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Saturday, March 30, 2013

Semantic Processing - Impaired early in MCI and Dementias

Since semantic processing has its seat in the left temporal lobe this may be a useful way to assess impairment in people with FTD at early stages where most of the tests used for Alzheimer's are inconclusive. We certainly need better methods of assessment. Not only for diagnosis, but also for
The left temporal lobe is about "here".
determining any benefits of medications in trials. Most of the tests currently used fail to differentiate changes in people with FTD because they were developed specifically to test Alzheimer's symptoms which in the early stages of the diseases are very different.

MANHASSET, NY -- People who study or treat Alzheimer’s disease and its earliest clinical stage, mild cognitive impairment (MCI), have focused attention on the obvious short-term memory problems. But a new study suggests that people on the road to Alzheimer’s may actually have problems early on in processing semantic or knowledge-based information, which could have much broader implications for how patients function in their lives.

Terry Goldberg, PhD, a professor of psychiatry and behavioral science at the Hofstra North Shore-LIJ School of Medicine and director of neurocognition at the Litwin Zucker Center for Research in Alzheimer's Disease and Memory Disorders at The Feinstein Institute for Medical Research in Manhasset, NY, said that clinicians have observed other types of cognitive problems in MCI patients but no one had ever studied it in a systematic way. Many experts had noted individuals who seemed perplexed by even the simplest task. In this latest study, published in this month's issue of the American Journal of Psychiatry, investigators used a clever series of tests to measure a person’s ability to process semantic information.

Do people with MCI have trouble accessing different types of knowledge? Are there obvious semantic impairments that have not been picked up before? The answer was "yes."

In setting out to test the semantic processing system, Dr. Goldberg and his colleagues needed a task that did not involve a verbal response. That would only confuse things and make it harder to interpret the results. They decided to use size to test a person’s ability to use semantic information to make judgments between two competing sets of facts. “If you ask someone what is bigger, a key or an ant, they would be slower in their response than if you asked them what is bigger, a key or a house,” explained Dr. Goldberg. The greater the difference in size between two objects, the faster a person -- normal or otherwise -- can recognize the difference and react to the question.

Investigators brought in 25 patients with MCI, 27 patients with Alzheimer's and 70 cognitively fit people for testing. They found large differences between the healthy controls and the MCI and Alzheimer's patients. “This finding suggested that semantic processing was corrupted,” said Dr. Goldberg. “MCI and AD (Alzheimer's disease) patients are really affected when they are asked to respond to a task with small size differences."

They then tweaked the task by showing pictures of a small ant and a big house or a big ant and a small house. This time, the MCI and AD patients did not have a problem with the first part of the test -- they were able to choose the house over the ant when asked what was bigger. But if the images were incongruent – the big ant seemed just as big as the small house – they were confused, they answered incorrectly or took longer to arrive at a response.

Patients with MCI were functioning somewhere between the healthy people and those with AD. “When the decision was harder, their reaction time was slower,” he said.

Would this damaged semantic system have an effect on everyday functions? To answer this question, investigators turned to the UCSD Skills Performance Assessment scale, a tool that they have been using in MCI and AD patients that is generally used to identify functional deficits in patients with schizophrenia. The test taps a person’s ability to write a complex check or organize a trip to the zoo on a cold day.

This is actually a good test for figure out whether someone has problems with semantic knowledge. Semantic processing has its seat in the left temporal lobe. “The semantic system is organized in networks that reflect different types of relatedness or association,” the investigators wrote in their study. “Semantic items and knowledge have been acquired remotely, often over many repetitions, and do not reflect recent learning.”

Dr. Goldberg said the finding is critically important because it may be possible to strengthen these semantic processing connections through training. “It tells us that something is slowing down the patient and it is not episodic memory but semantic memory," he said. They will continue to study these patients over time to see if these semantic problems get worse as the disease advances.

In an accompanying editorial, David P. Salmon, PhD, of the Department of Neurosciences at the University of California in San Diego, said that the “semantic memory deficit demonstrated by this study adds confidence to the growing perception that subtle decline in this cognitive domain occurs in patients with amnestic mild cognitive impairment. Because the task places minimal demands on the effortful retrieval process, overt word retrieval, or language production, it also suggests that this deficit reflects an early and gradual loss of integrity of semantic knowledge.”

He added that a “second important aspect of this study is the demonstration that semantic memory decrements in patients with mild cognitive impairment may contribute to a decline in the ability to perform usual activities of daily living.”

Thursday, March 14, 2013

Why There Are No Approved Treatments For bvFTD: Regulatory Innovation and Drug Development

Though not specifically about bvFTD, this article should apply to all drugs being approved for use in treating early stages of dementia, no matter what flavor.

Regulatory Innovation and Drug Development for Early-Stage Alzheimer's Disease

Nicholas Kozauer, M.D., and Russell Katz, M.D.
March 13, 2013DOI: 10.1056/NEJMp1302513
In reviewing new-drug applications for the treatment of Alzheimer's disease, the Food and Drug Administration (FDA) has maintained that claims of improved cognition should be accompanied by evidence of improvement in function. However, the premise that effective cognitive improvement will be manifested in the functional assessment of patients is untenable in the case of early-stage Alzheimer's disease, which is increasingly the target of drug-development efforts. We simply do not yet have drug-development tools that are validated to provide measures of function in patients with Alzheimer's disease before the onset of overt dementia. Improvement in function, moreover, could lag substantially behind cognitive improvement mediated by pharmacologic agents early in the course of the disease. In view of the devastating effects of this disease on patients and their families, along with its growing prevalence, innovative approaches to trial design and end-point selection are urgently needed, especially as the drug-development community turns its sights on early stages of the disease.

The current landscape of research and drug development in Alzheimer's disease offers a study in contrasts. On the positive side, numerous discoveries over the past decade have begun to unmask complex pathophysiological processes that underlie disease progression. Such advances have, in part, resulted from large, well-organized observational studies, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), that have elucidated various disease biomarkers that reflect, or even predict, the progression of disease. On the negative side, drug discovery has been disappointing. Despite all best efforts to translate mechanistic insights concerning Alzheimer's disease into new drug products, several candidate agents have failed to demonstrate efficacy in large, well-designed, phase 3 clinical trials of late-stage disease.

The hallmark pathological feature of Alzheimer's disease is the presence of brain plaques, consisting primarily of β-amyloid peptide aggregates. Accordingly, the abnormal production and aggregation of β-amyloid peptide, associated particularly with late-stage disease, has been the principal target of many drug-development efforts, including the recent phase 3 efforts that failed to result in new drug products. To account for these disappointing results of trials involving patients with overt dementia, a leading theory posits that the attempts at intervention may have been made too late in the progression of disease, at a stage when neuronal damage had become too widespread. According to some models, levels of β-amyloid peptide in the brain reach a plateau before the earliest symptoms of Alzheimer's disease are apparent.1 A further hurdle to interpreting clinical failures is our limited understanding of how β-amyloid production may contribute to the pathophysiology of the disease. Because the biologic role of β-amyloid peptides is uncertain, researchers are also investigating alternative targets of intervention at various stages of progression.

The focus of drug development in Alzheimer's disease has increasingly been earlier disease stages, before overt dementia. This refinement of focus, however, raises important new challenges because the subtleties of cognitive impairment in patients with early-stage Alzheimer's can be difficult to assess. Moreover, the range of focus must extend to healthy people who are merely at risk for the disease but could benefit from preventive therapies. In recognition of these shifting challenges, the FDA has developed guidance for the design and execution of clinical trials involving patients who do not present with dementia.
One aspect of the FDA guidance covers the selection of patients for trials in early-stage Alzheimer's disease. In particular, we have acknowledged the consensus emerging within the Alzheimer's research community that clinical diagnosis of early cognitive impairment might be paired productively with appropriate biomarkers of disease — criteria that have been delineated and are being validated by various working groups. Such biomarkers might include brain amyloid load (e.g., as measured by positron-emission tomography) and cerebrospinal fluid levels of β-amyloid and tau proteins. Ongoing efforts by the research community to qualify biomarkers in clinical trial designs and methods for enriching study populations with patients with early-stage Alzheimer's disease reflect important FDA priorities.

A specific suggestion that is also offered in the agency's guidance for trials focusing on patients in whom overt dementia seems imminent is the use of a single scale that combines assessment of both cognition and function, such as the score on the Clinical Dementia Rating Sum of Boxes (CDR-SB), which rates patients on a series of six domains covering various aspects of cognition and daily functioning. For patients whose disease is at an even earlier clinical stage, so that functional impairment would be more difficult to assess, it might be feasible to approve a drug through the FDA's accelerated approval pathway on the basis of assessment of cognitive outcome alone. The accelerated-approval mechanism allows drugs that address an unmet medical need to be approved on the basis of a surrogate end point or an intermediate clinical end point (e.g., a sensitive cognitive measure), with the stipulation that postapproval studies will be conducted to verify the clinical benefit. Such a regulatory process may hold promise for facilitating the approval of treatments that appear to be effective in early Alzheimer's disease, when patients might be expected to derive the greatest benefit.

Despite our growing understanding of the relationship between various disease-based biomarkers and the clinical course of Alzheimer's disease, it remains unclear whether the effect of a drug on one or more such biomarkers can actually predict a meaningful clinical benefit. This concern was reinforced by the recent phase 3 trials of amyloid-lowering agents that failed to improve cognition despite appearing to interact with putative targets in the brain. It remains possible that an effect of an intervention on one or more biomarkers could someday be accepted as predictive of a clinical benefit, but further research will clearly be needed before the effect of an intervention on a single biomarker alone could be considered an adequate surrogate measure for the purposes of accelerated approval of a candidate drug for early Alzheimer's disease.

As the focus of drug development has shifted to earlier stages of Alzheimer's disease, many new and challenging scientific questions have emerged, and the regulatory framework under which such therapies are evaluated should evolve accordingly. The FDA remains committed to innovative approaches to the evaluation of drugs that are in clinical development. Effective treatments for the devastating disorder that is Alzheimer's disease are urgently needed, as the world's population continues to age.

Wednesday, March 6, 2013

Green Tea Extract Interferes With the Formation of Amyloid Plaques in Alzheimer's Disease

Though this article is specifically dealing with Alzheimer's rather than bvFTD, anything which dissolves or interferes with plaques or protein aggregation is of interest. This just published on Science Daily:

Green Tea Extract Interferes With the Formation of Amyloid Plaques in Alzheimer's Disease

Mar. 5, 2013 — Researchers at the University of Michigan have found a new potential benefit of a molecule in green tea: preventing the misfolding of specific proteins in the brain.

The aggregation of these proteins, called metal-associated amyloids, is associated with Alzheimer's disease and other neurodegenerative conditions.

A paper published recently in the Proceedings of the National Academy of Sciences explained how U-M Life Sciences Institute faculty member Mi Hee Lim and an interdisciplinary team of researchers used green tea extract to control the generation of metal-associated amyloid-β aggregates associated with Alzheimer's disease in the lab.

The specific molecule in green tea, ( -- )-epigallocatechin-3-gallate, also known as EGCG, prevented aggregate formation and broke down existing aggregate structures in the proteins that contained metals -- specifically copper, iron and zinc.

"A lot of people are very excited about this molecule," said Lim, noting that the EGCG and other flavonoids in natural products have long been established as powerful antioxidants. "We used a multidisciplinary approach. This is the first example of structure-centric, multidisciplinary investigations by three principal investigators with three different areas of expertise."

The research team included chemists, biochemists and biophysicists.
While many researchers are investigating small molecules and metal-associated amyloids, most are looking from a limited perspective, said Lim, assistant professor of chemistry and research assistant professor at the Life Sciences Institute, where her lab is located and her research is conducted.
"But we believe you have to have a lot of approaches working together, because the brain is very complex," she said.

The PNAS paper was a starting point, Lim said, and her team's next step is to "tweak" the molecule and then test its ability to interfere with plaque formation in fruit flies.
"We want to modify them for the brain, specifically to interfere with the plaques associated with Alzheimer's," she said.

Lim plans to collaborate with Bing Ye, a neurobiologist in the LSI. Together, the researchers will test the new molecule's power to inhibit potential toxicity of aggregates containing proteins and metals in fruit flies.

Other authors of the paper, all from U-M, are: Sanghyun Lee and Jung-Suk Choi of the Life Sciences Institute; Alaina DeToma, Suk-Joon Hyung, Akiko Kochi and Brandon Ruotoloa of the Department of Chemistry; and Jeffrey Brender, Ayyalusamy Ramamoorthy and Subramanian Vivekanandan of the Department of Chemistry and Biophysics.

The work was supported by the National Institutes of Health, Alzheimer's Association, Alzheimer's Art Quilt Initiative, American Heart Association, and a Graduate Research Fellowship from the National Science Foundation Study.

University of Michigan (2013, March 5). Green tea extract interferes with the formation of amyloid plaques in Alzheimer's disease. ScienceDaily. Retrieved March 6, 2013, from http://www.sciencedaily.com­ /releases/2013/03/130305145137.htm