Beta amyloid

How Coconut Oil May Rescue The Brain From Alzheimer’s Disease.

Posted by

0


A promising new study soon to be published in the Journal of Alzheimer’s Disease titled, “Coconut Oil Attenuates the Effects of Amyloid-β on Cortical Neurons In Vitro.“[i]  The study lends fresh experimental support to an accumulating body of anecdotal reports that coconut oil may alleviate and/or regress cognitive deficits associated with aging and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s.


Medical researchers from the Memorial University of Newfoundland, St. John’s, NL, Canada, undertook a pilot study to investigate the effects of coconut oil supplementation directly on cortical neurons treated with amyloid-β (Aβ) peptide in vitro.  Aβ peptide is the main component of certain deposits found in the brains of patients with Alzheimer’s disease believed to contribute to the disease.

The researchers noted that a recent clinical trial, which we reported on in our article MCT Fats Found in Coconut Oil Boost Brain Function in Only One Dose, reported significant improvements in Alzheimer’s disease patients after 45 and 90 days of treatment with medium chain triglycerides from coconut oil.  They pointed out that this trial led to the marketing of the FDA-approved ‘medical food’ caprylidene (trade name Axona), but that the public has shown greater interest in coconut oil itself as a potential therapy, owing to its far greater affordability and availability.

The researchers sought to test the hypothesis that coconut oil is beneficial for neurodegenerative conditions using a cell model.  Live rat neurons were exposed to various combinations of Aβ peptide and coconut oil, with the result that Aβ peptide reduced survival of neurons and coconut protected against this Aβ-induced reduction in survival time.  The researchers noted that coconut treated Aβ cultured neurons appeared “healthier,” and that coconut oil “rescued” Aβ-treated neurons from mitochondrial damage caused by their toxicity.  The researchers observed coconut oil preventing Aβ-induced changes in mitochondrial size and circularity. These findings have great significance, as mitochondria function is often compromised in the brains of Alzheimer’s disease patients.

According to the researchers, “The rationale for using coconut oil as a potential AD [Alzheimer’s Disease] therapy is related to the possibility that it could be metabolized to ketone bodies that would provide an alternative energy source for neurons, and thus compensate for mitochondrial dysfunction.”  The researchers proposed that ketone bodies formed as a byproduct of coconut oil metabolism may offset Aβ-induced impairment of mitochondrial function and thus energy metabolism.  Considering that the medium chain triglyceride found in coconut known as caprylic acid does cross the blood-brain barrier, and has recently been found to have anti-convulsant, in addition to, ketogenic effects, coconut oil likely does have a neuroprotective effect.

 

Continue reading at greenmedinfo.com

Shorter Sleep Duration and Poorer Sleep Quality Linked to Alzheimer’s Disease Biomarker.

Posted by

0


Poor sleep quality may impact Alzheimer’s disease onset and progression. This is according to a new study led by researchers at the Johns Hopkins Bloomberg School of Public Health who examined the association between sleep variables and a biomarker for Alzheimer’s disease in older adults. The researchers found that reports of shorter sleep duration and poorer sleep quality were associated with a greater β-Amyloid burden, a hallmark of the disease. The results are featured online in the October issue of JAMA Neurology.

“Our study found that among older adults, reports of shorter sleep duration and poorer sleep quality were associated with higher levels of β-Amyloid measured by PET scans of the brain,” said Adam Spira, PhD, lead author of the study and an assistant professor with the Bloomberg School’s Department of Mental Health. “These results could have significant public health implications as Alzheimer’s disease is the most common cause of dementia, and approximately half of older adults have insomnia symptoms.”

Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills. According to the National Institutes of Health, as many as 5.1 million Americans may have the disease, with first symptoms appearing after age 60. Previous studies have linked disturbed sleep to cognitive impairment in older people.

In a cross-sectional study of adults from the neuro-imagining sub-study of the Baltimore Longitudinal Study of Aging with an average age of 76, the researchers examined the association between self-reported sleep variables and β-Amyloid deposition. Study participants reported sleep that ranged from more than seven hours to no more than five hours. β-Amyloid deposition was measured by the Pittsburgh compound B tracer and PET (positron emission tomography) scans of the brain. Reports of shorter sleep duration and lower sleep quality were both associated with greater Αβ buildup.

“These findings are important in part because sleep disturbances can be treated in older people. To the degree that poor sleep promotes the development of Alzheimer’s disease, treatments for poor sleep or efforts to maintain healthy sleep patterns may help prevent or slow the progression of Alzheimer disease,” said Spira.  He added that the findings cannot demonstrate a causal link between poor sleep and Alzheimer’s disease, and that longitudinal studies with objective sleep measures are needed to further examine whether poor sleep contributes to or accelerates Alzheimer’s disease.

A Phase 3 Trial of Semagacestat for Treatment of Alzheimer’s Disease.

Posted by

0


BACKGROUND

Alzheimer’s disease is characterized by the presence of cortical amyloid-beta (Aβ) protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer’s disease.

METHODS

We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer’s disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer’s Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used.

RESULTS

The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, −9.0 points in the placebo group, −10.5 points in the 100-mg group, and −12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated.

CONCLUSIONS

As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections.

Source: NEJM

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

Posted by

0


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.5 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 post approval 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 .

 

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.

 

Source:NEJM

Accuracy of Florbetapir PET Imaging in Alzheimer Disease.

Posted by

0


The imaging modality is highly accurate, but its role in diagnosis and its social implications need consideration.

Imaging biomarkers have been studied as a means of detecting amyloid-beta (Aβ) pathology in vivo. One such marker, the FDA-approved positron emission tomography (PET) amyloid imaging agent [18F]florbetapir, previously demonstrated correlation with autopsy findings of Aβ plaque in 35 people with baseline cognitive status ranging from normal to severely demented (JW Neurol Feb 22 2011). Now, the same investigators have conducted a manufacturer-sponsored follow-up study with 24 additional cases that came to autopsy, to assess the accuracy of florbetapir PET imaging.

Of the 59 patients, 46 came to autopsy within 12 months after imaging; the remainder did so within 2 years. The primary analysis compared ratings of florbetapir PET images by five physician readers with binary histopathological findings at autopsy (no or few Aβ plaques vs. moderate or frequent plaques). The majority rating by the five readers was 92% sensitive and 100% specific for imaging done within 2 years of autopsy; it was 96% sensitive and 100% specific within 1 year of autopsy. Overall, individual reader accuracy was similar to the majority-rating accuracy, and semiquantitative analyses of PET images were also highly accurate.

Comment: This study offers encouragement to physicians and families who seek a definitive diagnosis of Alzheimer disease (AD) in vivo so that they can make informed decisions about participation in clinical trials and other major life decisions such as planning for family needs. However, implications for insurability, employment, behavioral health, and quality of life need to be carefully considered before proceeding with amyloid imaging, as the results may be perceived as being similar to those of genetic testing in AD and other neurodegenerative diseases. Although florbetapir has been approved by the FDA, many questions remain regarding its role in diagnosis, interpretation of a patient’s images by an inexperienced reader, and reimbursement (or lack thereof) by insurance providers.

Source: Journal Watch Neurology