I wrote a post over 2 years ago, eat, meditate, love that I continue to share with others concerned about the business model of Alzheimer's disease and more importantly--Is there reason to be hopeful?
In that post I mentioned Dale Bredesen MD and I am excited that his book has been published. The End of Alzheimer's: The First Program to Prevent and Reverse Cognitive Decline will add the patient level approach to prevention and potential reversal of symptoms.
I encourage you to seek it out, request it in your library, or click the link in this post. Your cost stays the same but Amazon throws a little cheddar to this blog--helping to keep the information ad-free.
To find out more about Dr. Bredesen, you can sign up for a free webinar on September 7th at 8:oo PM EST.
Share with anyone interested in the impact of cognitive decline as we age and the over medicalization of Alzheimer's disease.
Not too much news from the 2017 Alzheimer's Association International Conference seemed newsworthy. You know what it is like watching an interview and you are waiting for THE question to be asked but it seems lost in all of the softballs being swung at and missed? That should be the theme. Full disclosure I am still skeptical about the entire premise of hunting for monotherapeutic cures in Alzheimer's disease. For one, they keep measuring the wrong thing. But if we are about to pivot towards prevention? Sign me up!
The Alzheimer's Association today announced the launch of a $20 million U.S. two- year clinical trial to test the ability of a multi-dimensional lifestyle intervention to prevent cognitive decline and dementia in 2,500 older adults with no current cognitive symptoms but who are at increased risk for later cognitive decline. The announcement was made at the 2017 Alzheimer's Association International Conference (AAIC 2017) in London.
First, how much "protection" can we offer 60-79 year olds with co-morbid dementia risk factors "(e.g. hypertension and other cardiovascular events, elevated blood sugar)? We also forget collectively that the eponymous disease actually described early onset Alzheimer's--not what we talk about in our aging populations.
Why does it seem like diabetes and metabolic derangements are the data signature in so many chronic diseases? I would like to see this study extended to additional social determinants of health in younger at-risk populations but I remain hopeful.
I don't have the answer but I do like to look at trends. Starting with a diabetes data signature and digging a little deeper seems like an interesting place to become curious.
In looking for data to see if obesity, sugar consumption, or dementia might show similar patterns--knowing correlation is not causation--but why not look where the hypothesis generation is ripe?
There is also interesting information from a brain donation program of 202 American football players. Results from the neuropathology and clinical features include evidence of cognitive decline and presence of phosphorylated tau and amyloid in addition to unique pathology associated with chronic traumatic encephalopathy. My thoughts are always perhaps the brain makes tau and amyloid in response to insults to the brain including trauma associated with head injury and the as yet not characterized trigger in Alzheimer's disease? "Deposition of amyloid-β was present in a subset of participants at all stages of CTE pathology, predominantly as diffuse amyloid-β plaques, but neuritic amyloid-β plaques and amyloid angiopathy were also present".
Click the title to download a free PDF of a report from The National Academies Press
Easing back into writing from my home office (at last) after months of travel is always welcomed--but a bit unfamiliar. Working between meetings, conferences, and scheduled collaborations requires a level of discipline not typically required from your home base. I do well if I remain on my east coast time zone regardless of where I end up (within reason). I always walk to my destination whenever possible (within 3 miles) and carry healthy snacks such as avocados, jerky, or nuts.
As many citizens can attest, the U.S. is a great place to get sick, but a terrible place to stay well. This requires a shift in the way both doctors and patients approach health maintenance and disease prevention.--Rob Wittman
Most of us do the best we can. Our lives are busy and our responsibilities are many. The easiest thing to do is to sacrifice a work-out, grab a quick snack--albeit not the healthiest option, or cut back on sleep to meet busy deadlines. But what about "staying well"?
From a historical perspective the US healthcare system had stellar results when the assaults were tuberculosis and acute infectious agents. The discovery of antibiotics provided small molecule solutions for acute disease. One pill could save large numbers of patients reliably and consistently.
Unfortunately we seem to apply that model of research and pharmacology to chronic disease. Chronic disease demonstrates inherent complexity not likely solved by a monotherapeutic cure. Metabolic derangements are common to heart disease, diabetes, and Alzheimer's disease. We search for cures that mirror successes from our past. We fund research for symptom management but not at the necessary scale for prevention.
If you are a data professional you might enjoy FlowingData. Jonas Scholey re-envisioned data to demonstrate the relationship between cause of death not only as we age but also as a historical perspective.
An immediate observation is that as we age the predominant cause of death is chronic disease. Just 20 or 30 years ago we had more infectious disease in the top 5, now the majority are chronic in nature. Click on the interactive image below. It will take you to The Burden of Disease and the Changing Task of Medicine 200th anniversary article in NEJM.
In many respects, our medical systems are best suited to diseases of the past, not those of the present or future. We must continue to adapt health systems and health policy as the burden of disease evolves. But we must also do more. Diseases can never be reduced to molecular pathways, mere technical problems requiring treatments or cures. Disease is a complex domain of human experience, involving explanation, expectation, and meaning. Doctors must acknowledge this complexity and formulate theories, practices, and systems that fully address the breadth and subtlety of disease.--NEJM Jones et al.
The advancement in preventing or curing chronic diseases like Alzheimer's disease reside in adaptive clinical trial designs and modernization of how we cure advanced disease frameworks with complex deranged pathways. Prevention clinical trials are not well funded but their findings are important. We are ready for a new model of health--not just symptom relief but a "realistic understanding of determinants of disease".
Disease is always generated, experienced, defined, and ameliorated within a social world. Patients need notions of disease that explicate their suffering. Doctors need theories of etiology and pathophysiology that account for the burden of disease and inform therapeutic practice. Policymakers need realistic understandings of determinants of disease and medicine's impact in order to design systems that foster health. The history of disease offers crucial insights into the intersections of these interests and the ways they can inform medical practice and health policy.--NEJM
Its impossible to study neuroscience and not know about Phineas Gage. What I didn't know was how handsome he was--even with scars from being impaled through the brain by an iron rod in an 1848 explosion. In fact he greeted the first doctor on the scene by deadpanning "Here is business enough for you." He surprisingly survived eventually dying from seizures years later--likely as a result of catastrophic neurodegeneration.
The relevant finding for neuroscience was the abrupt change in personal and functional ability. Not unlike the decline in cognition experienced in Alzheimer's disease--it seems to also portray the heterogeneity of not only dementia but brain injury as well. Phineas Gage may have regained a degree of normalcy and routine in his life. It made me think that although Alzheimer's disease diminishes cognition there are many patients where poor ambulation is the profound symptom--or language processing. A recent podcast, Two Scientists Walk into A Bar, examines The Degenerating Brain. Genentech brilliantly produces the podcast and surprisingly Geoff Kerchner, Neurologist and Medical Director of Early Clinical Development at Genentech is one of the first industry experts to discuss the brain in a matter-of-fact informative discussion. He is both a practicing neurologist AND a research scientist. I think this makes all the difference.
Modern neuroscientific knowledge makes the idea of Gage’s recovery all the more plausible. Neuroscientists once believed that brain lesions caused permanent deficits: Once lost, a faculty never returned. More and more, though, they recognize that the adult brain can relearn lost skills. This ability to change, called brain plasticity, remains somewhat mysterious, and it happens achingly slowly. But the bottom line is that the brain can recover lost functions in certain circumstances.--Slate
But what if the "diagnostic" protein accumulation is just the low-hanging fruit? Is aggregation a cause, or a bystander effect, of the disease? Neurodegenerative diseases have different symptoms but one unifying concept at the biologic level--abnormal protein accumulation in nerve cells. In Alzheimer's disease a variety of proteins including TDP-43 are associated with abnormal aggregation leading to death of these cells. We aren't talking about foreign proteins--these are proteins normally found within our bodies. In many instances, the human brain can withstand a lot of damage but this isn't usually the case in the motor cortex. Think of the neurodegenerative process in ALS--the number of neurons is so low in this area that even minimal damage can yield profound effects.
No surprise that the brain is the least understood organ of the body. The interconnectivity alone is vastly complex. Experiential influencers transmit to neurons as well. Research has demonstrated this by studying the brain of multi linguists musicians and creatives, as well as other "active" disciplines. So we do crosswords, learn foreign languages, and enjoy music when time allows. Clearly AD does not look the same in all individuals. Geoff Kerchner, MD PhD shares how common themes like memory loss are seen in many of his patients although other patients report visual spatial and navigation impairment as the most profound symptom. He reminds us that aggregating proteins is what our brain does when it is assaulted. Who is to say which of the proteins is actually driving the dysfunction?
My research question is if brain biologically responds to insult with protein accumulation, perhaps we need to look at earlier phenotypic traits of neurodegeneration like metabolic derangements and mitochondrial dysfunction. I believe the answer will be a network solution--definitely not a monotherapeutic intervention targeting only one signal in a complex mechanism.
Paula Wolfert and the complex questions of dementia...
My neighbor sent me the link to a recent NY Times article. I was excited after reading the title albeit bristling at "fighting" once again used to separate winners from losers--to be greeted by a smiling face. Articles about Alzheimer's disease and dementia are typically sturm und drang without hope or possibility unless you donate or face your fate and the upcoming zombie apocalypse.
You might not recognize the face or even the name but her seminal cookbooks focused on middle eastern dishes were groundbreaking in the days before celebrity chefs and mindless cooking themes shows. In the midst of a dire diagnosis, she is publishing a biography Unforgettable: The Bold Flavors of Paula Wolfert's Renegade Life.
Thus, the so-called bulletproof coffee she makes every morning and the squares of dark chocolate she eats after lunch, in the belief they will bolster her brainpower. In between, she eats a carbohydrate-free diet built on salmon, berries and greens, along with extracts of turmeric, cinnamon and eggplant.
The cookbook will focus on brain-centric healthy dishes and stories about memory and food. Her Kickstarter campaign quadrupled its initial goal and I am so happy to order this beautiful book--It appears to be a recipe for joy, hope, and acceptance--and a delicious cous cous.
The gripping narrative traces the arc of her career, from her Brooklyn childhood to her adventures in the farthest corners of the Mediterranean. Anecdotes and adventure stories come Paula's extensive personal archive, from over 50 interviews with Paula herself, and from dozens of interviews with food writers and chefs whom she influenced and influenced her—from Alice Waters and Thomas Keller to Diana Kennedy, André Daguin, and Jacques Pépin.--unforgettablepaula.com
The best documentaries are the ones you stumble upon quite by accident. The title of First Cousin Once Removed didn't reveal much as I meandered through the offerings of HBO--an often disappointing way to look for a good documentary film. What caught my interest was a face, a smile, and the name of an accomplished poet--Edwin Honig.
Edwin Honig was many things to many people. A really complex person with a traumatic history of his own revealed through interviews and conversations with his cousin, Alan Berliner, an accomplished filmographer. Although the stories I tell aren't about me, they are written by me--and I am fairly critical of storytellers of Alzheimer's disease. The zombie apocalypse isn't coming and there is humanity in every life experience.
This is a beautiful documentary--even when it becomes painful to watch--the journey remains hopeful and magical.
Since Honig was a poet, Berliner felt it was important to honor his cousin's memory by making the film an exploration into the life of a poet, and his film was conceived in poetic terms. "Poets' lives are not arbitrary," Berliner states. "For poets, it's all or nothing. They are the translators of human experience. They're the people we turn to in order to put words and images to the feelings, emotions and experiences we don't understand or know how to deal with. He even says at one point in the film,
The Poet's Alzheimer's reveals a mind lost to Alzheimer's disease returning to recite a forgotten passage, detail, or clarification. My father was a musician. He played the double bass in symphonies and local orchestras and retained an abiding love for classical and jazz his entire life.
This documentary highlights the unique journey of a mysterious diagnosis. I have never been a fan of continually interrogating patients with dementia. A barrage of frightening questions, "Do you know who I am?" "What day is it?"-- to what purpose? Perhaps rather than thinking about memory as a construct, they are just living it. Acting out an activity that is limited by its definition.
Alzheimer's: Every Minute Counts opens dramatically. A brightly lit cityscape slowly becomes dim as one by one--lights go out and leave total darkness. Cue the dramatic music and opening scene of a family in the midst of caring for a declining Alzheimer's patient and bam--you can't get to your check book fast enough.This documentary feels like an awareness of marketing campaign. Fear? Check. Dramatic music? Check. Heartbreaking scenarios? Check. Mention (multiple times) of need for funding but no mention of the amount of money already sunk into unsuccessful drug pipelines.
The problem? The opening scene depicts a woman with early onset Alzheimer's disease. A rare form of the condition that strikes fear in everyone--especially since the recent blockbuster Still Alice. The real truth lives somewhere between normal senescence and whatever triggers the abnormal pathology of Alzheimer's disease. You may be surprised to learn that we actually have no idea.
I particularly found the haunting warning of a zombie apocalypse a bit toothless. Especially since JAMA Internal Medicine recently published the data on the decline of dementia rates. A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012
I don't know. The PBS documentary seemed like nothing more than a marketing campaign to increase fundraising efforts for Alzheimer's disease. I agree it is a formidable task but we certainly need to fail better and quicker. Wouldn't the funding be better utilized in prevention or symptom management? Do we really think there is a mono-therapeutic cure for comorbidity at the end of our lifespan? I suggest a more meaningful documentary Monster in The Mind. Here we learn about hope, prevention, and healthy aging.
Here is the current pipeline as reported recently in Alzheimer's & Dementia: Translational Research & Clinical Interventions
I will quietly hope for better outcomes but I will actively bring awareness to prevention and social correlates of health. Stay-tuned...
I first attended the Lown Conference a few years ago in San Diego. It was an amazing time to meet other industry stakeholders questioning overdiagnosis and overtreatment in healthcare. John Ioannidis spoke about questionable research findings with dubious ties to industry and profit mechanisms.
I participated in panel discussions about end of life care, mental health issues, and reporting risks as well as benefits associated with medical interventions.
Many one on one discussions would end up along the water. We walked along the sea listening to each other's stories, motivation for attending, or lingering barriers to critical thinking in a healthcare framework that may or may not have the provider or patient's best interest top of mind.
I recall a discussion about how Alzheimer's Disease was captured on a death certificate. A mid-career physician treating many patients with dementia admitted the criteria was not clear. Yes we have many patients with dementia--what we don't have is a lot of patients dying from dementia.
This may surprise you if you have been listening to the media and the claims of the pending zombie apocalypse. A recent article in the Washington Post succinctly stated Too Many Medical Trials are Moonshots in the Dark. A powerful update on the Eli Lilly drug solanezumab provides context for the debate.
The episode underscores that it is time to rethink how we pursue biomedical research and drug development. This shift is especially pressing for diseases of the brain, such as autism and Alzheimer’s disease, which are becoming increasingly important for our society but lack effective treatments. One reason for this lag in treatments is that we have failed to invest enough in obtaining a fundamental understanding of diseases. Instead, we have spent too much on costly clinical trials and studies on human patients that, for ethical reasons, have to be guided by the interests of the patients rather than research goals.-- Thomas C Sudhof, Nobel Prize in Medicine 2013
If you follow the blog, you are familiar with the head scratching and arched eyebrow directed at R&D investments in monotherapeutic solutions for complex chronic disease, metabolic derangements, and illness toward the end of life. Clearly I am not discussing hereditary or early onset AD or dementia--the statistics often reported are referring to the later years--and they have many of us frightened and feeling helpless.
These powerful images from What Does it Take to Produce a Breakthrough Drug published in Nature Reviews | Drug Discovery are visual reminders of the failed framework for evaluating drug candates for Alzheimer's Disease. The only reason for the anemic push forward could be described as the sunk cost fallacy.
The Misconception: You make rational decisions based on the future value of objects, investments and experiences.
These are clearly contemplative thoughts lacking immediate answers but deserving of better questions.
Some people see a focus on basic research as insistence on wastefully pursuing knowledge for its own sake. That assessment is false. Basic research provides the underpinnings for any understanding of disease, so we need to reassess how we spend our precious funds for development of therapies.
I recommend either full participation or at least a cursory review of literature provided in a free online course at Future Learn. Social Determinants of Health: What is Your Role? Much of the data integrated into real world evidence pulls from environmental and economic factors that have been demonstrated to impact health outcomes.
Do you find it impossible to envision a mono-therapeutic solution to a complex framework of chronic disease? Pathways of metabolic derangements nestled within a socioeconomic and political context don't seem amenable to a pharmaceutical panacea. Diseases of aging remind us of how little we know about healthy senescence and the pathology of age.
Consistent with the prevailing ideology of disease, adequate access to healthcare has long been identified as a credible goal for medicine. Not as much credence has been attributed to governance, social position, material circumstances, or social cohesion. Healthcare costs most specifically drug prices are being defended as the price we must pay for innovation. A recent article in Forbes presents a short-sighted view of drug industry pricing--described as a kerfuffle!? Here is where my thoughts land.
Innovation in healthcare and medicine is somewhat limited by biology at the interface of technology and trade-offs in quality of life. Instead of gargantuan investments in R&D or biotech company acquisitions--why don't we look at the real problems. If drug companies stop investing in "innovation" because their billion dollar collective bonuses are being slashed--what will be there new business model?
There is historical precedence for regulations and governance to help direct the "invisible hand" described in 1776 in the Wealth of Nations. Our modern society indeed has evolved into a holistic denial of social determinants of health and their impact on health inequities.
Unfortunately, discussions of investments in healthcare cluster around the medicalization of disease vs. preventative policy and oversight. Data presented by Yale Global Health Leadership Institute highlights the low investment in social service spending by the US. Interesting to note that we spend more on healthcare than any other nation, have the worst outcomes, and one of the smallest--if not the smallest--investment in social determinants of health.
The animals we eat--domesticated or wild--contain PCBs, hormone disruptors, and radioactivity, the fish has too much mercury, the tap water tastes of chlorine and contains copper, some tap water from fracking areas catches fire, buildings have toxic indoor air, we breathe in dust and nitrogen oxides, and there's too much ozone near the ground but tool little up in the stratosphere where it should be. The oceans are going acidic. Temperatures have gone off the charts. Forests are burning and fertile soil is getting depleted, eroded, or drought stricken. The entire atmosphere seems to have caught some kind of fever, which is gradually infecting the oceans. The lament and complaints over nature's disruptions go on and on. The earth and the sky have now become full of seemingly meaningless symptoms and suffering.-What We Think About When We Try Not to Think About Global Warming
This is the world we live in. But we are anxiously waiting for an even smaller cohort of a previously unsuccessful clinical trial ,(EXPEDITION, EXPEDITION2, and EXPEDITION3 (ongoing) in patients with mild Alzheimer's disease. Basically Eli Lilly seems to be looking for a problem--for its 25 year 3 billion dollar solution.
As the Alzheimer's Association struggled for an identity, the name evolved and with it--the role of public sources of funding.
“We are the world’s leading voluntary health organization in Alzheimer’s care,
Additional topics discussed in the evolving book, Alzheimer's Disease: The Brand, include the balance sheets of a well-funded non-profit patient advocacy group as well as how funds are channeled to local chapters. Many of the largest advocacy chapters have separated from the Alzheimer’s Association in the last year, disagreeing with their priorities of research, and centralization of resources. The deprioritized local programs actually help people and families dealing with dementia.
I recently discovered an article originally published in Harvard Business Review in 1977. The discussion of organizational learning sheds insight on how "change" can most effectively be initiated--if the current culture is supportive.
Organizational learning is a process of detecting and correcting error. Error is for our purposes any feature of knowledge or knowing that inhibits learning. When the process enables the organization to carry on its present policies or achieve its objectives, the process may be called single loop learning. Single loop learning can be compared with a thermostat that learns when it is too hot or too cold and then turns the heat on or off. The thermostat is able to perform this task because it can receive information (the temperature of the room) and therefore take corrective action.
Think about first-loop learning as our short-sided approach to Alzheimer's Disease prevention or research. We think if we develop diagnostics or prescribe drugs to remove amyloid plaques and neurofibrillary tangles--viola! The target was defined and we adjusted actions to be able to measure our success.
First-loop learning identifes a drug or drug class that lowers the targeted plaques or tangles. Now when we consider the second-loop learning--things get uncomfortable. We need to question the defined target. Our first-loop brain has verified that the problem is "solved". But what about patients with normal cognition having brains riddled with plaques? Do we have the right target? Is it possible to identify a monotherapeutic target for a chronic disease with metabolic derangements?
What we actually need is whole-system redesign.
Even when one is diagnosed with an illness, it should not define them.
I am choosing to celebrate today thinking about the day to day with my dad during his Alzheimer's journey. Not all bad days, not all good days, but precious memories all the same. Read the article above for a heartfelt series of photographs and observations by Allison Hess.
A medical writer and insight analyst focuses the lens on the evolution of Alzheimer's Disease as a diagnosis into a billion dollar healthcare juggernaut
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