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So My Brain Amyloid Level is “Elevated”—What Does That Mean?

Testing drugs to prevent or delay the onset of Alzheimer’s dementia and using them in the clinic will mean identifying and informing adults who have a higher risk of Alzheimer’s but are still cognitively normal. A new study from the Perelman School of Medicine at the University of Pennsylvania has shed light on how seniors cope with such information.

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

Elevated Levels of Copper in Amyloid Plaques Associated with Neurodegeneration in Mouse Models of AD

Metals such as iron, copper, and zinc are important for many biological processes. In recent years, studies have shown that these nutritionally-essential metals are elevated in human Alzheimer’s disease (AD) brains and some animal models of AD. Scientists are now exploring whether these metals are causing the neurodegeneration seen in AD or are indicative of other ongoing pathologic processes.

In a new study, investigators used synchrotron x-ray fluorescence microscopy to image metal ions in the brain, focusing on the amyloid plaques that are the hallmark of AD. They found that, in two AD mouse models that exhibit neurodegeneration, the plaques contained about 25% more copper than an AD mouse model that shows little neurodegeneration. Looking at other metals, they found that none of the mouse models had significant increases in iron and very little increases in zinc. Metal content was not related to the age of the plaque. The study is reported in the current issue of Biomedical Spectroscopy and Imaging.

“Since excess copper should not be ‘free’ in the brain to bind to the plaques, these data suggest that the cellular control of copper is altered in AD, which may lead to toxic reactions between free copper ions and neurons,” comments lead investigator Lisa M. Miller, PhD, a biophysical chemist in the Photon Sciences Directorate at Brookhaven National Laboratory. In previous work, Dr. Miller’s group found very high levels of copper in human AD plaques.

Since elevated iron in the AD brain is well documented in both human brains and AD mouse models, the researchers measured iron content in the cortex of all three mouse models. They found that iron content was doubled in all AD mouse model cortices compared to controls, whether or not the models showed neurodegeneration. Upon further investigation, spectroscopic data revealed that the excess iron was present in the ferric (oxidized) state and consistent with the iron storage protein ferritin. “The increase in iron may be a reflection of changes in metalloprotein content and metal storage within the brain that is not well understood,” says Dr. Miller.

Nevertheless, since iron in ferromagnetic and detectable through MRI, Dr. Miller suggests that in the future iron may be used as a biomarker for AD at early stages of disease, even before plaques are formed.

Source: Elevated copper in the amyloid plaques and iron in the cortex are observed in mouse models of Alzheimer’s disease that exhibit neurodegeneration [Biomedical Spectroscopy and Imaging]

Source: EurekAlert!

Path of Plaque Buildup in Brain Shows Promise as Early Biomarker for Alzheimer’s Disease

The trajectory of amyloid plaque buildup—clumps of abnormal proteins in the brain linked to Alzheimer’s disease—may serve as a more powerful biomarker for early detection of cognitive decline rather than using the total amount to gauge risk, researchers from Penn Medicine’s Department of Radiology suggest in a new study published online July 15 in Neurobiology of Aging.

Amyloid plaque that starts to accumulate relatively early in the temporal lobe, compared to other areas and in particular to the frontal lobe, was associated with cognitively declining participants, the study found. “Knowing that certain brain abnormality patterns are associated with cognitive performance could have pivotal importance for the early detection and management of Alzheimer’s,” said senior author Christos Davatzikos, PhD, professor in the Department of Radiology, the Center for Biomedical Image Computing and Analytics, at the Perelman School of Medicine at the University of Pennsylvania.

Today, memory decline and Alzheimer’s—which 5.4 million Americans live with today—is often assessed with a variety of tools, including physical and bio fluid tests and neuroimaging of total amyloid plaque in the brain. Past studies have linked higher amounts of the plaque in dementia-free people with greater risk for developing the disorder. However, it’s more recently been shown that nearly a third of people with plaque on their brains never showed signs of cognitive decline, raising questions about its specific role in the disease.

Now, Dr. Davatzikos and his Penn colleagues, in collaboration with a team led by Susan M. Resnick, PhD, Chief, Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA), used Pittsburgh compound B (PiB) brain scans from the Baltimore Longitudinal Study of Aging’s Imaging Study and discovered a stronger association between memory decline and spatial patterns of amyloid plaque progression than the total amyloid burden.

“It appears to be more about the spatial pattern of this plaque progression, and not so much about the total amount found in brains. We saw a difference in the spatial distribution of plaques among cognitive declining and stable patients whose cognitive function had been measured over a 12-year period. They had similar amounts of amyloid plaque, just in different spots,” Dr. Davatzikos said. “This is important because it potentially answers questions about the variability seen in clinical research among patients presenting plaque. It accumulates in different spatial patterns for different patients, and it’s that pattern growth that may determine whether your memory declines.”

The team, including first author Rachel A. Yotter, PhD, a postdoctoral researcher in the Section for Biomedical Image Analysis, retrospectively analyzed the PET PiB scans of 64 patients from the NIA’s Baltimore Longitudinal Study of Aging whose average age was 76 years old. For the study, researchers created a unique picture of patients’ brains by combining and analyzing PET images measuring the density and volume of amyloid plaque and their spatial distribution within the brain. The radiotracer PiB allowed investigators to see amyloid temporal changes in deposition.

Those images were then compared to California Verbal Learning Test (CLVT) scores, among other tests, from the participants to determine the longitudinal cognitive decline. The group was then broken up into two subgroups: the most stable and the most declining individuals (26 participants).

Despite lack of significant difference in the total amount of amyloid in the brain, the spatial patterns between the two groups (stable and declining) were different, with the former showing relatively early accumulation in the frontal lobes and the latter in the temporal lobes.

A particular area of the brain may be affected early or later depending on the amyloid trajectory, according to the authors, which in turn would affect cognitive impairment. Areas affected early with the plaque include the lateral temporal and parietal regions, with sparing of the occipital lobe and motor cortices until later in disease progression.

“This finding has broad implications for our understanding of the relationship between cognitive decline and resistance and amyloid plaque location, as well as the use of amyloid imaging as a biomarker in research and the clinic,” said Dr Davatzikos. “The next step is to investigate more individuals with mild cognitive impairment, and to further investigate the follow-up scans of these individuals via the BLSA study, which might shed further light on its relevance for early detection of Alzheimer’s.”

Study: Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden

Source: EurekAlert!