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  • Reply to: What is wrong with Alzheimer’s disease clinical research?   2 weeks 12 hours ago

    Dr. Alzheimer's state something to the effect of "The clinics should drive laboratory discovery, not the other way around." Since this other way around is substantially what is done, the results are understandable.  Dr. de la Torre has been trumpeting the AD/CVD connection for decades. Brown University coiled the term "type 3 diabetes" a decade ago. It's clear this is a multifactorial disease. Now the proof comes from the functional medicine side as this mountain of a disease begins to crumble. Guys like Tanzi and Selkoe will or are jumping on the band wagon claiming they knew it all along.  But if they did - which I'm certain they will claim - then they are criminals.

  • Reply to: What is wrong with Alzheimer’s disease clinical research?   2 weeks 16 hours ago

    This comment is from Gary Morris, Ian Clark and Bryce Vissel.

    The Amyloid Cascade Hypothesis is simple, elegant and provides a basic framework for hypothetically approaching Alzheimer’s disease (AD), satisfying Occam’s razor. However, often forgotten in the effervescent elegance of the Amyloid Cascade Hypothesis is that many fundamental tenants underlying it have not been conclusively proven. Our deep-seated concerns about this, considering the over-reliance of the field on the Amyloid Cascade Hypothesis, were the catalyst for our recent article [1], in which we do not argue Aβ has no role, but that current data can be interpreted independently of a primary role for amyloid in all AD cases.

    We recommend heeding the learnings from other areas of medicine. Billions of dollars were spent on drugs that blocked stomach acid as an approach to cure stomach ulcers. Alternative ideas, such as the idea that bacteria cause ulcers, were widely ridiculed, supported by the weight of evidence of the apparent efficacy of acid blocking drugs. In the end, the Nobel prize winning discovery was that the cause of stomach ulcers was not stomach acid but, in most cases, a different unexpected cause altogether (the cause was bacterial infection of the stomach). So too is it likely to be true that while, like stomach acid, amyloid is likely associated with AD in some way, it is unlikely to be the sole cause, especially as more evidence mounts to suggest that the amyloid hypothesis may not be correct in its entirety. Clearly a broader view of the disease is required.

    Importantly, we know little of the normal role of Aβ. We must therefore consider that the role of Aβ and indeed the mechanisms of brain and neurological diseases like AD are unlikely to be as simple as the Amyloid Cascade Hypothesis suggests. Only recently, for instance, have we truly begun to appreciate the breadth of roles non-neuronal cells play in physiological brain function, not to mention the myriad of complex interactions between thousands of proteins, derived from many interacting cell types, including neurons, glia and the extracellular matrix. Many of these interactions converge at synapse, which are highly sensitive to destruction in AD [2].

    There have long been outstanding thinkers who have questioned the amyloid hypothesis and despite how it may appear at first glance, the AD literature is packed full of alternative ideas, as we have reviewed [1]. Unfortunately, however, opposing theories have often stagnated, possibly because they have not enjoyed the same levels of attention or devotion (in basic research, by granting bodies, pharmacological companies and even the media) as the Amyloid Cascade Hypothesis. To cite two specific examples of equally plausible Aβ-independent hypotheses of disease, both the presenilin hypothesis and several versions of the inflammatory hypothesis (e.g. [3]) do not need to rely on a model in which Aβ is central [1]. Instead of ignoring these equally valid interpretations of data and in concert with exciting new research on normal brain physiology and pathophysiology, we should aim to embrace these ideas within new theoretical models of AD.

    We agree with the comments by Prof. de la Torre that the drivers of this change will be the new generation of AD researchers, who we should aim to bring up on a healthy diet of scepticism of past approaches to enable innovative thinking that integrates current data regarding amyloid with emerging advances in neuroscience, to create a more holistic theoretical understanding of AD. The catch is that this will require dedicated thought, which requires time away from the lab bench, reading extensively. We would like to see more supervisors and PhD committees support that goal.

    Bryce Vissel is the Professor of Neuroscience and Director of the Centre Neuroscience and Regenerative Medicine in the Faculty of Science at University of Technology Sydney, Ian Clark is Professor of Biology at Australian National University and Gary Morris is a scientist in Prof. Vissel’s laboratory.

    References
    [1] Morris GP, Clark IA, Vissel B (2014) Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer's disease. Acta Neuropathol Commun 2, 135.
    [2] Morris GP1, Clark IA, Zinn R, Vissel B (2013) Microglia: A new frontier for synaptic plasticity, learning and memory, and neurodegenerative disease research. Neurobiol Learn Mem 105, 40-53.
    [3] Clark IA, Vissel B (2015) Amyloid β: one of three danger-associated molecules that are secondary inducers of the proinflammatory cytokines that mediate Alzheimer's disease. Br J Pharmacol 172, 3714-3727.

  • Reply to: What is wrong with Alzheimer’s disease clinical research?   2 weeks 1 day ago

    Think about it. Even though the Aβ trials by the pharmaceuticals continue to fall off the cliff, they did have a valid reason to commit millions. Remember, the government and other agencies funded those early academic studies via our trust-worthy peer-review system, while some reviewers covertly blocked the funding and publishing of alternative hypotheses. Let me pose a sensitive question: would a grant/manuscript reviewer approve a contradictory hypothesis and from a competitive institution?

    Although I would demand an affirmative response, my personal experience says no. Conflict-of-interest thrives in almost every walk of life, and sadly in our medical/scientific field; perhaps it’s the worse side of Darwinism’s survival. Shouldn’t we expect fairness and objectivity especially in a field that should thrive on novelty; for isn’t that how you define research?

    Perhaps I’m wrong, but I believe the oath or duty of a reviewer is to objectively review the work for reproducibility, accuracy, and merit (and budget for grants) while effectively representing other similar supportive and contradictive work in-context. I do not impose my opinion, nor give attention to the author’s names, their institution, and/or funding source.

    And so what do we have to show for all those millions/billions of dollars funding the Aβ sink-hole, and for all those peer-reviewers, who protected their own interest by rejecting grants, manuscripts, and other opportunities that propose alternative hypotheses? Apparently nothing to date for the AD patient, and lost time and sour grapes for those with suppressed contrary work.

    My feeling is that the peer-review process should either be a blind-blind system (remove names and affiliations) or an open-open system to have a slightly better chance at removing bias, as the current open-blind system allows those threaten to conceal motives, hide behind their reviews, and even obtain fresh ideas. You see, we really don’t have to wait for the grim reaper (as per Jack’s reference to Max Planck), only a new policy to prevent future dead-horse sink-holes.

  • Reply to: What is wrong with Alzheimer’s disease clinical research?   2 weeks 1 day ago

    J. L. de la Torre does the field a service by articulating his impatience, which I share, with the continuing focus of so much scientific talent, so much grant and industry funding, on the role of beta-amyloid - to the exclusion of other ideas - in the causation of Alzheimer’s disease. It is easy to agree with his analysis of causation and to value his reference to Max Planck’s impatience with his colleagues of nearly a century ago (though I have never been able to identify the issue that gave rise to Planck's famous aphorism - it wasn’t dementia). And Dr. de la Torre's willingness to be the devil’s advocate for a few paragraphs shows a valuable open-mindedness.

    To me the key point (and Jack has made it) is the responsibility we have to millions who are suffering dementia, and to the many millions about to suffer it; and to whoever it is that puts up the funds we spend on our research. The scientific issue will sort itself out, sooner or later; but sooner if we are rigorous and open to new ideas, however uncongenial. And sooner is important to people.

    Because there is a non-scientific challenge here, not present in debates on non-medical issues: At what point must we accept a new idea into our thinking? because, however uncongenial to our hopes, it might prove better than our own ideas? and accelerate the treatment or the prevention of a disease? the very treatment and prevention that we promised when we applied for our grants? Sooner is important, morally; to vulnerable people.

    I can remember when molecular geneticists located APP on chromosome 21, sequenced it, showed its association with sporadic dementia and with familial, early-onset dementia. And I shared their excitement that they had identified the cause of dementia. But the brain is penetrated by blood vessels at the sub-millimetre level; the cerebral vasculature has to be considered in any cerebral disease. And, when the role of vasculature in age-related dementia is considered, the evidence is (I submit) compelling; Alzheimer’s disease is a small-vessel vascular dementia. A vasocognopathy de la Torre called it, over a decade ago.

    Of course any scientist must be free to explore, and to adhere to, any idea, according to our judgement. But freedom always comes with duties; and there is a particular duty on biomedical researchers - to the sick, to the still-healthy, to our benefactors - to stretch our mind beyond the excitement of our own ideas, to embrace those less congenial, with rigour, dispassion, and even passion.

  • Reply to: When do we diagnose severe Alzheimer's disease?   2 months 3 weeks ago

    Dr. Salmeron's blog post above highlights some very important aspects of Alzheimer's Disease in a stage that devastates the lives of the patient and the caregivers and for a long time, was the stage where family members knew for certain that their loved one had dementia/Alzheimer's. For the past few decades’ awareness about AD has increased substantially and stages of cognitive impairment have been somewhat clearly delineated for mild and moderate AD. However, there is less clarity available for the designation of cognitive impairment as 'severe' or "advanced". This is the stage which requires the patient’s family to plan accordingly and timely assessment of function can provide accurate insight to the patient’s management team. There are two ways to characterize this change from moderate to severe: on a cognitive scale (such as MMSE or DRS) and on functional status (such as the Global Deterioration Scale or the Functional Assessment Staging). Dr. Salmeron's blog explains the advantages for these functional scales as this is the time when supervision and other changes are required to be made for the patient. It is important to understand the limitations of these functional scales as well. His short explanation does conclude that we should use both cognitive and functional scales to evaluate the patient in this late stage. The lack of tools to assess and manage this disease at this stage makes it very difficult for caregivers and providers. More research, suggested above, needs to focus on development of better care and management as well as awareness for severe AD.

  • Reply to: When do we diagnose severe Alzheimer's disease?   2 months 3 weeks ago

    Dr. Salmeron provides an excellent commentary regarding how best to diagnose patients with advanced AD. He correctly points out that most cognitive tests have floor effects that would preclude them from being useful while functional tests, which are generally administered less frequently, are probably more helpful. However, in advanced dementia, even functional scales may have limited utility given most patients with advanced dementia have no or very limited functional ability. Nevertheless, they are more sensitive than cognitive scales to subtle changes, particularly in patients with more advanced disease. Interestingly, behavioural symptoms often improve with progression from moderate to advanced dementia so may have limited utility. I myself find that certain cognitive scales, such as the severe impairment battery, which are sensitive to changes in social awareness, may be useful in helping to differentiate moderate from advanced dementia. The lack of valid and reliable tools highlights the need for future research in this area.