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As Michael J. Fox Returns to Primetime, His Research Foundation Urgently Pursues the Cure for Parkinson’s

Last month, Michael J. Fox returned to television as the star of his own sitcom after more than two decades living with Parkinson’s disease. Fox’s decision to return to primetime has injected Parkinson’s into the national conversation — a conversation already transformed by The Michael J. Fox Foundation for Parkinson’s Research (MJFF), which the actor launched in 2000 with the exclusive goal of funding research to speed a cure for the disease.

Researchers Agree that Alzheimer’s Test Results Could be Released to Research Participants

A leading group of Alzheimer’s researchers contends that, as biomarkers to detect signals of the disease improve at providing clinically meaningful information, researchers will need guidance on how to constructively disclose test results and track how disclosure impacts both patients and the data collected in research studies. A survey conducted by a group including experts from the Perelman School of Medicine at the University of Pennsylvania found that a majority of Alzheimer’s researchers supported disclosure of results to study participants. The study is published online in Neurology.

“While this is not a call to immediately tell subjects their biomarker results, it does show that the field is moving to a point where experts want to share valid and meaningful results with participants,” said co-senior author Jason Karlawish, MD, professor of Medicine and Medical Ethics and Health Policy. “As we gain more data on the predictive abilities of these measurements, we will need models and methods to effectively reveal results.”

The study surveyed 139 Alzheimer’s clinical trial leaders and coordinators from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) in April 2012, just before the U.S. Food and Drug Administration approved the amyloid-binding radiotracer known as Amyvid (florbetapir). 73 percent of respondents supported disclosing amyloid imaging results to study participants with mild cognitive impairment, whereas 58 percent supported giving amyloid imaging results to those with normal cognition.

Six themes emerged from the survey, regarding participant preferences and cognition levels, researchers’ requests to develop standardized counseling procedures, participant education, and standardization of data-gathering, and concerns regarding potential harms and benefits to participants, as well as the ways disclosure could impact study results.

Currently, ADNI has a policy to not disclose results to participants, but the survey showed a growing trend of experts who would favor revising this policy. In addition to finding amyloid imaging results valuable, Alzheimer’s experts also valued other biomarker data collected in ADNI, such as spinal fluid tests, PET imaging, and other psychometric tests, suggesting that if amyloid imaging results were allowed to be disclosed, it would likely lead to disclosure of other test results.

Study: Using AD biomarker research results for clinical care [Neurology] 

Source: EurekAlert!

Comprehensive Parkinson’s Biomarker Test Has Prognostic and Diagnostic Value, Penn Medicine Team Reports

Perelman School of Medicine researchers at the University of Pennsylvania report the first biomarker results reported from the Parkinson’s Progression Markers Initiative (PPMI), showing that a comprehensive test of protein biomarkers in spinal fluid have prognostic and diagnostic value in early stages of Parkinson’s disease. The study is reported in JAMA Neurology.

Compared to healthy adults, the study found that people with early Parkinson’s had lower levels of amyloid beta, tau and alpha synuclein in their spinal fluid. In addition, those with lower concentrations of tau and alpha synuclein had greater motor dysfunction. And early Parkinson’s patients with low levels of amyloid beta and tau were more likely to be classified as having the postural instability-gait disturbance- dominant (PIGD) motor type of disease, where falling, freezing, and walking difficulty are common.

“Biomarkers for Parkinson’s disease such as these could help us diagnose patients earlier, and we’ve now shown that the simultaneous measurement of a variety of neurodegenerative disease proteins is valuable,” said study senior author Leslie M. Shaw, PhD, professor of Pathology and Laboratory Medicine at Penn Medicine. Dr. Shaw and John Q. Trojanowski, MD, PhD, director of the Penn Udall Center for Parkinson’s Research, are co-leaders of the Bioanalytics Core for the Parkinson’s Progression Markers Initiative, an international observational clinical study sponsored by The Michael J. Fox Foundation for Parkinson’s Research.

The team evaluated spinal fluid collected from baseline visits of the first 102 PPMI participants – 63 with early, untreated Parkinson’s disease and 39 healthy controls. The spinal fluid was evaluated for levels of five biomarkers: amyloid beta, total tau, phosphorylated tau, alpha synuclein and the ratio of total tau to amyloid beta. Spinal fluid measures of amyloid and tau are currently used in research to distinguish Alzheimer’s disease from other neurodegenerative diseases. In contrast to Alzheimer’s, where tau levels are higher than healthy controls, the study found that early Parkinson’s patients had lower levels of tau than healthy controls. One reason, researchers suggest, could be that interactions between tau and alpha synuclein may limit the release of tau into the cerebrospinal fluid of Parkinson’s patients.

“Through PPMI, we are hoping to identify subgroups of Parkinson’s patients whose disease is likely to progress at a different rate, as early as possible,” said Dr. Trojanowski. “Early prediction is critical, for both motor and dementia symptoms.”

The Parkinson’s PIGD motor subtype has been associated with a more rapid cognitive decline as well as greater functional disability. Using the biomarker test, this initial study found that levels of all spinal fluid biomarkers were lower in the PIGD motor subtype than other types of PD as well as healthy controls. In addition, amyloid beta and phosphorylated tau were at lower levels in the PIGD motor subtype, but were no different in tremor or indeterminate subtypes compared to normal controls.

This spinal fluid testing procedure is only being used in research studies, and will be continued to be evaluated and validated in a larger study of the PPMI cohorts.

In addition to leading the Bioanalytics Core of PPMI, Penn’s Parkinson’s Disease and Movement Disorders Center is one of the two dozen trial sites where volunteers are evaluated throughout the PPMI study. The Penn PDMDC has been part of the PPMI group studying people with early Parkinson’s disease as well as healthy adults since 2010, and began enrollment for a new, pre-symptomatic arm of the study in the summer of 2013. The pre-motor arm of PPMI is enrolling participants who do not have Parkinson’s disease and are living with one of three potential risk factors for PD: a reduced sense of smell (hyposmia); rapid eye movement sleep behavior disorder (RBD; a disorder in which the individual acts out his/her dreams); or a mutation in the LRRK2 gene (the single greatest genetic contributor to PD known to date).

“In addition to biomarker tests, validating risk factors could enable earlier detection of the disease and open new avenues in the quest for therapies that could slow or stop disease progression,” said PPMI trial site study leader Matthew Stern, MD, professor of Neurology and director of Penn’s Parkinson’s Disease and Movement Disorders Center.

Study: Association of Cerebrospinal Fluid β-Amyloid 1-42, T-tau, P-tau181, and α-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease [JAMA Neurology]

Source: Penn Medicine

Spinal Fluid Biomarkers of AD and Brain Functional Network Integrity on Imaging Studies

Both Aß and tau pathology appear to be associated with default mode network integrity before clinical onset of Alzheimer disease (AD), according to a study by Liang Wang, M.D., and colleagues at Washington University in St. Louis, Missouri.

Accumulation of Aß and tau proteins, the pathologic hallmarks of AD, starts years before clinical onset. Pathophysiological abnormalities in the preclinical phase of AD may be detected using cerebrospinal fluid (CSF) or neuroimaging biomarkers, according to the study background.

A total of 207 older adults with normal cognition participated in the cross-sectional group study. Researchers examined the relationship between default mode network integrity and cerebrospinal fluid biomarkers of Alzheimer disease pathology in cognitively normal older individuals using resting-state functional connectivity magnetic resonance imaging.

According to the study results, decreased cerebrospinal fluid Aß42 and increased cerebrospinal fluid phosphorylated tau181 were independently associated with reduced default mode network integrity, with the most prominent decreases in functional connectivity observed between the posterior cingulate and medial temporal regions (regions of the brain associated with memory). Observed reductions in functional connectivity were unattributable to age or structural atrophy in the posterior cingulate and medial temporal areas.

Study: Cerebrospinal Fluid Aβ42, Phosphorylated Tau181, and Resting-State Functional Connectivity [JAMA Neurology]

Source: EurekAlert!

New Biomarker Could Reveal Alzheimer’s Disease Years Before Onset

A study published recently reported the identification of what may be the earliest known biomarker associated with the risk of developing Alzheimer’s disease (AD). The results suggest that this novel potential biomarker is present in cerebral spinal fluid (CSF) at least a decade before signs of dementia manifest.

“If our initial findings can be replicated by other laboratories, the results will change the way we currently think about the causes of Alzheimer’s disease,” said Dr. Ramon Trullas, research professor at the CSIC Institute of Biomedical Research of Barcelona and lead author of the study that was published in Annals of Neurology. “This discovery may enable us to search for more effective treatments that can be administered during the preclinical stage.”

Difficult Diagnosis

Alzheimer’s disease affects more than five million Americans and is the sixth leading cause of death in the United States. At present, the only way to accurately diagnose the disease is by post-mortem neuropathological analysis. The relationship of currently known biomarkers with the cause of the disease is unclear, making it nearly impossible to diagnose preclinical stages of the disease with any real certainty.

The CSIC researchers demonstrated that a decrease in the content of mitochondrial DNA (mtDNA) in CSF may be a preclinical indicator for Alzheimer’s disease; furthermore, there may be a directly causative relationship. The hypothesis is that decreased mtDNA levels in CSF reflect the diminished ability of mitochondria to power the brain’s neurons, triggering their death. The decrease in the concentration of mtDNA precedes the appearance of well-known biochemical Alzheimer’s biomarkers (the Aβ1-42, t-tau, and p-tau proteins), suggesting that the pathophysiological process of Alzheimer’s disease starts earlier than previously thought and that mtDNA depletion may be one of the earliest predictors for the disease.

In addition to enabling an investigation of the potential causal relationship of mtDNA and Alzheimer’s progression, the use of mtDNA as an index of preclinical Alzheimer’s disease provides an important advantage over previous biochemical markers: the detection of this novel nucleic acid biomarker is unhampered by the technical difficulties associated with protein detection. mtDNA can be readily quantified by real-time quantitative PCR (qPCR) or droplet digital PCR (ddPCR).

Quantitation of mtDNA

Prior to this study, researchers had not reported that circulating cell-free mtDNA could be detected in human CSF. But with this study, Dr. Trullas’ team was able to both detect and reproducibly quantitate mtDNA using qPCR, carefully optimized by adhering to the MIQE guidelines.

To validate their qPCR findings, Dr. Trullas’ team used Bio-Rad Laboratories’ QX100™ Droplet Digital™ PCR system. Unlike qPCR assays, the QX100 system provides an absolute quantification of target DNA molecules without the need for a standard curve. In addition, an important factor for their CSF analysis was that the Droplet Digital PCR system did not require sample purification to remove PCR inhibitors, as is necessary for qPCR assays.

“Droplet Digital PCR allowed us to validate our initial qPCR measurements because it provides absolute quantitation at the single-molecule level without relying on a standard curve,” said Dr. Trullas. “As the technology becomes more widely adopted, we anticipate that Droplet Digital PCR will be the future of detecting mtDNA in cerebral spinal fluid.”

Dr. Trullas hopes that other laboratories and hospitals will successfully replicate his group’s research results, confirming that reduced mtDNA levels should be investigated as a possible cause of Alzheimer’s disease. By finding a way to block this degeneration, clinicians may be able to diagnose and treat Alzheimer’s disease before symptoms appear.

Study: Low CSF concentration of mitochondrial DNA in preclinical Alzheimer’s disease [Annals of Neurology]

Source: Bio-Rad