ group, have found increased mortality with antipsychotic use among patients who have dementia in the general population. Since 2005 the FDA has mandated “black box” warnings on antipsychotic drug packaging, noting the apparently increased risk of death when these drugs are used in dementia patients.
Although most dementia cases are accounted for by Alzheimer’s disease, there are other forms of dementia, including one that eventually emerges in about 80 percent of Parkinson’s patients, usually many years after their Parkinson’s diagnosis. However, a study by Weintraub, Kales and colleagues in 2011 found that the FDA warnings had done little to curb antipsychotic prescriptions for Parkinson’s dementia patients.
For the new study, Weintraub, Kales and colleagues examined the possibility that antipsychotic drug use is associated with higher mortality not just in Parkinson’s dementia patients, but in all Parkinson’s disease patients. Psychosis in Parkinson’s, although it is associated with dementia and later-stage disease, can occur even in the early stages of illness and in the absence of dementia. “It happens not uncommonly earlier in the course of the illness,” Weintraub said.
The underlying causes of psychosis in Parkinson’s are not well understood, but are thought to include the spread of the neurodegenerative disease process to certain brain areas, as well as particular or higher doses of Parkinson’s drugs that enhance dopamine function.
For the study, the researchers examined records from a large Veterans Affairs database, comparing a group of 7,877 Parkinson’s patients who were prescribed antipsychotic drugs at any time during 1999-2010 to an equal-sized “control group” of Parkinson’s patients who did not use antipsychotic drugs. To reduce differences between the groups that could bias the comparison, the investigators paired each patient in the antipsychotic group with a control patient who was matched for age, gender, race, years since diagnosis, presence of dementia, and other relevant factors.
The analysis revealed that in the 180 days after they first took antipsychotic drugs, patients in the first group died in much larger numbers, compared with the matched control patients during the same periods. Overall the Parkinson’s patients who used antipsychotics had 2.35 times the mortality of the non-users.
The relative risk seemed to vary by the specific drug—for example, 2.16 times higher for quetiapine fumarate compared with non-treatment, 2.46 for risperidone, 2.79 for olanzapine, and 5.08 for haloperidol. First-generation or “typical” antipsychotics, which include haloperidol, collectively were associated with about 50 percent greater relative mortality risk, compared to more recently developed “atypical” antipsychotics such as risperidone and quetiapine.
Antipsychotic drugs have a variety of potential side-effects, including reduced alertness, increased risks of diabetes and heart disease, decreased blood pressure, and—with longer-term use—movement disorders that can resemble those seen in Parkinson’s. The initial FDA warnings were based on findings of increased strokes among antipsychotic users. But researchers still do not fully understand why these drugs are linked to higher mortality in certain patient groups. “In this study we looked at the dataset for clues,” said Weintraub, “but the most common cause of death listed was ‘Parkinson’s disease’—so there really wasn’t anything that pointed to a specific cause or mechanism.“
Weintraub, Kales and colleagues are now conducting a follow-up study that might shed more light on that mechanism. They will examine the same VA database, looking not at mortality but at “morbidity”—disease diagnoses, injuries and other new episodes of ill-health—among Parkinson’s patients taking antipsychotic drugs, comparing them with the same matched controls.
For the present, Weintraub and Kales suggest that neurologists, psychiatrists and other physicians should prescribe antipsychotics to Parkinson’s patients only after looking for other possible solutions, such as treating any co-morbid medical conditions associated with psychosis, reducing the dosage of dopamine replacement therapies, and simply managing the psychosis without antipsychotics.
Kales notes, “Clinicians really need to assess whether the psychosis is actually ‘threatening’ the health/safety of the person with Parkinson’s or those around them. If not, use other modalities including family education and behavioral and environmental modifications. ” Further, “patients should not be left on these drugs long-term without re-evaluation,” Weintraub said.
Other co-authors of the study were Jayne Wilkinson and Eugenia Mamikonyan of Penn and the Philadelphia VA; Claire Chiang, Hyungjin Myra Kim, and Barbara Stanislawski, the University of Michigan and the VA Ann Arbor Healthcare System; and Connie Marras of the University of Toronto.
Funding was provided by the Veterans Health Administration (IIR 12-144-2).
Penn Study Identifies Enzyme Key to Link Between Age-Related Inflammation and Cancer
For the first time, researchers have shown that an enzyme key to regulating gene expression -- and also an oncogene when mutated -- is critical for the expression of numerous inflammatory compounds that have been implicated in age-related increases in cancer and tissue degeneration, according to new research from the Perelman School of Medicine at the University of Pennsylvania. Inhibitors of the enzyme are being developed as a new anti-cancer target.
Aged and damaged cells frequently undergo a form of proliferation arrest called cellular senescence. These fading cells increase in human tissues with aging and are thought to contribute to age-related increases in both cancer and inflammation. The secretion of such inflammatory compounds as cytokines, growth factors, and proteases is called the senescence-associated secretory phenotype, or SASP.
In a study published this week in Genes & Development, genetic and pharmacological inhibition of the enzyme, called MLL1, in both human cells and mice prevents the deleterious activation of the DNA damage response, which causes SASP expression.
“Since tumor-promoting inflammation is one of the hallmarks of cancer, these findings suggest that MLL1 inhibitors may be highly potent anti-cancer drugs through both direct epigenetic effects on proliferation-promoting genes, as well as through the inhibition of inflammation in the tumor microenvironment,” says first author Brian Capell, MD, PhD, a medical fellow in the lab of Shelley Berger, PhD, the Daniel S. Och University Professor in the Departments of Cell & Developmental Biology, Genetics , and Biology.
Berger is also the director of the Penn Epigenetics Program. Capell is an instructor and attending physician in the Department of Dermatology and is a postdoctoral fellow in the Berger lab.
The mechanism of this inhibition is through the direct epigenetic regulation by MLL1 of critical proliferation-promoting cell cycle genes that are required for triggering the DNA damage response in the body. MLL1 is an enzyme that adds methyl groups to loosen chromatin, the proteins around which DNA winds, so that part of the genome can be “read” and translated into proteins – its epigenetic role. However, MLL1 is also commonly mutated in numerous human cancers, particularly in pediatric and adult blood cancers.
“We show that MLL1 inhibition blocks the expression of inflammatory genes in both senescent and cancerous human cells, including those derived from human breast cancer” Capell said.
Knowing that MLL1 has been implicated in cell-cycle regulation, when the researchers inhibited MLL1, proliferation-promoting genes were shut down and the DNA damage response and resulting inflammation was suppressed. Indeed, in the case of applying this result to fighting cancer, this is a desired effect, since an increase in inflammation can promote both the development and progression of cancer.
“In cancer, this could be a potent one-two punch, by blocking both proliferation-promoting genes as well as the cancerous inflammation,” Capell explained. “One could imagine taking an MLL1 inhibitor as a primary treatment, but also as an adjuvant therapy to tamp down the rampant inflammation caused by drugs like chemotherapies. More speculatively, given that the SASP has been implicated in numerous other age-related disorders, it will be worth testing the effects of MLL1 inhibition in other aging and inflammatory disease models.”
The research was supported in part by the National Institute of Aging (P01AG031862), the Dermatology Foundation, the American Skin Association, and the Melanoma Research Foundation.
Adults with OCD Can Benefit from Exposure Therapy When Common Drug Treatment Options Fail, Penn Study Finds
Researchers first to test therapy next to drug treatment.
PHILADELPHIA – Patients with Obsessive-Compulsive Disorder (OCD) can improve their symptoms significantly by adding exposure and response prevention therapy to their treatment regimen when common drug treatment options have failed, according to new research from psychiatrists at the Perelman School of Medicine at the University of Pennsylvania. Exposure and response prevention therapy is a type of cognitive behavior therapy in which the patient is asked to confront triggers that give rise to their obsessions in order to refrain from performing the rituals in response to these obsessions. The study is published in the Journal of Clinical Psychiatry.
OCD is marked by the performing of “rituals” to decrease distress related to one’s obsessions—such as excessive hand-washing to cope with a fixation on hand hygiene, for example.
“We know that exposure and response prevention therapy (EX/RP) can benefit these patients,” said lead author, Carmen McLean, PhD, an assistant professor of clinical psychology in the department of Psychiatry at the Center for the Treatment and Study of Anxiety at Penn. “But this study showed that EX/RP is also effective for OCD sufferers who do not benefit sufficiently from common drug treatments for OCD.”
A previous study compared the effects of adding risperidone, pill placebo, and up to 17 twice-weekly therapist-led sessions of EX/RP to medication for OCD. “We found compared to patients who received medication or placebo, those who received EX/RP showed significantly more reductions in OCD symptoms and depression, as well as significantly more increases in insight, quality of life, and social function after only eight weeks,” McLean said.
The current study included 32 patients who crossed over to receive 17 weeks of EX/RP treatment after not benefitting sufficiently from risperidone. Evaluation at 12 and 16 weeks showed significant symptom improvement, with 25 (78 percent) of patients completing treatment; 17 (53 percent) of them were classified as treatment responders and 11 (34 percent) classified as excellent responders at a 32-week follow-up evaluation. The remaining patients required medication changes during the follow-up period, which enabled them to shift to excellent-responder status.
This study adds to the large body of research that shows the benefits of exposure therapy for patients with OCD. “We want patients to know that there is another option, if common drug treatments have failed them,” explained senior author, Edna Foa, PhD, professor of Clinical Psychology in the department of Psychiatry and director of the Center for the Treatment and Study of Anxiety at Penn and the creator of exposure therapy. “The therapy can be life-saving, if patients are aware of it.”
Additional Penn authors include Laurie J. Zandberg, PsyD; and Joseph K. Carpenter, BA.
This research was supported by the National Institute of Mental Health (R01 MH45404) and (R01 MH045436).
Brain's Hippocampus is Essential Structure for All Aspects of Recognition Memory, Penn Medicine Researchers Find
PHILADELPHIA – The hippocampus, a brain structure known to play a role in memory and spatial navigation, is essential to one’s ability to recognize previously encountered events, objects, or people – a phenomenon known as recognition memory – according to new research from the departments of Neurosurgery and Psychology in the Perelman School of Medicine at the University of Pennsylvania and the Penn School of Arts and Sciences. Their work is published in PNAS.
Recognition memory is composed of two processes: recollection, or recognizing something along with vivid details of the initial encounter; and familiarity, a general sense of having previously encountered something. These processes often break down as a result of aging, neurodegenerative disorders (e.g. Alzheimer's disease), or traumatic brain injury, and the new findings provide a roadmap to examine strategies to improve these functions.
“There has been a longstanding debate in the field of recognition memory about how the human hippocampus contributes to our ability to recognize,” said lead author Maxwell Merkow, MD, NeurosurgeryChief Resident at the Hospital of the University of Pennsylvania. “One segment of the scientific literature contends that neural activity in the hippocampus only contributes to recollection, whereas some believe hippocampal activity supports both recollection and familiarity. Our study aimed to get to the bottom of this.”
The Penn team, led by Michael Kahana, PhD, director of the Computational Memory Lab, hypothesized that the hippocampus supported both recollection and familiarity, the twin processes believed to underlie recognition memory. Showing a clear link between hippocampal activity and recognition memory performance in general has previously proven elusive, having been documented in just a few earlier studies. This paper is the first to also record a link between hippocampal activity and both the processes of recollection and familiarity.
Merkow and colleagues studied 66 patients who were already undergoing intracranial monitoring of their hippocampus for epilepsy. Using these direct electrical recordings, the team was able to test the level of high frequency neuronal activity (a marker of neurons firing) in this region, a very precise measure which captures activity tied to cognition processes lasting mere hundreds of milliseconds.
The team administered a memory task in which participants were shown and asked to remember a series of words. Patients were then tested by being shown a second series of words, some of which they had seen before, and some that were new. Patients had to determine whether or not each word had been part of the group they had learned initially. While all of this was going on, the team recorded electrical data directly from the patient's hippocampus.
They found elevated high frequency activity during those trials in which the patient correctly identified a word they had previously seen. This was opposed to lower activity during trials where they either failed to recognize an old word or in which they saw a new word, whether or not they correctly identified it as new.
Another major finding was that the strength of hippocampal activity predicted behavioral performance, thereby directly linking the hippocampus to recognition memory. Crucially, both the recollection and familiarity components of recognition correlated with hippocampal activity. These data show that the cognitive processes we use for recognition memory are both supported by actions within the hippocampus.
“This work directly addresses the issue of where in the brain recognition takes place,” Merkow said. “We now need to focus our efforts on how these processes occur.” The team plans to use the same high frequency recordings from smaller electrodes to answer this question. This work brings science one step closer to understanding how brain activity supports memory and potentially improving memory through future interventions.
Additional Penn authors include John F. Burke.
This work was supported by the National Institutes of Health (MH055687)
Penn Bioethicist Calls on Researchers for More Evidence-based End-of-Life Care Programs
End-of-Life Program Approvals Should More Closely Mirror Drug Approval Process, Author Says.
PHILADELPHIA – Although the public and private sectors are currently engaged in an unprecedented array of efforts to improve end-of-life care, too many of these programs are not evidence-based, according to a scholar from the Perelman School of Medicine at the University of Pennsylvania. Writing in the New England Journal of Medicine, Scott Halpern, MD, PhD, associate professor of Medicine, Epidemiology, and Medical Ethics and Health Policy, says that despite recent federal decisions that signal a renewed interest in improving end-of-life care, investigators and research sponsors must be more involved to “identify, develop and rigorously test interventions so they can offer guidance” on implementing programs that work among the terminally ill.
In his commentary, Halpern says if end-of-life care policies were approached in the same way the United States adopts new drug policies, the long-term interests of patients, health systems, insurers, and the government would be better served.
“In July 2015, the Centers for Medicare and Medicaid Services (CMS) announced its plans to reimburse physicians for engaging their patients in advance care planning discussions,” Halpern writes. Although he notes that the decision was based on the “valid premise” that communication among all patients and clinicians is an important way to improve the quality of end-of-life care, Halpern says the problem is that “no current policy or practice designed to improve care… is backed by a fraction of the evidence” required for drug approvals in the United States.
Halpern suggests four developments that he calls “attainable,” and describes how achieving these goals will help achieve evidenced-based end-of life-care:
- Increased use of large randomized trials and experimental studies that help determine whether current and novel interventions improve outcomes that are important to patients and society. For example, Halpern describes the literature on advance care planning and completing advance directives as “provocative” but “insufficient” to determine whether these widely advocated practices actually improve patient care and reduce costs.
- Better measures used in studies to quantify the effectiveness of end-of-life interventions. Technological advances that allow for processing of electronic medical record data make it easier to evaluate measures of care that matter to patients and their families. Implementation of these technologies will make it easier to develop large-scale, low-cost assessments of which interventions improve patient and family goals.
- Development of interventions that more accurately show how patients, their families and care teams make decisions about which care plan to pursue. Novel insights into the decision-making process may bring to light options that better serve patients.
- Health systems, insurers, and other entities must be more open to experimentation. Instead of simply being motivated to “do something,” opportunities abound for rigorously testing new initiatives, thereby benefiting the long-term interests of both the organizations and the patients they serve. By contrast, Halpern notes that implementing change absent a rigorous evaluation plan crowds out opportunities for learning.
Though encouraged by the enthusiasm of federal organization and their willingness to intervene in end-of-life care programs, Halpern says the central challenge today is to “avoid complacency regarding plausibly useful but non-evidence-based initiatives. Researchers, research sponsors, and large insurers, employers and health systems can work together to advance knowledge about what works best for whom.”
Penn Team Pinpoints Developmental Gene that Regulates Repair and Regeneration in Adult Lungs
New role for hedgehog gene offers better understanding of lung disease.
PHILADELPHIA - The whimsically named sonic hedgehog gene, best known for controlling embryonic development, also maintains the normal physiological state and repair process of an adult healthy lung, if damaged, according to new research from the Perelman School of Medicine at the University of Pennsylvania published online in Nature in advance of the print edition.
Tissues are not all created equal in their ability to regenerate. Skin and blood cells are continually turning over, making entirely new populations of cells every few days. At the other end of the spectrum, heart and brain cells regenerate slowly, if at all, after injury. Between these two extremes are tissues such as the lung and liver, which have little cellular turnover in normal adults, but can regenerate extensively after injury. Such tissues, overall, are thought to be quiescent.
This inactive state was previously thought to be the default mode of many tissues, including the lung, in the absence of a proliferative stimulus such as injury. However, it has remained unclear how quiescence is maintained in organs such as the lung that display a low level of cell turnover.
“We demonstrated that quiescence in the adult lung in an animal model is an actively maintained state and is regulated by hedgehog signaling,” said senior author Ed Morrisey, PhD, the Robinette Foundation Professor of Medicine and a professor of Cell and Developmental Biology. Morrisey is also director of the Penn Center for Pulmonary Biology and scientific director of the Penn Institute for Regenerative Medicine.
“We were surprised,” Morrisey recalled. “This was the exact opposite of what other researchers had suggested and pretty much the opposite of what happens during development. We scratched our heads for a long time.”
First author Tien Peng, MD and other members of the Morrisey lab used multiple approaches to determine what hedgehog was doing in the adult lung. First, they deleted the gene sonic hedgehog in airway epithelial cells of the adult lung. The protein made from sonic hedgehog is secreted from airway epithelial cells and acts on the adjoining cells surrounding the airways called mesenchymal cells.
The team observed that after the loss of sonic hedgehog expression,mesenchymalcells began to spontaneously proliferate. This also occurred when they directly inactivated hedgehog signaling in mesenchymal cells themselves.
To determine what occurred after lung injury, the researchers performed multiple different injuries to lung tissue and found that in contrast to previous reports,hedgehogsignaling decreased. This decline correlated with the loss of the cells that normally express the sonic hedgehog gene, which were destroyed as a result of the injury.
With this new concept of what sonic hedgehog is doing in the adult lung, the researchers then asked what would happen if they turned on the hedgehog pathway after lung injury. Consistent with their other observations, the Morrisey team found that activation of the hedgehog pathway inhibited proliferation of the mesenchymal cells surrounding the lung airways.
Overall, they found that activation of hedgehog during an injury to epithelial cells weakens replication of mesenchymal cells, whereas inactivation of hedgehog signaling prevents the restoration of quiescence after an injury. Finally, they showed that hedgehog signaling in mesenchymal cells also regulates epithelial quiescence and loss of this regulation leads to abnormal epithelial regeneration after injury. Loss of hedgehog in the adult lung leads to too many epithelial cells lining the airways after injury whereas increased hedgehog signaling blocks regeneration of the airway epithelium. Such results suggest that increased hedgehog signaling causes a breakdown of the normal regenerative properties of the lung airways, leading to degenerative disease states.
“These results demonstrate that epithelial-mesenchymal interactions coordinated by hedgehog maintains the normal state of a healthy lung, and turning off hedgehog during injury can lead to abnormal cell repair and regeneration in the lung,” Morrisey said. “We think that mistakes in the hedgehog feedback loop could contribute to many adult lung diseases characterized by a chronic injury and regeneration cycle.”
Indeed, the hedgehog pathway has been implicated in previous genome-wide association studies of adult lung disease. “We now have a better idea of what is going on in lung disease – in adults, hedgehog suppresses proliferation and maintains cell quiescence, as opposed to its opposite role in embryo development,” Morrisey explained. “These surprising findings suggest that researchers have to be careful in predicting the function of developmental pathways in adult organs. We need to remember that they will not always function in the same manner.”
These studies were supported by funds from the National Heart, Lung & Blood Institute (HL110942, HL100405, HL087825, K08-HL121146), an American Heart Association Fellow-to-Faculty Transition Award, and an Actelion ENTELLIGENCE Award.
Coauthors are Tien Peng, David B. Frank, Rachel S. Kadzik, Michael P. Morley, Komal S.Rathi, Tao Wang, Su Zhou, Lan Cheng, and Min Min Lu, all from Penn.
Cell Aging Slowed by Putting Brakes on Noisy Transcription
Experiments in yeast hint at ways to extend life of some human cells.
PHILADELPHIA - Working with yeast and worms, researchers found that incorrect gene expression is a hallmark of aged cells and that reducing such “noise” extends lifespan in these organisms. The team published their findings this month in Genes & Development.
The team was led by senior author Shelley Berger, PhD, a Daniel S. Och University Professor in the departments of Cell & Developmental Biology, Biology & Genetics at the Perelman School of Medicine at the University of Pennsylvania, and Weiwei Dang, PhD, a former Penn postdoctoral fellow who is now an assistant professor at Baylor College of Medicine, along with first author Payel Sen, PhD, currently a postdoctoral fellow in the Berger lab. Berger is also director of the Penn Epigenetics Program.
Gene expression is regulated by chemical modifications on chromatin -- histone proteins tightly associated with DNA. Certain chemical groups on histones allow DNA to open up, and others to tighten it. These groups alter how compact DNA is in certain regions of the genome, which in turn, affect which genes are available to be made into RNA (a process called transcription) and eventually proteins.
“Researchers have just started to appreciate how these epigenetic histone modifications may be playing essential roles in determining lifespan,” said Berger. She has been studying such epigenetic markings for over two decades and was among the first to pinpoint specific histone modifications that not only are altered during aging, but also directly determine longevity.
“In this study, we found that a type of abnormal transcription dramatically increases in aged cells and that its reduction can prolong lifespan,” said Dang, who initiated this line of research while working in Berger’s laboratory. “This longevity effect is mediated through an evolutionarily conserved chemical modification on histones. This is the first demonstration that such a mechanism exists to regulate aging.”
“We used budding yeast, a single-cell organism, to study the epigenetic regulation of aging and this simple model turned out to be quite powerful,” explained Sen. In yeast, aging is measured by the number of times a mother cell divides to form daughters before it stops. This number – a mean of 25 divisions -- is under tight control and can be either reduced or increased by altering histone modifications, as the researchers found. They showed that when fewer chemical groups of a certain type attach to yeast histones, the abnormal transcription greatly increases in old cells. In contrast, the team found that in yeast strains with a certain enzyme deletion, this abnormal transcription is reduced and lifespan is extended by about 30 percent.
“We have started investigating whether such a longevity pathway can also be demonstrated in mammalian cells”, says Berger. “However, these investigations are confounded by the complexity of the genome in more advanced organisms. One of our long-term goals is to design drugs that can help retain these beneficial histone modifications and extend healthy lifespan in humans.”
Coauthor Greg Donahue, computer specialist in the Berger lab, also played a central role in the bioinformatics analysis for this research.
Higher-level Occupations May Increase Survival in Patients with a Common Form of Early-onset Dementia, Finds New Penn Medicine Research
A high level of mental activity earlier in life may buffer against disease.
PHILADELPHIA - Doctors, lawyers and other "high level" professionals may have a built-in survival edge if they're diagnosed with the disease frontotemporal dementia (FTD), according to new research from the Perelman School of Medicine at the University of Pennsylvania. Their work is published in Neurology.
FTD is a family of devastating disorders of the brain that lead to the progressive loss of brain cells (neurons) in the frontal and temporal regions of the brain, most commonly in patients between ages 50 and 65 and often causing symptoms ranging from behavioral impairments to language difficulty. Nearly 10,000 patients are diagnosed with the disease each year. As the disease progresses, it can slowly deprive an individual of their cognitive abilities, personality and eventually their independence.
"There is a notion that ones 'cognitive reserve' is built up over the course of a lifetime through experiences such as education, occupation and mental engagement," said Lauren Massimo, PhD, CRNP, a post-doctoral fellow in the department of Neurology in Penn's Frontotemporal Degeneration Center. "We believe that those with higher occupational levels are able to build up an additional level of defense against the disease through rich neural connectivity and this could contribute to longer survival."
Massimo and colleagues retrospectively examined the autopsy reports of 83 patients in the Center for Neurodegenerative Disease Research at the University of Pennsylvania, 34 of whom had confirmed FTD and 49 with autopsy-confirmed Alzheimer's disease (AD).
Each patient's occupation was recorded and ranked according to U.S. Census categories, with jobs such as factory workers and service workers in the lowest level; jobs such as tradesworkers and sales people in the next level; and professional and technical workers, such as lawyers and engineers, in the highest level. Education level was also measured in years of schooling completed.
Their analysis showed that median survival for patients with FTD was six years and nine months, and just shy of eight years for those with AD, with survival defined as the time from symptom onset until death.
Further analysis showed that patients with FTD in the highest occupation level survived an average of nine years, while people in the lower occupation group survived an average of six years, suggesting that higher occupation level is associated with longer survival in patients with FTD. Occupational level was not associated with longer survival time for patients with Alzheimer's disease. Interestingly, the team found that years of education were not associated with survival time for either group.
"These results provide support for the protective effects of occupation in FTD," Massimo said. "There may be other factors at work here such socioeconomic factors tied to occupational status that contributes to the longevity of this group. Further studies might also want to expand the sample size and occupations characterized, as ours left no room for occupations such as 'homemaker' or those outside traditional lines of work."
Other Penn researchers include Jarcy Zee, PhD; Sharon X. Xie, PhD; Corey T. McMillan, PhD; Katya Rascovsky, PhD; David I. Irwin, MD; Murray Grossman, MD, MedD.
This research was funded by the U.S. Public Health Service (F32NR014777, AG017586, AG015116, AG010124, AG043503, NS053488 and NS044266) and the Wyncote Foundation.
Plasma ApoA1 Associates with Age at Onset and Motor Severity in Early Parkinson's Disease Patients, Penn Medicine Researchers Find
New Study Indicates Plasma ApoA1 as a Possible Biomarker for Parkinson's Disease.
WASHINGTON, D.C. - Building on previous research showing that plasma Apolipoprotein A1 (ApoA1) may be a useful biomarker for Parkinson’s disease, researchers from the Perelman School of Medicine at the University of Pennsylvania have replicated these findings in approximately 1,000 patients from across the world, upholding their initial findings from a screen of many candidate proteins. Their work was presented at the American Academy of Neurology annual meeting in Washington, D.C. on Thursday, April 23, 2015.
First author Christine Swanson, PhD, a post-doctoral researcher in Neurology and a team led by senior author Alice Chen-Plotkin, MD, an assistant professor of Neurology at Penn were also the first to use plasma samples from the Michael J. Fox Foundation's flagship biomarker program, the Parkinson's Progression Marker Initiative (PPMI).
In the PPMI cohort, the team measured Plasma ApoA1 and HDL, as ApoA1 is a large component of the HDL cholesterol fraction, at baseline, six months, and 12 months after diagnosis in 154 patients with PD and 100 normal controls. They found that lower baseline plasma ApoA1 levels were associated with an earlier age at PD onset in early-stage patients who were not yet taking medications for PD. Moreover, they showed that lower baseline ApoA1 levels trend towards association with worse motor severity.
"Our results confirm the association of lower plasma ApoA1 levels with indicators of poorer integrity of the dopamine system in early-stage PD patients not yet on medication," Swanson said. The dopaminergic system encompasses the complex group of nerve cells that facilitate movement, thinking and reward. A lack of dopamine causes the system to malfunction leads to the short, rigid movements that are the hallmark of PD.
Swanson, Chen-Plotkin and colleagues then performed a meta-analysis of five PD cohorts, including the PPMI cohort, encompassing more than 1,000 patients, which confirmed significant association of lower plasma APoA1 with earlier age at PD onset and greater motor severity.
"We are thrilled at these results," Chen-Plotkin said. "In the biomarker field, many candidates may initially appear promising, but it has been very difficult to replicate these promising leads until now." The findings suggest the development of robust plasma-based biomarkers in PD could lead to new approaches for identifying those at risk for PD and developing novel therapies."
Funding for the study was provided by the National Institutes of Health (P50 NS053488, U01 NS082134), the Brody Family Foundation, and the Doris Duke Charitable Foundation. Additional data used in the preparation of this article were obtained from the Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data).
Two Penn Medicine Studies Examine Diabetes Severity in Parkinson's, Sex Differences in Parkinson's Disease Caregiving
Findings reveal severe diabetes worsens Parkinson's symptoms.
WASHINGTON, D.C. - A pair of studies from the Perelman School of Medicine at the University of Pennsylvania demonstrate a correlation between diabetes severity and parkinsonism, or parkinsonian tremors; and examine the caregiving differences between men and women with PD.
The findings were presented at the American Academy of Neurology's 67th Annual Meeting in Washington, D.C.
Diabetes Severity is Associated with Worse Parkinsonism
The study enrolled 1,100 subjects over the age of 55 without Parkinson’s disease or dementia from the existing Philadelphia Healthy Bran Aging cohort at the University of Pennsylvania. At baseline testing, 34 percent of subjects were found to have diabetes. A Hemoglobin A1c glucose test was performed and a diabetes severity score created that combined the presence of retinopathy, neuropathy, nephropathy and insulin dependence.
Subjects were then assessed for parkinsonian signs and cognitive impairment. The median hemoglobin A1c was 6.6 (less than 6.5 is ideal in most cases) and the median parkinsonism score was 8.3 (anything above zero is abnormal).
Higher parkinsonian scores were associated with greater diabetes severity, older age, African-American race and a past history of arthritis. Further analysis showed diabetes severity remained significantly associated with higher parkinsonian sign scores.
"Our study was based on emerging evidence that the presence of diabetes may increase the risk of both Parkinson's disease and specific motor features in parkinsonism," said Nabila Dahodwala, MD, an assistant professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania and director of the National Parkinson Foundation Center of Excellence at the Parkinson's Disease and Movement Disorders Center at Pennsylvania Hospital.
"We hypothesize that the high burden of cardiovascular risk from diabetes contributes to brain injury, which can impact cognition and parkinsonism," explains Dahodwala. Further studies are needed to show causality between diabetes and parksonism. These could indicate that aggressive management of diabetes could provide additional motor benefit.
This work was funded by the Parkinson Council, National Institute on Aging (K23 AG034236 and P30 AG031043) and Penn Minority Aging Research for Community Health (MARCH).
Sex Differences in Parkinson's Disease Caregiving
Researchers looked at caregiving patterns among PD patients to determine if there are sex differences in caregiver accompaniment to visits, paid caregiving and caregiving strain and found that women with PD have fewer informal caregiving resources and are more likely to use formal, paid caregiving.
"Parkinson's patients rely on formal and informal caregiver support as the disease worsens," Dahodwala said. Previous research has shown that there is a higher incidence of Parkinson's disease among men, but little is known about caregiving patterns by sex.
Dahodwala and her team collected information on each of 4,718 men and 2,788 women in the National Parkinson Foundation Parkinson's Outcomes Project's medication, disease duration as well as caregiver presence and the caregiver type, time to first paid caregiver and more.
Their analysis showed that compared with women, men were significantly more likely to have a regular care partner (88 versus 80 percent), but less likely to have a paid caregiver at baseline than women (2.2 versus 4.9 percent). In addition, women were found to have lower odds of caregiver accompaniment at baseline visit, but faster time to first paid caregiver. Caregiver strain was found to be higher among caregivers of male subjects.
"We hope that this study spurs some of the key stakeholders in PD to develop policies that ensure adequate support for women with the disease. Our analysis shows there is a real need for it," Dahodwala said.
This work was funded by the National Parkinson Foundation.
Dahodwala presented the findings for "Diabetes Severity is Associated with Worse Parkinsonism," on Wednesday, April 22nd, 2015 at 7:30 AM in the Walter E. Washington Convention Center, 801 Mt. Vernon Pl. NW, Washington, DC. P4: Poster Session IV: Neuroepidemiology: Movement Disorders, ALS, and Neuromuscular (7:30 AM-12:00 PM), [P4.148].
She presented "Sex Differences in Parkinson's Disease Caregiving" on Thursday, April 23rd, 2015 at 3:30 P.M. in the Walter E. Washington Convention Center, 801 Mt. Vernon Pl. NW, Washington, DC.
Penn Medicine Researchers Pinpoint Potential New Drug Target for Protection against Certain Neurodegenerative Diseases
Findings Could Pave Way for Precision Medicine Approach to Treatment of Neurological Diseases.
PHILADELPHIA - Penn Medicine researchers have discovered that hypermethylation - the epigenetic ability to turn down or turn off a bad gene implicated in 10 to 30 percent of patients with Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Degeneration (FTD) - serves as a protective barrier inhibiting the development of these diseases. Their work, published this month in Neurology, may suggest a neuroprotective target for drug discovery efforts.
"This is the first epigenetic modification of a gene that seems to be protective against neuronal disease," says lead author Corey McMillan, PhD, research assistant professor of Neurology in the Frontotemporal Degeneration Center in the Perelman School of Medicine at the University of Pennsylvania.
Expansions in the offending gene, C9orf72, have been linked with TAR DNA binding protein (TDP-43) which is the pathological source that causes ALS and FTD. "Understanding the role of C9orf72 has the possibility to be truly translational and improve the lives of patients suffering from these devastating diseases," says senior author, Edward Lee, PhD, assistant professor of Neuropathology in Pathology and Laboratory Medicine at Penn.
McMillan and team evaluated 20 patients recruited from both the FTD Center and the ALS Center at the University of Pennsylvania who screened positive for a mutation in the C9orf72 gene and were clinically diagnosed with FTD or ALS. All patients completed a neuroimaging study, a blood test to evaluate C9orf72 methylation levels, and a brief neuropsychological screening assessment. The study also included 25 healthy controls with no history of neurological or psychiatric diseases.
MRI revealed reduced grey matter in several regions that were affected in patients compared to controls. Grey matter is needed for the proper function of the brain in regions involved with muscle control, memory, emotions, speech, and decision-making. Critically, patients with hypermethylation of C9orf72showed more dense grey matter in the hippocampus, frontal cortex, and thalamus, regions of the brain important for the above described tasks and affected in ALS and FTD, suggesting that hypermethylation is neuroprotective in these regions.
To validate these findings, the Penn team also looked at autopsies of 35 patients with C9orf72 expansions and found that their pathology also suggested that increased methylation was associated with reduced neuronal loss in both the frontal cortex and hippocampus.
Longitudinal analysis was performed in 11 of the study patients to evaluate the neuroprotective effects of hypermethylation in individuals over their disease course. This showed reduced changes in grey matter of the hippocampus, thalamus, and frontal cortex, associated with hypermethylation suggesting that disease progresses more slowly over time in individuals with C9orf72 hypermethylation. Longitudinal neuropsychological assessments also showed a correlation between protected memory decline and hypermethylation.
These findings are consistent with a growing number of studies which have suggested the neuroprotective effects of the hypermethylation of C9orf72. "We believe that this work provides additional data supporting the notion that C9orf72 methylation is neuroprotective and therefore opens up the exciting possibility of a new avenue for precision medicine treatments and targets for drug development in neurodegenerative disease," says McMillan.
Additional Penn authors include Jenny Russ, PhD; Elisabeth M. Wood, MSc; David J. Irwin, MD; Murray Grossman, MD, EdD; Leo McCluskey, MD; Lauren Elman, MD; and Vivianna Van Deerlin, MD, PhD.
This research was funded by the National Institutes of Health (AG043503, AG017586, AG039510, AG10124, AG032953) and the Wyncote Foundation. Dr. Lee is supported by the Doris Duke Charitable Foundation Clinical Scientist Development Award.
Penn Study Describes New Models for Testing Parkinson's Disease Immune-based Drugs
Understanding how disease spreads from neuron to neuron is key to finding treatments.
PHILADELPHIA – Using powerful, newly developed cell culture and mouse models of sporadic Parkinson's disease (PD), a team of researchers from the Perelman School of Medicine at the University of Pennsylvania, has demonstrated that immunotherapy with specifically targeted antibodies may block the development and spread of PD pathology in the brain. By intercepting the distorted and misfolded alpha-synuclein (a-syn) proteins that enter and propagate in neurons, creating aggregates, the researchers prevented the development of pathology and also reversed some of the effects of already-existing disease. The a-sync clumps, called Lewy bodies, eventually kill affected neurons, which leads to clinical PD. Their work appears in Cell Reports.
Earlier studies by senior author Virginia M.-Y. Lee, PhD, and her colleagues at Penn's Center for Neurodegenerative Disease Research (CNDR) haddemonstrated a novel pathology of PD in which misfolded a-syn fibrils initiate and propagate Lewy bodies via cell-to-cell transmission. This was accomplished using synthetically created a-syn fibrils that allowed them to observe how Parkinson's pathology developed and spread in a mouse and in neurons in a dish. The present study is a proof-of-concept of how these models might be used to develop new PD therapies.
"Once we created these models, the first thing that came to mind is immunotherapy," says Lee, CNDR director and professor of Pathology and Laboratory Medicine. "If you can develop antibodies that would stop the spreading, you may have a way to at least retard the progression of PD." The current work, she explains, uses antibodies that were generated and characterized at CNDR previously to see if they would reduce the pathology both in cell culture and in animal models.
Lee's team focused on anti0a0syn monoclonal antibodies(MAbs). "In animal models," Lee explains, "the question we want to ask is, can we reduce the pathology and also rescue cell loss to improve the behavioral deficits?"
Using their previously established sporadic PD mouse model, the researchers conducted both prevention and intervention preclinical studies. For preventional studies, they injected mouse a-syn synthetic preformed fibrils into wild-type, normal mice, as a control, and then immediately treated the mice with Syn303, one of the MAbs used (or lgG, another type of common antibody, for the control mice).
The control group without MAb administration showed PD pathology in multiple brain areas over time, while the mice treated with Syn303 showed significantly reduced pathology in the same areas. For intervention studies, they treated PD mice with Syn303 several days after fibril injections when Lewy bodies were already present. They found that the progression of pathology was markedly reduced in the Syn303-treated mice versus mice that did not receive Syn303.
"But there are some limitations to experiments in live mice since it is difficult to directly study the mechanism of how it works," Lee says. "To do that, we went back to the cell culture model to ask whether or not the antibody basically prevents the uptake of misfolded a-syn." The cell culture experiments showed that MAbs prevented the uptake of misfolded a-syn fibrils by neurons and sharply reduced the recruitment of natural a-syn into new Lewy body aggregates.
Next steps for the team will be to refine the immunotherapeutic approach. "We need to make better antibodies that have high affinity for pathology and not the normal protein," says Lee.
The team's models also open up new opportunities for studying and treating PD. "The system really allows us to identify new targets for treating PD," Lee says. "The cell model could be a platform to look for small molecular drugs that would inhibit pathology." Their approach could also serve as a foundation for genetically based studies to identify specific genes involved in PD pathology.
"Hopefully more people will use the model to look for new targets or screen for treatments for PD. That would be terrific," concludes Lee.
The work was supported by an National Institute on Aging training grant (T32-AG000235), the National Institute of Neurological Disorders and Stroke Morris K. Udall Parkinson's Disease Center of Excellence (P50 NS053488), the Michael J. Fox Foundation, the Keefer family, and the Parkinson Council.
Coauthors, all from Penn are Hien T. Tran, Charlotte Hiu-Yan Chung, Michiyo Iba, Bin Zhang, John Q. Trojanowski, and Kelvin C. Luk.
Role of Calcium in Familial Alzheimer's Disease Clarified in Penn Study, Pointing to New Therapeutic Options
PHILADELPHIA – In 2008, researchers at the Perelman School of Medicine at the University of Pennsylvania showed that mutations in two proteins associated with familial Alzheimer's disease (FAD) disrupt the flow of calcium ions within neurons. The two proteins interact with a calcium release channel in an intracellular compartment. Mutant forms of these proteins that cause FAD, but not the normal proteins, result in exaggerated calcium signaling in the cell.
Now, the same team, led by J. Kevin Foskett, PhD, chair of Physiology, and a graduate student, Dustin Shilling, has found that suppressing the hyperactivity of the calcium channels alleviate FAD-like symptoms in mice models of the disease. Their findings appear in the Journal of Neuroscience.
Current therapies for Alzheimer's include drugs that treat the symptoms of cognitive loss and dementia, and drugs that address the pathology of Alzheimer's are experimental. These new observations suggest that approaches based on modulating calcium signaling could be explored, says Foskett.
The two proteins, called PS1 and PS2 (presenilin 1 and 2), interact with a calcium release channel, the inositol trisphosphate receptor (IP3R), in the endoplasmic reticulum. Mutant PS1 and PS2 increase the activity of the IP3R, in turn increasing calcium levels in the cell. "We set out to answer the question: Is increased calcium signaling, as a result of the presenilin-IP3R interaction, involved in the development of familial Alzheimer's disease symptoms, including dementia and cognitive deficits?" says Foskett. "And looking at the findings of these experiments, the answer is a resounding 'yes.'"
Exaggerated intracellular calcium signaling is a robust phenomenon seen in cells expressing FAD-causing mutant presenilins, in both human cells in culture and in mice. The team used two FAD mouse models to look for these connections. Specifically, they found that reducing the expression of IP3R1, the dominant form of this receptor in the brain, by 50 percent, normalized the exaggerated calcium signaling observed in neurons of the cortex and hippocampus in both mouse models.
In addition, using 3xTg mice - animals that contain presenilin 1 with an FAD mutation, as well as expressed mutant human tau protein and APP genes — the team observed that the reduced expression of IP3R1 profoundly decreased amyloid plaque accumulation in brain tissue and the hyperphosphorylation of tau protein, a biochemical hallmark of advanced Alzheimer's disease. Reduced expression of IP3R1 also rescued defective electrical signaling in the hippocampus, as well and memory deficits in the 3xTg mice, as measured by behavioral tests.
"Our results indicate that exaggerated calcium signaling, which is associated with presenilin mutations in familial Alzheimer's disease, is mediated by the IP3R and contributes to disease symptoms in animals," says Foskett. "Knowing this now, the IP3 signaling pathway could be considered a potential therapeutic target for patients harboring mutations in presenilins linked to AD."
The 'Calcium Dysregulation' Hypothesis
"The 'calcium dysregulation' hypothesis for inherited, early-onset familial Alzheimer's disease has been suggested by previous research findings in the Foskett lab. Alzheimer's disease affects as many as 5 million Americans, 5 perfect of whom have the familial form. The hallmark of the disease is the accumulation of tangles and plaques of amyloid beta protein in the brain.
The 'amyloid hypothesis' that postulates that the primary defect is an accumulation of toxic amyloid in the brain has long been used to explain the cause of Alzheimer's," says Foskett. In his lab's 2008 Neuron study, cells that carried the disease-causing mutated form of PS1 showed increased processing of amyloid beta that depended on the interaction of the PS proteins with the IP3R. This observation links dysregulation of calcium inside cells with the production of amyloid, a characteristic feature in the brains of people with Alzheimer's disease.
Clinical trials for AD have largely been directed at reducing the amyloid burden in the brain. So far, says Foskett, these trials have failed to demonstrate therapeutic benefits. One idea is that the interventions started too late in the disease process. Accordingly, anti-amyloid clinical trials are now underway using asymptomatic FAD patients because it is known that they will eventually develop the disease, whereas predicting who will develop the common form of AD is much less certain.
"There has been an assumption that FAD is simply AD with an earlier, more aggressive onset," says Foskett. "However, we don't know if the etiology of FAD pathology is the same as that for common AD. So the relevance of our findings for understanding common AD is not clear. What's important, in my opinion, is to recognize that AD could be a spectrum of diseases that result in common end-stage pathologies. FAD might therefore be considered an orphan-disease, and it's important to find effective treatments, specifically for these patients - ones that target the IP3R and calcium signaling."
Coauthors are Dustin Shilling, Marioly Muller, Hajime Takano, Don-On Daniel Mak, Ted Abel, Douglas A. Coulter, all from Penn.
This work was supported by the National Institute of Mental Health (MH059937) and a National Research Service Award Grant (AG038240)
Shape-shifting Disease Proteins May Explain Variable Appearance of Neurodegenerative Diseases, Penn Study Finds
Targeting Distinct Alpha-synuclein Strains a Potential Treatment Approach.
PHILADELPHIA – Neurodegenerative diseases are not all alike. Two individuals suffering from the same disease may experience very different age of onset, symptoms, severity, and constellation of impairments, as well as different rates of disease progression. Researchers in the Perelman School of Medicine at the University of Pennsylvania have shown one disease protein can morph into different strains and promote misfolding of other disease proteins commonly found in Alzheimer's, Parkinson's and other related neurodegenerative diseases.
Virginia M.Y. Lee, PhD, MBA, professor of Pathology and Laboratory Medicine and director of the Center for Neurodegenerative Disease Research, with co-director, John Q. Trojanowski MD, PhD, postdoctoral fellow Jing L. Guo, PhD, and colleagues, discovered that alpha-synuclein, a protein that forms sticky clumps in the neurons of Parkinson's disease patients, can exist in at least two different structural shapes, or "strains," when it clumps into fibrils, despite having precisely the same chemical composition.
These two strains differ in their ability to promote fibril formation of normal alpha-synuclein, as well as the protein tau, which forms neurofibrillary tangles in individuals with Alzheimer's disease.
Importantly, these alpha-synuclein strains are not static; they somehow evolve, such that fibrils that initially cannot promote tau tangles acquire that ability after multiple rounds of "seeded" fibril formation in test tubes.
The findings appear in the July 3rd issue of Cell.
Morphed Misfolding Proteins Found In Overlapping Neurodegenerative Diseases
Tau and alpha-synuclein protein clumps are hallmarks of separate diseases – Alzheimer's and Parkinson's, respectively. Yet these two proteins are often found entangled in diseased brains of patients who may manifest symptoms of both disorders.
One possible explanation for this convergence of Alzheimer's and Parkinson's disease pathology in the same patient is a global disruption in protein folding. But, Guo and Lee showed that one strain of alpha-synuclein fibrils which cannot promote tau fibrillization actually evolved into another strain that could efficiently cause tau to fibrillize in cultured neurons, although both strains are identical at the amino acid sequence level. Guo and Lee called the starting conformation "Strain A," and the evolved conformation, "Strain B."
To figure out how A and B differ, Guo showed that the two strains folded into different shapes, as indicated by their differential reactivity to antibodies and sensitivity to protein-degrading enzymes. The two strains also differed in their ability to promote tau fibrillization and pathology in mouse brains, mimicking the results from cultured cells. When analyzing post-mortem brains of Parkinson's patients, the team found at least two distinct forms of pathological alpha-synuclein.
Lee and her team speculate that in humans, alpha-synuclein aggregates may shift their shapes as they pass from cell to cell (much like a cube of silly putty being re-shaped to form a sphere), possibly developing the ability to entangle other proteins such as tau along the way. That process, in turn, could theoretically yield distinct types of alpha-synuclein pathologies that are observed in different brain regions of Parkinson's disease patients.
While further research is needed to confirm and extend these findings, they have potentially significant implications for patients afflicted with Parkinson's and other neurodegenerative diseases. For example, Lee explains, they could account for some of the heterogeneity observed in Parkinson's disease. Different strains of pathological alpha-synuclein may promote formation of distinct types of alpha-synuclein aggregates that may or may not induce tau pathology in different brain regions and in different patients. That, in turn, could explain why some Parkinson's patients, for example, experience only motor impairments while others ultimately develop cognitive impairments.
The findings also have potential therapeutic implications, Lee says. By recognizing that pathological alpha-synuclein can exist in different forms that are linked with different impairments, researchers can now selectively target one or the other, or both, for instance with strain-selective antibodies.
"What we've found opens up new areas for developing therapies, and particularly immunotherapies, for Parkinson's and other neurodegenerative diseases," Lee says.
Other study authors are Dustin J. Covell, Joshua P. Daniels, Michiyo Iba, Anna Stieber, Bin Zhang, Dawn M. Riddle, Linda K. Kwong, Yan Xu, all from Penn.
Research funding was provided the National Institute on Aging and the National Institute of Neurological Disease and Stroke (AG017586, NS053488), the Marian S. Ware Alzheimer Program, the Parkinson's Council, the Dr. Arthur Peck Fund, and the Jeff and Anne Keefer Fund.
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