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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.

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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).

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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.

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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.

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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.

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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.'"

Robust Phenomenon

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)

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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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