Quantcast

Industry news that matters to you.  Learn more

Smell And Eye Tests Show Potential To Detect Alzheimer’s Early

A decreased ability to identify odors might indicate the development of cognitive impairment and Alzheimer’s disease, while examinations of the eye could indicate the build-up of beta-amyloid, a protein associated with Alzheimer’s, in the brain, according to the results of four research trials reported recently at the Alzheimer’s Association International Conference® 2014 (AAIC® 2014) in Copenhagen.

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!

The Medicines Company and Alnylam Form Strategic Alliance to Develop and Commercialize RNAi Therapeutics Targeting PCSK9 for the Treatment of Hypercholesterolemia

The Medicines Company (Nasdaq: MDCO) and Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, recently announced that they have formed an exclusive global alliance for the development and commercialization of Alnylam’s ALN-PCS RNAi therapeutic program for the treatment of hypercholesterolemia.

“This new alliance unites two organizations with a shared culture and commitment to innovation. In my view and past experience, there could be no stronger partner for our ALN-PCS program than The Medicines Company, which has demonstrated industry-wide leadership in the advancement of cardiovascular medicines to patients and remarkable success in its strategy of in-licensing, developing, and commercializing breakthrough products,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “For Alnylam, this new partnership enables the advancement of ALN-PCS, an important program within our ‘Alnylam 5×15’ product development and commercialization strategy focused on RNAi therapeutics directed toward genetically validated targets. We believe that the ALN-PCS program holds great promise for the development of a significant therapeutic option for patients with hypercholesterolemia, and that the unique mechanism of action for ALN-PCS could provide a differentiated and potentially best-in-class strategy for PCSK9 antagonism.”

“Our focus on acute and intensive care medicine has led us to a leadership position with Angiomax® (bivalirudin) and potentially with cangrelor in the management of patients in extreme risk as a consequence of the rupture of their vulnerable coronary artery plaque at and around the time of acute coronary syndromes. Meantime, we have made progress with MDCO-216 (ApoA-1 Milano), a turbocharged form of HDL-C (‘good cholesterol’) which has the potential to modify disease through reverse cholesterol transport,” said Clive Meanwell, M.D., Ph.D., Chairman and Chief Executive Officer of The Medicines Company. “Now, this exciting collaboration with Alnylam – leaders in their field of RNAi – adds a second potentially disease modifying approach and more cutting edge technology to our portfolio. We have seen that PCSK9 gene silencing can substantially reduce LDL-cholesterol in patients and has epidemiological and disease mechanisms studies suggest this can further reduce the risks of the world’s number one killer, coronary artery disease. Clearly we see the complementarity of approaches which increase ‘good cholesterol’ (HDL-C) and decrease ‘bad cholesterol’ (LDL-C). We look forward to working with our colleagues at Alnylam for whom we have the greatest respect and admiration based upon earlier collaborations particularly around Angiomax, which was invented by John Maraganore.”

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a protein that regulates low-density lipoprotein (LDL) receptor levels on hepatocytes; gain-of-function human mutations in PCSK9 are associated with hypercholesterolemia while loss-of-function mutations are associated with lower levels of LDL cholesterol and a reduced risk of cardiovascular disease. ALN-PCS is a PCSK9 synthesis inhibitor that reduces intracellular and extracellular levels of PCSK9 resulting in lowered plasma levels of LDL-C. MDCO-216 is a naturally occurring variant of a protein found in high-density lipoprotein, or HDL. It is a reverse cholesterol transport agent designed to reduce atherosclerotic plaque burden development and thereby reduce the risk of adverse thrombotic events.

Under this alliance, The Medicines Company and Alnylam intend to collaborate on the advancement of the ALN-PCS program. Alnylam’s ALN-PCS program includes ALN-PCS02 – an intravenously administered RNAi therapeutic which has completed a Phase I trial, and ALN-PCSsc – a subcutaneously administered RNAi therapeutic currently in pre-clinical development. Alnylam will continue the program for an estimated one to two years to complete certain pre-clinical and Phase I clinical studies. The Medicines Company is responsible for leading and funding development from Phase II forward and commercializing the ALN-PCS program if successful. Under the terms of the agreement, The Medicines Company will make an upfront cash payment of $25 million to Alnylam. Alnylam may also receive potential development and commercial milestone payments of up to $180 million. Alnylam will be eligible to receive scaled double-digit royalties on global products sales of ALN-PCS products.

Alnylam has completed a Phase I trial of ALN-PCS02 in healthy volunteer subjects with elevated baseline LDL-C. Results showed that administration of a single intravenous dose of drug, in the absence of concomitant lipid-lowering agents such as statins, resulted in statistically significant and durable reductions of PCSK9 plasma levels of up to 84% and lowering of LDL-C of up to 50%. ALN-PCS02 was shown to be generally safe and well tolerated in this study and there were no serious adverse events related to study drug administration. Alnylam has also presented pre-clinical data from its ALN-PCSsc program demonstrating potent knockdown of the PCSK9 target gene with an ED50 of less than 0.3 mg/kg after a single subcutaneous dose.

“Cardiovascular disease remains the leading cause of mortality worldwide, with elevated LDL-C a major modifiable risk factor. New strategies are needed to dramatically and rapidly reduce LDL-C and prevent acute cardiovascular events that result from the rupture of cholesterol rich plaque when patients are at their most vulnerable,” said Daniel J. Rader, M.D., professor of Medicine and chief, Division of Translational Medicine and Human Genetics, at the Perelman School of Medicine at the University of Pennsylvania. “As a key regulator of the LDL receptor, liver-expressed PCSK9 is one of the most important and best validated new targets in molecular medicine for the treatment of hypercholesterolemia. The ALN-PCS data generated to date are very encouraging and I look forward to continued clinical studies that highlight the unique mechanistic approach of PCSK9 synthesis inhibitors.”

Dr. Rader serves as a member of Alnylam’s Scientific Advisory Board and as a consultant on Alnylam’s ALN-PCS program, and Alnylam and Dr. Rader collaborate on research for which Alnylam provides materials.

Source: The Medicines Company

Shiel Medical Laboratory’s Oxidized LDL Triple Marker Test Uncovers Symptoms of Latent Heart Disease Better than Standard Lipid Test

The primary clinical laboratory test used by physicians to identify patients with coronary artery disease (CAD) fails to measure oxidized low-density lipoprotein (LDL), the plaque-specific protein directly involved in the disease process. A key study demonstrated that nearly half the patients with documented coronary events had LDL cholesterol readings within healthy range, exposing a major weakness in the standard lipid panel and the need for measuring oxidized LDL levels.

Shiel Medical Laboratory’s Oxidized LDL Triple Marker Test is the only blood test that measures oxidized LDL, which reflects atherosclerotic disease activity in the arterial wall. As an identifier of clinical and subclinical CAD, the test is superior to any other laboratory test available to assess patient risk of cardiovascular disease, which kills 400,000 Americans annually and costs $110 billion in medical services and lost productivity.

“Research studies show measuring LDL cholesterol alone is insufficient to determine whether a patient is at risk for heart attack or stroke,” said Shiel Medical Laboratory Technical Services Director, Harold M. Bates, Ph.D., who was involved in the commercial development of the oxidized LDL test. “Oxidized LDL as a biomarker test could easily become the successor to the regular LDL test because of its greater clinical efficacy.”

Shiel’s Oxidized LDL Triple Marker Test overcomes the weaknesses of conventional lipid tests by measuring oxidized LDL, a plaque-specific protein. Oxidized LDL is the atherogenic form of LDL cholesterol linked to the deposition of plaque in the artery walls. The CAD disease process depends on the oxidation of LDL, making oxidized LDL the primary culprit molecule in cardiovascular disease.

In addition to oxidized LDL, the Oxidized LDL Triple Marker Test measures two additional biomarkers linked to CAD: HDL cholesterol, an anti-atherogenic substance that inhibits the disease-causing action of oxidized LDL; and high-sensitivity C-reactive protein (hs-CRP), an independent biomarker that at certain lower levels is associated with cardiovascular disease.

Like oxidized LDL, hs-CRP is not included in the standard lipid panel even though elevated oxidized LDL and chronically elevated hs-CRP may explain why half of all patients hospitalized with CAD have lipid readings that appear normal.(1)

In published medical studies assessing known and emerging lipid biomarkers, oxidized LDL measurements rendered the most accurate snapshot of CAD risk. A 2006 study of 921 subjects, including 490 CAD patients and 431 healthy individuals in the control group, compared the relative potency of oxidized LDL to LDL cholesterol in identifying patients with CAD.(2 )Oxidized LDL showed a six-fold ability over LDL cholesterol in indicating disease. Measuring the oxidized LDL/HDL ratio and adding hs-CRP levels to round out the Triple Marker profile produced a 16-fold ability over LDL cholesterol in identifying CAD disease.

“Every physician needs to know that standard lipid panels do not measure elevated oxidized LDL even in patients with low to moderate LDL. I’m certain more patients would request the Oxidized LDL test if they knew how much more effective it is in detecting CAD than the standard LDL test,” said Charles Mitgang, M.D., an internist in Rockville Centre, N.Y. “The test has become part of my routine in identifying, treating and monitoring patients who are at risk for CAD.”

Shiel Medical Laboratory is the first and only laboratory to develop the automated Oxidized LDL Test and establish reference ranges allowing physicians to better interpret results. Shiel introduced the test in 2006, following lab validation and approval by the New York State Department of Health. The laboratory exhibits annually at Scientific Sessions for the American Heart Association and the American College of Cardiology and researchers and clinicians have embraced this lipid biomarker test as a much-needed addition to the cardiac disease prevention arsenal.

Source: PR Newswire