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Monday, January 23, 2017

Alzheimer’s disease—Flunking Drug Trials: What Next?

As life expectancy is rising, we need to avoid avoidable decline in health by learning and practicing such behaviour which ensures long years of healthy and productive life. 
Changing socio-economic conditions
With the advent of globalization and the resultant free-flow of capital, people and information across the national borders, lifestyle in India has undergone dramatic changes since mid-1990s. This wave is indeed getting intensified as it is making inroads into hinterland from the metros. In the anxiety to catch up with the new-wave and perhaps, not to fall behind, everyone is madly rushing to own it without paying attention to its consequences, of course, in the long run. People are no longer living and growing old among their known communities, society, and environment. Instead, they are  getting planted in some altogether unknown surroundings with a totally new activity to better their lives. Gone are the days when we used to walk miles together to schools, to farms, to markets and to greet friends and relatives on the eve of important celebrations. No longer anyone is even pedalling to the offices. With the increasing mechanization, human activity even on the farm-front is slowly waning. We are getting more and more sedentary – more so in urban centres.
On the economic front, good education in general and higher education, in particular, have become very expensive. And securing employment has become even more a daunting task. Even, if one secured a job, there is no guarantee that it lasts lifelong, for skill sets demanded by the employer are fast changing. With the government spending on providing healthcare  coming down year by year, even medical care has become costlier. On the other hand, life expectancy has gone up. Over it, pension schemes are getting drastically altered. This, in turn, is forcing people to work for longer years—into their old age even. Another disturbing trend that is taking deep roots in today’s India of easy credit, free flowing credit cards and swanky malls is: declining ability to delay gratification. Amidst this flux, living has simply become highly stressful.
As people are however slowly becoming aware of these complexities, things are fast changing all around. For instance, 50 years back, dementia was hardly a threat to mankind. But today, it has become a problem for many families. Dementia is a “syndrome, usually chronic, characterized by a progressive, global deterioration in intellect including memory, learning, orientation, language, comprehension and judgment due to disease of the brain.” It mainly affects older people, while about 2% of cases are reported to be starting before the age of 65 years. The dementia syndrome is linked to a very large number of underlying causes and diseases in the brain such as Alzheimer’s Disease (AD), vascular dementia, Dementia with Lewy Bodies (DLB) and Frontotemporal dementia. 
Alzheimer’s  Disease
Incidentally, 50-75% of dementia cases are said to be solely due to Alzheimer’s disease. Again, the borders between these different subtypes are so indistinct that mixed pathologies are much more common. It is more so in the case of AD and vascular dementia, and AD and DLB. Over it, many people with AD pathology in the brain do not show signs of dementia, for the brain changes underlying AD probably develop over a period of at least 20-30 years, before symptoms become noticeable.
This fearful Alzheimer disease was first reported in 1906 by a German physician Alois Alzheimer. Examining a lady patient, he found her suffering from profound memory loss, language problems, and unpredictable behavior. On her death, conducting autopsy of the brain, he noticed dramatic shrinkage of brain and abnormal deposits in and around nerve cells. Today, Alzheimer is considered as an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to even carry out the simplest tasks. In most people, its symptoms are first noticed in their mid-60s. However, its course is not the same in every person. Nevertheless, symptoms seem to develop over the same general stages. Scientists believe that it progresses on spectrum with three stages:
           ·         an early, pre-clinical stage with no symptoms;
·         a middle stage of mild cognitive impairment; and
·         a final stage of Alzheimer’s dementia. 

Though the disease was diagnosed a century back, its causative factors are still not clear and its cure is still eluding the medical fraternity:

·      One section of scientists believe that it is the build-up of a sticky plaque called beta amyloid protein in the brain which stops synapses from facilitating cell-to-cell communication as the cause of Alzheimers.
·   There is, of course, another school of thought which considers tangles—twisted fibers of a protein known as tau protein—that form inside cells which stop nutrients and other supplies from feeding the cells as a result of which they eventually die causing Alzheimers.
           ·       According to William Jagust of University of California, it is tau that “may incite                        the whole process of neuro-degeneration.” 
Taking a lead from the amyloid hypothesis, Eli Lilly developed a drug—Solanezumab, or Sola—that is supposed to clean up the amyloid from the brain but its recent failure at the trials had dashed all the hopes for a breakthrough in Alzheimer’s treatment. Its failure is indeed questioning the very validity of the amyloid hypothesis underlying the cause of the disease. Now the moot question is: If the amyloid hypothesis is to be cast off, what then is to replace it as a central theory of the cause of Alzheimers? Of course, some scientists believe that tau tangles are the real culprits, while another section looks at the signs of inflammation and brain’s fading ability to metabolize energy as people get older as the probable cause but none of these hypotheses has been tested yet.
There is still hope of finding a cure to the disease: Frank Longo, professor of neurology and neurological sciences at the Stanford School of Medicine, came up with an astounding pill—molecule, LM11A-31—that looks promising. According to Longo, “it targets a receptor on the surface of neurons and, in doing so, counteracts much of the abnormal signalling”—the stage at which synaptic function begins to suffer and neurons begin to die and degenerate, due to which patients begin to suffer memory loss—“that occurs in Alzheimer’s disease.” Longo further asserts that “the drug counteracts an unusually large number of mechanisms thought to be associated with Alzheimer’s, rather than targeting a single mechanism” and hence many researchers believe that it could prove as an effective treatment for Alzheimer’s disease. For, the drug is said to be agnostic about the cause of the disease and mainly focuses on keeping brain cells strong and protected against neurological onslaughts.  Having determined its safe use for humans, his firm is about to launch a phase 2a clinical trial of the drug—the first time it will be tested in patients with Alzheimer’s disease—and all are waiting for the results.
Interestingly, Dale Bredesen of the UCLA Mary S Easton Center for Alzheimer’s Disease Research and the Buck Institute for Research on Aging, believes that Alzheimers stems from an imbalance in nerve cell signalling. In the normal brain, specific signals foster nerve connections and memory making, while balancing signals support memory loss, allowing irrelevant information to be forgotten. As against this, in people with Alzheimer’s the balance of these opposing signals is disturbed. As a result, nerve connections are suppressed and memories are lost. He therefore prescribes a novel, comprehensive, and personalized therapeutic program that is based on the underlying pathogenesis of Alzheimer’s disease, involving multiple modalities designed to achieve metabolic enhancement for arresting neurodegeneration. He found that six out of ten patients whose cognitive decline had a major impact on job performance were able to return to work or continue working without difficulty after undergoing this therapeutic program. Of course, these anecdotal results, as the author averred, need a controlled clinical trial of the therapeutic program for adoption.
Impact of the Disease on the Society/Families
While the efforts to understand the etiology of and find a cure for Alzheimer are going on for more than a century, the disease has become a near epidemic: globally, nearly 50 million people are estimated to be living with dementia. And in the absence of proper cure, this number is predicted to double every 20 years. According to The Dementia India Report 2010, there are an estimated 3.7 million people aged over 60 with dementia (2.1 million women and 1.5 million men) in India. Future projections indicate an estimated twofold increase by 2030 and threefold by 2050.
Disease Induced Behavior
Once sets in, dementia impacts personal, family, and societal life of the patients. Living with dementia is a traumatic experience for both patients and caregivers for the affected persons forget even the words with which to identify things and tasks, forget even the faces that they loved once so deeply and forget how to bathe or to button up a shirt.
So, family members must first understand what the disease does to a person. For instance, a simple activity like plaiting hair by a woman involves six different parts of brain to trigger simultaneously: From deciding to comb hair to moving her hands and legs, from identifying and fetching comb and mirror to applying oil in right quantity and from un-tweaking the hair by combing and twirling the hair in such a style to finally make it look like a plait—each act comes from a different bit of the brain. And when these bits cannot connect with each other, plait cannot be made, though the woman had been doing this simple act for ages that too as a given. That is her today’s plight.
Occasionally, patients, besides losing their short-term memory, may also regress deep into their past. And this makes them demand for doing acts they did in the past, such as a woman insisting on putting her babies to sleep next to her. All this behavior obviously attracts irritation and impatience of caregivers for they cannot visualize how this once efficient woman suddenly became so silly. The only relief that the family can have is: though it cannot be cured, they can slow down its onslaught by helping the patient in skill-building, offering psychotherapy, group interventions, psycho-education, counselling, etc. This however, makes heavy demand on time and patience of the caretakers besides inflicting heavy strain on economic resources of the family. It also inflicts strain on national income in terms of productivity lost and provision of medical care. This burden is expected to increase in developing countries due to increase in longevity and increasing prevalence of risk factors such as hypertension and stroke and lifestyle changes (Shyamal K Das et al).
Debilitating Diabetes
Diabetes mellitus is another disease that is fast reaching potentially epidemic proportions in India. There are already 62 million Indians diagnosed with the disease and it is predicted that by 2030 diabetes mellitus may afflict up to 79.4 million individuals in India. Worryingly, diabetes is now being shown to be associated with a spectrum of complications:
  • neuropathy (24.6%) followed by
  • cardiovascular complications (23.6%),
  • renal issues (21.1%),
  • retinopathy (16.6%) and
  • foot ulcers (5.5%)
and to be occurring at a relatively younger age within the country. Obesity is one of the major risk factors for diabetes. Despite having lower overweight and obesity rates, India has a higher prevalence of diabetes compared to western countries, which makes one believe that Indians are genetically more vulnerable to the disease. Over it the steady migration of people from rural to urban areas, the economic boom, and corresponding change in lifestyle are all affecting the level of diabetes. And unfortunately, diabetes is strongly associated with dementia/Alzheimer: a recent study indicated that people with diabetes had a 39% increased risk of dementia. 
So, how to avoid this decline in health
 Against these growing complexities of modern life, let us take an exploratory look at “How to avoid the avoidable decline in health and thereby extend our productive lives”? This question is perhaps, more interesting to those who are in their 20s and are likely to take big career decisions. For, according to Laura L Carstensen, Founding Director of the Stanford Centre on longevity, our health and happiness that engender long productive years are nothing but the “sum of our habits”, including “countless choices that we make every day about
  • what we eat,
  • who we engage with, even
  • how much time we spend moving vs. sitting.”
When Carstensen, assembled a diverse set of scientists from medicine, economics, social epidemiology and psychology along with experts from industry and policy, to enquire as to what practices/behavior that are most influential in ensuring long and healthy life, the group came up with three key areas of action:
  • “healthful living,
  • financial security, and
  • social engagement.”
Healthy living to optimize longevity of productive life obviously demands a change in the way we live. And science tells that the few changes that are to be made are not hard to practice. In a trial carried out with healthy foods but containing 34% to 54% fewer calories than what the people in the study usually consumed for three months, Valter Longo, Director of University of Southern California’s Longevity Institute found notable drop in risk factors associated with aging, diabetes, heart diseases and cancer including lower blood sugar and reduced levels of the growth harmone IGF-1 that is known to hasten aging. So, he says that “diet is by far the most powerful intervention to delay aging and age-related diseases.” Based on her research, Susan Roberts, of Tufts University says that people with overweight have no option but to “lose weight and keep it off” if they want to keep themselves healthier for longer. Similarly, scientists warn that sedentary behavior—sitting all day—increases the risk of type 2 diabetes and non-alcoholic fatty liver diseases, and no matter how regularly one even exercised. The latest research suggests that “a body that’s moving is what matters” more than exercising a lot, in keeping one healthy.
Finally, it is one’s ‘mindset’ that defines how one gets aged. There is an axiom in Sanskrit:
Yad bhavam tad bhavati—you are what you thinketh! Volumes of research say that our emotions affect our biology: anger and stress release adrenalin—a stress hormone—into blood that triggers heart to beat faster and harder. This is even found to affect how our brain holds up against Alzheimer’s disease. Latest research revealed that people with ‘negative stereotypes’ about aging have a positive correlation with the onset of brain changes associated with Alzheimer’s disease. It is however not clear as to how the negative stereotypes impact the brain except to speculate that these sterotypes might be linked to stress, a known trigger of pathological changes in brain. Based on his studies, Elissa Epel, Professor of Psychiatry at University of California suggests that ‘mindfulness meditation’ reduces stress and also prevents people from harbouring negative emotions.
Research has also indicated that strong social ties are linked to better health, for it betters one’s outlook and reduces stress. It may however be difficult to foster such relationships on migration to new communities, nevertheless one needs to cultivate the ability to integrate with the surrounding communities. In the same vein, in today’s world of uncertainties—‘on bench’ and ‘pink slips’ have become the common words of the employment; no one knows how long the present employment runs and when one will be out of it; every business has a cycle of its own ups and downs—failing to save and invest for future in secured avenues, such as fixed deposits in banks, provident funds, pension schemes, capital markets, life and health insurance, etc., is sure to threaten long-term health of individuals. For paucity of funds vis-à-vis the demand for sustenance is highly stress-prone.
All this ultimately boils down to: we need to change the way we live to have long years of health and productivity. It is, of course, hard to redesign our lives but given the strength of science and its outcomes, we can make it happen—very effectively too—provided we will it.


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