T.S. Srinivasan
Conclave 2021
Prof. John C. Morris
“The Importance of Diversity in Alzheimer Disease Clinical Practice and Research”
Harvey A & Dorismae Hacker Friedman Professor of Neurology, Professor of Pathology & Immunology, Washington University & Director And Principal Investigator of the Alzheimer Disease Research Centre, USA
Harvey A & Dorismae Hacker Friedman Professor of Neurology, Professor of Pathology & Immunology, Washington University & Director And Principal Investigator of the Alzheimer Disease Research Centre, USA
Professor’s take away strong message: Study of AD ( in particularly clinical trials) must expand beyond White cohorts.
The keynote address on the opening day of the 3-day TS Srinivasan Knowledge Conclave, 2021, by Prof. John C. Morris “The Importance of Diversity in Alzheimer Disease Clinical Practice and Research” is most relevant at this juncture, when the pandemic has further exposed the global inequities in healthcare and research. The guiding principles of equity were admirably brought out by him as he narrated his over 2 decade commitment and personal journey toward an understanding of the key role of demographic variants, culture, and socioeconomic determinants of health in a diverse population with regard to Alzheimer disease. They play a significant role, in addition to the central scientific focus on clinical features, assessment by CDR and other associated scales in dementia, specialized lab and imaging modalities and genetics, he observed. From his comparative study of the Whites and diverse ethnic groups, he stressed the absolute need for AD biomarker race data to be adjusted for race and not pooled together.
Prof. Morris gave a broad outline of the global data on an ageing population, and alarming projected figures of dementia globally by 2050.
Regarding a diverse population, he started with his own country, USA, observing that 80% were White in 1998, which by 2020 dropped to 58%, while the rest of the population belonged to non-White ethnic groups. His ADRC KnIght Research had less than 3% Blacks in 1998, which was with conscious effort by his research group, increased to 18% in 2020. He questioned the ‘non-diverse sample of convenience’ with only 19 (0.6%) of Blacks , and the majority of Whites in Biogen’s Aducanumab FDA Accelerated Approval in June 2021. How can one extrapolate such (unsubstantiated) knowledge on safety and efficacy of a drug to other diverse subgroups? Non-inclusive research among the diverse groups are sparked in the ethnic groups by mistrust, concerns about complications and historical racism, aside from practical difficulties in adhering to regular follow up protocols. As a result, knowledge about many diseases come from studies limited to a particular subgroup-generally White, English speaking.
Such inequities in research spills over to include clinical practice, LMIC countries, with poor literacy and poor awareness of diseases in a large section, are also subject to similar discrimination. Many Neuropsychiatric tests were developed for the educated, English speakers and modifying the tests to be patient-friendly and lowering diagnostic cut-off levels is required. He referred to the Indian scene and the increase in the burden of non-communicable diseases. He stressed the need for the study of dementia in diverse settings and those that assess life course exposure which may reveal newer insights.
Prof. Jeffrey L. Cummings
“Neuropsychiatric Aspects of Neurodegenerative Disorders: Advances in Diagnosis and Treatment”
Joy Chambers-Grundy Professor of Brain Sciences, University of Nevada Las Vegas, United States.
Joy Chambers-Grundy Professor of Brain Sciences, University of Nevada Las Vegas, United States.
The content of Prof. Jeffrey L. Cummings’ keynote address reflects his dedicated journey and pioneering effort in the Neuroscience arena over several decades. He built systematically on the strong foundation gained in his fellowship training in Behavioural Neurology at University of Boston and in Neuropsychiatry at Hospital for Neurology and Neurosurgery, Queen Square, London to concentrate his energy on the Neuropathology of Ageing,(neurodegenerative disorders, dementias in particular, with long-term NAA funding) and to fine-tune aspects of neuropsychiatric syndromic diagnosis in these disorders. He simultaneously embraced the field of neurotherapeutics, taking a lead role in drug development. He is current Director of the Chambers-Grundy Center for Transformative Neuroscience. This is ‘a centre devoted to using the tools of neuroscience and neurologic drug development to transform people’s lives’- the interface of neuroscience and society.
Neuropsychiatric syndromes are increasingly recognized as core symptoms for diagnosis of neurodegenerative disorders. In Alzheimer’s disease (AD). psychosis prevalence is 40%, persists for 1-3 years, with highest incidence in moderate AD, agitation is 70%, again persists over1-3 years, with highest incidence in moderate and severe AD. Apathy is the most common neuropsychiatric syndrome of AD. It can present in preclinical or prodromal AD and through mild, moderate and severe AD. The impact of these syndromes on patients are in the case of psychosis- more rapid cognitive decline and functional decline, more hospital admissions and earlier admission to residential care; agitation- more rapid cognitive decline, greater executive dysfunction, more impaired activities of daily living and as a result, high caregiver burden. In apathy the cognitive impairment, impairment in executive function and decreased activity of daily living is prolonged, slowly progressive and accounts for poor quality of life. The professor went on to describe the symptom complex of other forms of dementia, namely the behavioural variant of fronto-temporal dementia, dementia with Lewy bodies and vascular cognitive disorder. The neuropsychiatric and behavioural symptoms are integrated, in the neurological diagnostic criteria and not disease-specific, he pointed out. Major Neurocognitive disorder on DSM 5 may be diagnosed on the basis of one cognitive and one behavior (social cognition ) change.
The above description is adequate criteria in the clinical diagnosis of the neuropsychiatric syndromes but research diagnostic criteria demand more precise definitions of the syndromes, be it in clinical research, interventional studies (drug trials or non-pharmacologic interventions) or in regulatory communication. Professor Cummings contributed to the establishment of the research criteria for psychosis and agitation. Apathy is a very complicated phenomenon and has an intricate research definition. He outlined these research definitions, of which we detail below the definition for agitation.
Agitation in Cognitive Impairment disorders (IPA definition):
One of the following, associated with distress, persistent or recurrent for 2 weeks; these changes being from premorbid behaviour
- 1. Excessive motor activities (like pacing the floor, wandering, trying to get away from institutional care premises); 2. verbal aggression, 3. physical aggression
- Severe enough to cause disability
- Comorbid conditions or environmental circumstances not entirely accounting for the behaviour - Cummings et al, Internat Psychogeriatrics : 2015
Much research has been extended to understand the neurobiology of psychosis, agitation and apathy in AD through various specialized research modalities which Prof. Cummings elaborated, projecting the visuals of the respective neuroimages,
- Psychosis:
- MRI –greater temporal/hippocampal atrophy, greater anterior/inferior and insular cortex atrophy
- FDG –PET- Orbito-frontal hypometabolism (ADNI-derived sample)
- Amyloid –PET More amyloid-positive scan patients had delusions than amyloid-negative scan patients
- Neurofibrillary tangle 2.-3-fold greater NFT burden in cortex of patients with psychosis, independent of the dementia severity,
- Tau-PET: Greater p-tau in dorsolateral prefrontal cortex in psychosis
- Agitation:
- FDG-PET : right frontal hypometabolism
- Amyloid PET: MCI with amyloid-positive scan more likely to agitation than MCI with amyloid- negative scan (MCI with agitation had faster progression to AD)
- Tau PET: tau signal greater in temporal and frontal regions
- NFT greater burden in orbito –frontal and left cingulate
- Apathy:
- fMRI: Decreased anteromedial frontal activation in resting state when compared to non-apathetic patient
- Amyloid PIB imaging correlation: More amyloid over orbito –frontal, medial frontal dorsolateral and prefrontal cortex amyloid
- Tau PET { greater Tau burden in orbito- frontal cortex
Professor went on to the FDA approved drug treatment in AD psychosis, agitation and apathy and the requirement for strict monitoring of psychotic medication. He elaborated on the drug trial in the newer drug Pimavanserin, and on Methylphenidate in apathy. He ended on the positive note ‘Drug development in these syndromes in AD is advancing’.
Live Stream Recordings :
Brain Health Focus needs to shift from distant risk management to current benefits says Dr. Vladimir Hachinski at the 41st TS Srinivasan Endowment Oration
The 41st TS Srinivasan Endowment Oration titled “Promoting Brain Health to Prevent Dementia, Heart Disease and Stroke” held virtually this year, underlined that the emphasis on promoting brain health needs to shift from distant risk management to current benefits. Delivering the oration, Dr. Vladimir Hachinski, MD, DSc, FRCPC, FRSC, FAAN, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada said that brain health is essential for physical and mental health, social well-being, productivity, and creativity. He advocated making brain health the top priority worldwide and urged communities to develop common measures and definitions to enhance research and policy and to apply comprehensive customised cost-effective prevention solutions in actionable implementation units.
“It is a well-known fact that stroke, heart disease and dementia, which are the greatest threats to the brain, are increasing worldwide and the situation will get worse in India. It is unfortunate that most medical practitioners consider dementia as a natural and inevitable part of aging. As we speak, only 27 of the 194 member countries who approved WHOs global action plan on public health response to Dementia, have functioning dementia risk reduction campaigns. Stroke increases the possibility of heart disease and doubles the chances of developing dementia. Dementia, Stroke and Heart Disease, however, share the common risks and protective factors. Risk factors include hypertension, lack of exercise, diet that is high in salt, sugar and fats and the protective factor among them is education. It therefore makes sense to look at the three together as they share the same protective factors by promoting brain health,” Dr. Vladimir Hachinski explained.
Worldwide, the number of people with ischemic Heart Disease, Stroke and Dementia is projected to affect 158.6 million people, 122.4 million people and 74.7 million people respectively.
Touching on the role air pollution plays he said, “Pollution causes harm to the heart, stress to the lungs and damages the brain. We breathe the same air in the bio-hemisphere since there are jet-streams of air in the atmosphere that move across oceans and continents. For example, pollution in New Delhi would affect even far off Canada. The urgency to do something to reduce pollution increases with each passing year.”
Advising individuals to concentrate on enhancing brain health, Dr. Vladimir Hachinski said, “At least half of all Strokes are preventable, yet only one in four people can identify a single risk factor for Stroke. If there is a family history of high blood pressure, we need to monitor that and control blood pressure by cutting down on salt intake and exercising regularly. On the other hand, if there is a strong family history of diabetes, you need to ensure that you do not gain weight. This would enhance brain health, which is the basis for overall health and in the long term decrease the chances of having a Stroke, or a Heart Attack or Dementia. This way, we can avoid a catastrophe which can happen decades later. The emphasis needs to shift from distant risk to current benefits by promoting brain health. You need to target brain health to some measurable goal that the individual can commit to such as sleep hygiene, exercising and eating well. It might be a good idea to partner this commitment with someone else. Individuals with healthy brains are more productive and happier. A comprehensive, cost-effective approach to the joint prevention of Stroke, Heart Disease and Dementia promises accelerated progress.”
The TS Srinivasan Oration is supported by the TS Srinivasan Charitable Trust and honours the memory of Mr. TS Srinivasan a scion of the TVS family who pioneered many automobile innovations and collaborations and was renowned for his humanistic qualities. The programme guided by an international advisory board of eminent neurologists is co-organised by Neurokrish, Chennai.
Vladimir Hachinski CM OOnt FRSC FRCPC is a Canadian clinical neuroscientist and researcher based at the Schulich School of Medicine and Dentistry at Western University. He is also a Senior Scientist at London’s Robarts Research Institute. His research pertains in the greatest part to stroke and dementia, the interactions between them and their joint prevention. He and John W. Norris helped to establish the world’s first successful stroke unit at Sunnybrook Hospital in Toronto and, by extension, helped cement stroke units as the standard of care for stroke patients. He discovered that the control of the heart by the brain is asymmetric, the fight/flight (sympathetic) response being controlled by the right hemisphere and the rest and digest (parasympathetic) response being controlled by the left hemisphere and damage to one key component (the insula) can lead to heart irregularities and sudden death. This discovery has added fundamental knowledge to how the brain controls the heart and blood pressure and lays the foundation for helping prevent sudden death. Hachinski has held many prominent positions in the global neurology community, including editor-in-chief of the journal Stroke the leading publication in the field and president of the World Federation of Neurology and founder of World Brain Alliance. He is a Fellow of the Royal Society of Canada (FRSC) and the Canadian Academy of Health Sciences (FCAHS), a Member of the Orders of Canada and Ontario, and the recipient of several national and international awards and recognitions for his research and advocacy.
All Our Past
Endowment Orations
Our Publications
One of the outcomes of the TS Srinivasan Knowledge Conclaves is this series of transcultural neurology publications from Cambridge University Press. Encouraged by an endowment from the TS Srinivasan Charitable Trust these publications bring together neuroscientists and mental health professionals from across the globe to address “Transcultural Issues” of import. Dementia (now with the second edition in press) and Epilepsy are the first two books in the series.
