Stemming the fading
The Centre for Brain Research has set its mind and resources on understanding how dementia and its variants can be predicted and managed
Ballabgarh, a town in Faridabad district of Haryana, is not exactly a major tourist attraction. Its origins as a small princely state that played a role in India’s independence struggle may not be common knowledge. But for some mental health professionals, Ballabgarh holds far greater significance.
In 1996, a study was conducted among Ballabgarh’s largely rural population — there were 5,000 respondents — to understand the extent to which those examined suffered from brain-related conditions such as dementia. (The idea behind the study was to select a rural cohort from India and one from the United States, and compare the two.)
According to the findings, 1.36% of respondents above the age of 55 had dementia, while 1.07% in the 65 years-plus category had Alzheimer’s disease. This study is perhaps the first-ever record of these disorders in India, at a time when age-related neurodegenerative conditions and mental health issues were not even understood, let alone researched; cognitive decline was simply attributed to old age.
Fast forward to the present and studying the brain has become imperative to unlock physical and mental health secrets. That was the context for the Tata Trusts, back in 2015, to collaborate with the Centre for Brain Research (CBR) at the Indian Institute of Science in Bengaluru and launch the Tata Longitudinal Study of Aging (TLSA). The intent: to comprehend how the brain ages and if the onset of disorders such as dementia can be predicted well ahead.
Minimising the burden
Established with a generous endowment from the Pratiksha Trust — cofounded by Kris Gopalakrishnan and Sudha Gopalakrishnan — CBR is committed to research, innovation and engagement aimed at minimising the burden of dementia and associated neurodegenerative disorders, thereby improving the quality of life of the affected.
“Our goal is to study the aging brain, focusing on both healthy and pathological aging,” says KVS Hari, CBR’s director. “As we age the brain, like any other organ, experiences a reduction in its performance. Neurodegenerative conditions accelerate this decline and lead to more severe cognitive impairments. When that happens interventions, through lifestyle changes or pharmacological solutions, become necessary. Yet despite the growing impact of brain disorders, we often hear more about deaths from heart attacks, lung infections or kidney failure than from conditions affecting the brain.”
According to the World Health Organization, brain disorders are now the sixth leading cause of death globally, in a list that includes heart ailments, diabetes and hypertension. And the numbers are only going up.
“If the 1996 study found that about 1% of elderly people suffered from dementia, today that number is likely to be 7-8%,” adds Prof Hari. “We are living longer today, which takes a toll on our bodies and our brains, giving diseases more time to take hold.”
Dementia is a blanket term that covers a range of neurodegenerative conditions involving memory loss, decline in cognitive function and reasoning, and behavioural changes that interfere with daily life. About 70% of people with dementia may have Alzheimer’s disease, while a smaller percentage have conditions such as Parkinson’s, vascular dementia and Lewy body dementia.
CBR’s mission is to develop biomarkers for the early detection of dementia, alongside approaches to prevent, postpone, or manage it. The transitional phase between normal age-related cognitive decline and more serious conditions like dementia is called ‘mild cognitive impairment’ (MCI) or pre-dementia.
Slip sliding slowly
This is characterised by noticeable changes in memory or other cognitive functions but not severe enough to adversely affect daily life. “If you are able to detect MCI in time, you may be able to halt or even reverse the cognitive impairment,” says Prof Hari.
To find solutions it is essential to, first, figure out exactly what the prevalence of brain disorders is in the Indian population. Since the aging brain has not been studied much in the country, CBR recognised the need to start by collecting data through research studies focused on elderly subjects.
The Tata Trusts-supported TLSA brings together volunteers, aged 45 and above and with no known neurological conditions. This longitudinal observational study then carries out multimodal assessments (clinical, cognitive, genetic, etc.) on the subjects over a 15- to 20-year period to better understand risk factors (and protective factors) for dementia.
If predictive patterns for the onset and progression of dementia can be found, then suitably effective interventions — such as trying to inhibit it with drugs, the most common option — can be created.
The TLSA cohort, all Bengaluru residents, are required to visit CBR once a year for blood work, scans and tests that relate to visual, aural and motor abilities; cognitive and spatial acuity; gait analysis; etc. These parameters are recorded annually and changes, if any, are tracked.
Working with a geriatric cluster such as this brings its own problems. Many participants drop out, either because of infirmity or death or a reluctance to come in for follow-ups. Since the study aims to collect and analyse longitudinal data from at least 1,000 participants, the team seeks new volunteers to replace the dropouts.
Prevent or delay
TLSA is currently in its second phase, where findings from the first phase are being compiled and a pilot multimodal trial has been launched to assess if non-pharmacological and lifestyle-based interventions can help prevent or delay the neurocognitive disorders associated with aging.
The success of TLSA has led the CBR team to launch a similar study in rural Karnataka in a largely agrarian community in Srinivaspura in Kolar district. Called CBR-Srinivaspura Aging Neuro Senescence and Cognition (CBR-SANSCOG), the study began in January 2018 and currently has nearly 10,000 subjects in the 45+ age group. Srinivaspura was picked for its proximity to Bengaluru — it is about 100km away — so that the CBR team could visit and collect data easily. As a significant proportion of this rural population has been engaged in mango farming over several generations, there is little urban migration, making it ideal for a 15- to 20-year study. A large number of endogamous marriages also presents a unique gene pool distinct from the cosmopolitan makeup of urban areas.
“The number of aging studies done in rural, community-based populations across the world is limited,” says Jonas S Sundarakumar, assistant professor and principal investigator of the CBR-SANSCOG study. “Most studies on aging and dementia are conducted among urban populations, with predominantly hospital or clinic-based subjects. These do not provide an accurate picture of community-level conditions and risks.”
Dr Sundarakumar adds that with rural populations the focus has to be on preventive strategies, while identifying signs of cognitive decline and dementia as early as possible, and then crafting appropriate interventions.
Straightforward strategies
“Simple, cost-effective strategies, like lifestyle changes, addressing nutritional deficiencies and promoting social connectedness, may go a long way in reducing dementia risk, and may be better suited for large-scale implementation in rural communities,” says Dr Sundarakumar.
India requires scalable and affordable solutions for MCIs. “Even testing must be reasonably priced and provided at primary healthcare centres,” says Prof Hari. “Once we understand the patterns [of disorders], we will know which tests and interventions may be effective and how we can design them to detect and treat MCIs among a larger number of people.”
The data being collected by CBR will certainly help in this regard. “India-specific data is needed to, first, validate the findings of similar studies conducted elsewhere in the world and, second, to understand the genetic differences between populations,” says Prof Hari. “An intervention that has been successful elsewhere may not work for our population because our lifestyle, diet and social conditions are different. We may have to adapt and modify.”
While longitudinal studies take decades, CBR has started parallel lines of investigation with animal models and other in-vitro approaches. “Mouse models have been in use for a long time, but we have decided to go a step further by using human stem cell models,” says Ravi Muddashetty, associate professor at CBR. “We want the results to be as close to humans as possible so that we create stem cell models from selected participants using information and test results collected from our cohort subjects.”
A team of geneticists and computational biologists works with neurobiologists to create these highly personalised stem cells, taking data from each volunteer in the urban and rural groupings.
“We get a lot of information about family history, clinical background, etc from each participant and we use this, along with genome sequencing data, to select subjects for stem cell generation,” says Prof Muddashetty. “Stem cell models are valuable in dementia research as they allow us to mimic the disease conditions and, therefore, enable studying the disease mechanisms and testing potential therapies in a controlled environment.”
Dementia is not an individual disease. It affects families and sometimes even entire communities because people with the condition often require caregivers. “With people living longer now, a growing proportion of the population will inevitably be affected by dementia,” says Prof Hari. “Today we may be a demographically young country but in 20 years, when our population is older, dementia will become a significant problem. We need to address the issue with a sense of urgency — and that we have yet to recognise.”
