What is going on here? A well-funded "volunteer" non-profit should do better. What is race a placeholder for? I am certain they know that risk is not determined by pigment. If there are social determinants of health--give them voice. If there are biologic measures, name them.
The news that Pfizer is re-allocating budget away from Alzheimer's disease and Parkinson's disease is newsworthy. It is likely a smart move. The complexity of chronic metabolic derangement in older age combined with potential discoveries of mysterious lymphatic systems hidden within the dura mater should point to "innovation" away from a monotherapeutic cure.
It is not sufficient, he argues, to simply collect and store massive amounts of data; they must be intelligently curated, and that requires a global framework. “We have all the pieces of the puzzle — now how do we actually assemble them so we can see the big picture?”--The Mathematical Shape of Big Science Data--Jennifer Ouellette
Standard methods of analyses have required a hypothesis. Unfortunately the focus appears to be too narrowly tuned on the role of tau protein and/or plaques. I would argue that small molecule solutions appear to be the preferred status quo even in the face of enormous financial loss and personal tragedies. I am patiently waiting for the game changer--but will it be a blockbuster drug?
Extracting insights from the shape of complex data using topology describes a method to analyze large complex data by using geometric representation. The advantage is the ability to identify smaller groups often over-looked in analyses allowing deeper stratification compared to standard methodology.
Standard methods are reliant on hypothesis validation and the underlying assignment of sound models or hypothesis. Topological Data Analysis (TDA) discussed in more detail at the link--describes a method where a defined hypothesis is not required to explore the shape of the data in breast cancer databases.
I know plenty of colleagues and science-minded people anxiously waiting for a drug they can begin taking today to avoid Alzheimer's disease in their twilight years. The message of prevention has fueled many a drug pipeline and although mediocre symptom alleviation strategies have somehow squeezed past the FDA there are things we can do right now. Granted we are learning how to analyze data from outside clinical trials and perhaps the most data savvy are hesitant to propagate the less profitable and less "sciencey" claims--we should be paying attention.
"After accounting for non-independence between risk factors, around a third of Alzheimer's diseases cases worldwide might be attributable to potentially modifiable risk factors. Alzheimer's disease incidence might be reduced through improved access to education and use of effective methods targeted at reducing the prevalence of vascular risk factors (eg, physical inactivity, smoking, midlife hypertension, midlife obesity, and diabetes) and depression."--The Lancet Neurology volume 13, issue 8, August 2014
Why don't we hear about prevention outside of pharmaceutical hype? Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging and any of the books or articles about Blue Zones should be written about right alongside the earnest efforts of small molecule cures.
“Now we have this new multimodal data [gleaned] from biological systems and human social systems, and the data is gathered before we even have a hypothesis.” The data is there in all its messy, multi-dimensional glory, waiting to be queried, but how does one know which questions to ask when the scientific method has been turned on its head?--The Mathematical Shape of Big Science Data
*"We can only connect the dots we collect"--Amanda Palmer
I am a big Systems Thinker and you should be too. The cost of being a one-dimensional thinker plays out in the latest R&D efforts in Alzheimer's disease. Believe it or not--we are still funding the failed hypotheses of decades earlier.
Adaptive Phase II Study of BAN2401 in Early Alzheimer’s Disease Continues toward 18-Month EndpointCriteria for Success at 12-Month Analysis of ADCOMS Not Met
Study to Remain Blinded Per Protocol until Final Readout of Comprehensive 18-Month Data
Study 201 (ClinicalTrials.gov identifier NCT01767311) is a placebo-controlled, double-blind, parallel-group, randomized study in patients with prodromal or mild Alzheimer’s disease (collectively known as early Alzheimer’s disease) and with positive biomarkers for brain amyloid pathology.
Indulge me in a brief tangent. A recent podcast shuffled my thinking. Debbie Millman is a powerhouse design expert with a broad range of interests and talents. Design Matters is a juggernaut source of creativity and ideas but underneath the hood are powerful conversations and observations about words, artistry, and engagement.
I thoroughly enjoyed a recent interview with Richard Saul Wurman--the founder of TED. Let me clarify. I enjoyed the banter as I ran 6 miles on a trail--I would not have wanted to be interviewing him. A tad bit belligerent and fussy but a riveting partner on a crisp fall morning. He talks about questions. We don't ask the right questions. He wants more from the media. For example, to just report the magnitude of an earthquake tells us nothing. If we know nothing of the depth, infrastructure, or a host of other variables we are unable to contextualize. I believe him. I lived in California and experienced both the Loma Prieta in 1989 and Northridge in 1994. Weaker magnitude earthquakes can have far more devastating consequences depending on building codes, tidal surges, and a host of other characteristics.
Here are a few questions for what is listed in Clinical Trials.gov for the latest clinical trial report from NCT01767311. I do research and data analytics for a living but the website is intended for patients, family members, health care professionals, and other members of the public easy access to information on clinical studies on a wide range of diseases and conditions. Again, there isn't any data available yet that I can find.
ADAPTIVE PHASE II STUDY OF BAN2401 IN EARLY ALZHEIMER’S DISEASE CONTINUES TOWARD 18-MONTH ENDPOINT
1.Criteria for success at 12-month analysis of The Alzheimer's disease Composite Score (ADCOMS) not met but study is still continuing. I am curious about the in-house developed endpoint ADCOMS to measure efficacy.
Assessment of safety reasons for stopping were not met--but what were the safety signals? Amyloid related imaging abnormalities (ARIA)? What were the interoperability scores for results?
2. Original primary outcomes was a 12-month time frame and now the current status 18 months (submitted 9.17.2015)
3. Secondary outcomes include hippocampal volume, composite clinical score (ADCOMS), and brain amyloid measured by amyloid PET.
4. The Bayesian design is a responsive design allowing "automatic changes to the design during the study, including adaptively changing the subject allocation ratio to treatment arms with higher probabilities based on the results of interim analyses in order to more efficiently identify the effectiveness and optimal dose regimen of BAN2401."
What do we really know about "diagnosing" patients for participation? What is the inter-operator variability for different assessments of cognition? If we are using PET scan and other imaging to define AD or dementia we are making a BIG leap that this is the causative agent. Given the history of evidence, Bayesian priors should point in a different direction, no?
The ADCOMS measures what investigators want it to measure. Composite study end points should focus separately on safety and effectiveness outcomes, and design separate composite end points to match these different clinical goals. Instead ADCOMS includes 4 Alzheimer's Disease Assessment Scale–cognitive subscale items, 2 Mini-Mental State Examination items, and all 6 Clinical Dementia Rating—Sum of Boxes items (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care)
Now if we return to Nobel laureate Dr Tonegawa we see research findings that red areas of hippocampus are essential for creating new memories but the short-term recall depends on a specialized area in green called the subiculum. This generates new ideas and what we might learn from measures of hippocampal volume as secondary endpoints.
How memories are indeed formed would be a smart place to start. How do we know what actually is responsible for cognitive decline of the scale observed in Alzheimer's disease and other dementias? Metabolic derangement definitely has a role but the solutions are bigger and need a system thinking approach...the brain demands it.
Bill Gates is making a bold move. I like his commitment--both financial and personal as well as his search for " a lot of ideas." I hope he hasn't spent the last year in the R&D drug focused echo-chamber because if he has, my enthusiasm will wane--quickly.
"You have a nearly 50 percent chance of developing the disease if you live into your mid-80s. In the United States, it is the only cause of death in the top 10 without any meaningful treatments that becomes more prevalent each year. That trend will likely continue as baby boomers age, which means that more families will watch their loved ones suffer from cognitive decline and slowly disappear. Despite this growing burden, scientists have yet to figure out what exactly causes Alzheimer’s or how to stop the disease from destroying the brain."--Why I'm Digging Deep Into Alzheimer's, Bill Gates
Publications by the Alzheimers Association perpetuate myths assigning race or ethnicity as a risk factor. If you read on, statements like this are pushed beneath sensationalized talking points, "Variations in health, lifestyle and socioeconomic risk factors across racial groups likely account for most of the differences in risk of Alzheimer’s and other dementias by race." Why race? Are we looking for biologic differences or the impact of social determinants? There is one race. The human race. I don't know what you think skin color will add to our search for answers. We need the granularity of genetic variants or we need the social constructs and political implications of how we answer questions of race in our society--but also in the field of medicine.
I sincerely want to see approaches outside the capitalistic forces upstream from disease but are we ready to change policy? Should we be gobsmacked that so many of us will suffer from dementias in our 80s? The insult of toxic air, agri-business, poor food policy, wealth inequality, poor education, food deserts, unequal access to healthcare, subsidized low nutritive school lunches, lack of attention to mental health, low literacy, and more should come to bear towards the end of any lifespan.
These chronic diseases are metabolic derangements and diseases of lifestyle and we seek pharmacologic cures? One monotherapeutic cure to unravel a life time of medical-industrial complex exposure and the politics of not only race but disease?
What could go wrong?
Social Correlates of Health: What if the bear comes home every night?
Go ahead. Take the test. The True Happiness Test. The overall goal is to build healthier and happier communities. If you have followed along you know how I build the blogs here and over at data & donuts. A big resource for new ideas and resolving tensions in projects might be my podcast habit. As an endurance athlete there are hours ripe for multitasking and I have quite the extensive podcast library. A recent return to the top spot in my queue goes to Rich Roll.
Don't we all want to be our best us? What does that look like if we scale up to the community level? A recent listen to Rich's interview with Dan Buettner about his latest book, The Blue Zones of Happiness: Lessons From the World's Happiest People.
The researchers who publish the annual World Happiness Report found that about three-quarters of human happiness is driven by six factors: strong economic growth, healthy life expectancy, quality social relationships, generosity, trust, and freedom to live the life that’s right for you. These factors don’t materialize by chance; they are intimately related to a country’s government and its cultural values. In other words the happiest places incubate happiness for their people-- Dan Buettner
The Blue Zone project brilliantly partners with communities to provide a packet of policies that impact different levels of satisfaction among successful communities. Although not prescriptive, community leaders are able to select workable and scalable policy adoption or change to better reflect the goals of a successful initiative. Here is a brief list of policy recommendation highlights:
1. Commitment to well being (for example, incentivizes for good health) and testing effectiveness of programs
2. Investments in learning
3. Access to fresh fruits and vegetables
4. Safe places to exercise
5.Access to dental visits
Ranking of Happiness 2014-2016 -- World Happiness Report (Chapter 2)
A recent article in National Geographic Magazine featured the happiest places on earth. I think of the article as a great summary but the book is the strategic tool to help implement and make changes necessary.
These Are the World’s Happiest Places--National Geographic Magazine
Gallup divides its surveys into five distinct categories contributing to well-being ( social, purpose, physical, community, and financial). Different aspects of life within these communities impact the percentage of population thriving in different categories.
This is what I think about when the debates around research and development (R&D) in Pharma, a pending zombie apocalypse on the horizon, or when we are scared into pre-medicating for diseases of aging that nobody has yet effectively diagnosed or treated. Our best prevention strategy is to invest in our social infrastructure and build blue zones. A proven outcome with the data to support the investment.
10th Annual FDA/Alzheimer’s Disease Meeting on Thursday, November 16, 2017 at the Bethesda North Marriott Hotel & Conference Center
Metabolic derangements mediate cognitive impairment and Alzheimer's disease: role of peripheral insulin-resistance diseases
We can observe the integration of extrinsic mechanisms of brain insulin/insulin-like growth factor (IGF) resistance (defined in wikipedia) and neurodegeneration. Processes describing excess lipid accumulation (top of graphic) lead to insulin resistance and ultimately inflammation, endoplasmic reticulum (ER) stress--synthesizes proteins and creates and stores lipids, and oxidative stress.
The positive (and destructive) feedback loop leads to the accumulation of toxic ceramides (lipid or fat molecules) and downstream myelin breakdown (neurodegeneration) and dysregulated lipid metabolism--propagating chronic diseases.
de la Monte and colleagues have authored a paper, Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer's disease (embargoed until January 2018 in PubMed). Here is the abstract:
Alzheimer's disease (AD) should be regarded as a degenerative metabolic disease caused by brain insulin resistance and deficiency, and overlapping with the molecular, biochemical, pathophysiological, and metabolic dysfunctions in diabetes mellitus, non-alcoholic fatty liver disease, and metabolic syndrome.
Key Points (from article):
I am working on a collection of stories derived from the blog and ongoing research detailing the history of Alzheimer's disease and subsequent evolution into a brand and global pandemic. Follow along here or subscribe to the newsletter. The e-book will be evolving live and interested subscribers will receive the chapters as they are completed.
A Webinar with Dr. Dale Bredesen and Dr. Wahls
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.
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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