Epidemiology of Motoric Cognitive Risk Syndrome in the Kerala Einstein Study: Protocol for a Prospective Cohort Study

Background The southern India state of Kerala has among the highest proportion of older adults in its population in the country. An increase in chronic age-related diseases such as dementia is expected in the older Kerala population. Identifying older individuals early in the course of cognitive decline offers the best hope of introducing preventive measures early and planning management. However, the epidemiology and pathogenesis of predementia syndromes at the early stages of cognitive decline in older adults are not well established in India. Objective The Kerala Einstein Study (KES) is a community-based cohort study that was established in 2008 and is based in the Kozhikode district in Kerala state. KES aims to establish risk factors and brain substrates of motoric cognitive risk syndrome (MCR), a predementia syndrome characterized by the presence of slow gait and subjective cognitive concerns in individuals without dementia or disability. This protocol describes the study design and procedures for this KES project. Methods KES is proposing to enroll a sample of 1000 adults ≥60 years old from urban and rural areas in the Kozhikode district of Kerala state: 200 recruited in the previous phase of KES and 800 new participants to be recruited in this project. MCR is the cognitive phenotype of primary interest. The associations between previously established risk factors for dementia as well as novel risk factors (apathy and traumatic brain injury) and MCR will be examined in KES. Risk factor profiles for MCR will be compared between urban and rural residents as well as with individuals who meet the criteria for mild cognitive impairment (MCI). Cognitive and physical function, medical history and medications, sociodemographic characteristics, lifestyle patterns, and activities of daily living will be evaluated. Participants will also undergo magnetic resonance imaging and electrocardiogram investigations. Longitudinal follow-up is planned in a subset of participants as a prelude to future longitudinal studies. Results KES (2R01AG039330-07) was funded by the US National Institutes of Health in September 2019 and received approval from the Indian Medical Council of Research to start the study in June 2021. We had recruited 433 new participants from urban and rural sites in Kozhikode as of May 2023: 41.1% (178/433) women, 67.7% (293/433) rural residents, and 13.4% (58/433) MCR cases. Enrollment is actively ongoing at all the KES recruitment sites. Conclusions KES will provide new insights into risk factors and brain substrates associated with MCR in India and will help guide future development of regionally specific preventive interventions for dementia. International Registered Report Identifier (IRRID) DERR1-10.2196/49933


Strengths
• Significance is high.Dementia is rapidly becoming a major public health burden in LMICs, coincident with the decline in infectious diseases and other conditions that cause premature death.
• The MCR syndrome is a readily assessed condition which has clear clinical relevance and can be directly targeted with preventative interventions.

Weaknesses
• The KES does not incorporate several important tools which have made major impacts in disease in ADRD in developed countries, such as the use of genomics and protein biomarkers.
Given the circumstances and unique genetics in southern India, there are likely to be important insights that arise from such studies.

Strengths
• The investigators are outstanding.Dr. Verghese graduated from medical school in India and trained in neurology in England and the US.He is a senior investigator who has worked his entire career at Albert Einstein College of Medicine and is currently chief of the divisions of cognitive and motor aging in the Departments of Neurology and Geriatrics.He has been a pioneer on the concept of Motoric Cognitive Risk and has many important papers and grants on this issue.
• The other members of the investigative team are also highly productive investigators, both at Albert Einstein and in India.Most have published extensively as a team and have experience working together.
• There are well-established connections with local investigators in India.

Strengths
• Innovation is modest.The MCR syndrome has been widely studied throughout the world.
Contribution from vascular pathologies or other pathologies such as mild TBI are likely to be important and likely to be enriched in LMICs.
• The populations studied in the KES will include a substantial number of rural dwellers, which is likely to provide novel insights regarding risk factors.
• The focus on TBI is moderately innovative.While TBI has been long-recognized as a risk factor for late life dementia, it has rarely been directly studied as is proposed here.A local adaptation of a Brain Injury Screening Questionnaire will be used.

Weaknesses
• No use is made of valuable Biorepository resources (we are told that genetic samples from >500 carefully phenotypes individuals exist).While this is a relatively modest number by GWAS standards, it is reasonable for candidate gene studies, including analysis of polygenic risk scores.
• Additional focus on the contribution of diet to dementia risk is warranted.In particular, southern India and Kerala are areas where cassava is widely consumed.

Strengths
• The KES has been very successful over the prior funding cycles in establishing valuable research infrastructure, including the capability for advanced neuroimaging and collection of biological samples.
• 18 publications have come from the prior funding cycle.
• Recruitment will be from urban, rural, and exurban settings.800 new participants will be recruited.MCR, MCI, self-reported history of mild TBI, and self-reported apathy/depression symptoms will be assessed.A focused neuropsychometric battery will also be administered.
• Neuroimaging will be carried out in a subset (n=220), initially on a 1.5 T scanner, with plans to transition to a 3 T scanner.Volume and cortical thickness will be quantified, as well as white matter integrity using DTI.
• Follow-up 12 months after the initial visit will be done on all rural participants and all those who completed an MRI.

Weaknesses
• Assessment of vascular risk factors, although a key goal of this application, is superficial.

Strengths
• The KES study is well-established, and an outstanding platform for conducting the proposed study.
• Kerala State is among more urbanized and the better educated regions of India, and by some development indices is on par with some HICs.The life expectance in Kerala state (73.5 years is substantially higher than in India as a whole (61.7 years).• Excellent capacity building plans are included.This comes on top of substantial past success.
Additional ex-urban and rural sites are added, which were not part of the project in prior funding cycles.

Strengths
• Gannt chart is included.

Protections for Human Subjects:
• Acceptable Risks and/or Adequate Protections Data and Safety Monitoring Plan (Applicable for Clinical Trials Only): Overall Impact: The overall goal of the study is to identify risk factors related to MCR, a disorder that has been shown to be a physiological state that precipitates the pathogenesis of AD and related dementias.As such, this proposal is highly significant.The investigators complement each other, and their expertise ensures that the project will be completed successfully, as was the initial study.The approach is sound, but this project tends to suffer from a lack of innovation.As in, this proposal relies mostly upon prior evidence and to expand upon those results.While MCR is an innovative concept, much of the innovation is derived from the initial study and other ongoing projects, rather than from novel concepts and experimental designs/approaches.

Strengths
• The overall goal of the study is to build on research that was previously conducted using the same funding mechanism that focused on Alzheimer's disease (AD) and related dementias in the Indian state of Kerala.The collaborative efforts of the Indo-US team resulted in establishing both a bio-repository as well as a clinical research center in Kozhikode, Kerala as well as several other accomplishments, including implementing neuroimaging protocols and building research databases.The investigators now seek to build upon those results by focusing on risk factors and brain substrates that contribute to the onset of Motoric Cognitive Risk syndrome (MCR), a new pre-dementia disorder identified by these investigators that is characterized by cognitive complaints and slow gait.Risk factors for MCR in high income countries include depression, sedentariness, and obesity.The aim of this study is to identify modifiable risk factors for MCR in low-and-middle income countries (LMICs), which are believed to include apathy and traumatic brain injury.This proposal also seeks to make a distinction between MCR and mild cognitive impairment (MCI), and further, to identify neuropathologies associated with MCR.Given the recently identified disease burden of MCR, and the disease burden of AD this proposal is highly significant.

Weaknesses
• No weaknesses were noted.

Weaknesses
• No weaknesses were noted.

Strengths
• MCR is an innovative concept, proposed by Dr. Verghese and his team.The expansion of MCR as a concept has led to the need to identify risk factors for the disorder, which have been determined to be TBI, apathy, and cognitive reserve.The inclusion of these as risk factors is innovative, and the emphasis on neuroimaging as diagnosis is innovative in rural environments such as this one.Further, the diagnostic approach to identifying MCR, particularly the assessment of gait repurposing the GAITRite System to diagnose pre-dementia and the addition of an algorithm to diagnose patients, is innovative.

Weaknesses
• While this proposal is novel overall, the investigators have placed most of the emphasis on their prior accomplishments and on how they extend the innovative aspects of the initial study and various other studies that Dr. Verghese is involved in to the renewal.As a result, this study is not entirely novel on its own, but rather in the context of the other projects.

Strengths
• The investigators intend to comprehensively evaluate the contribution of risk factors to the occurrence of MCR, and their project is designed in such a way that will enable them to do so.The data is scarce, and specifically, the neuroimaging data is severely lacking.This project will rectify these and enhance our understanding of dementia and pre-dementia in rural and urban communities in LMICs.

Weaknesses
• No weaknesses were noted.and Meitra Hospital have neuroimaging facilities, including an MRI scanner, and fully operational labs that will enable the investigators to execute their studies and to properly examine patients to look for MCR.The National Institute of Mental Health and Neuroscience provides support to Dr. Mathuranath.Additionally, the investigators have included Kakkodi village as their rural environment.While there isn't any hospital in Kakkodi, the site offers investigators the unique opportunity to assess MCR prevalence and incidence in rural settings.The project will greatly benefit from the unique features of the multiple environments.

Weaknesses
• No weaknesses were noted.

Capacity Building:
• The research strategy does contain appropriate plans to address the capacity building component of the RFA.

Strengths
• The study timeline is appropriate for the proposal.

Weaknesses
• No weaknesses were noted.

Protections for Human Subjects:
• Acceptable Risks and/or Adequate Protections • The risks for human subjects proposed here are acceptable and the protections are adequate.

Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):
• Acceptable • The data and safety monitoring plan in this application is acceptable.

Inclusion of Women, Minorities and Children:
• Sex/Gender: Distribution justified scientifically • This application is a renewal of previously funded grant.The investigators seek to build on their prior findings by refocusing on risk factors and brain substrates for MCR in Kerala seniors.

Budget and Period of Support:
Recommend as Requested

CRITIQUE 3
Significance: 2 Investigator(s): 1 Innovation: 2 Approach: 2 Environment: 1 Overall Impact: This is an excellent renewal proposal by a well-established, highly productive team of investigators to study MCR, MCI and related risk factors in both an urban and rural LMIC setting.These studies are impactful and innovative with strong scientific premise.Only minor concerns are noted.

Strengths
• Study of MCR and risk factors in LCMI is significant.
• Scientific premise is supported by preliminary data and literature.
• The consideration of another predementia syndrome in addition to MCI is highly significant.
• The collection of data from a rural sample is also highly significant.
• TBI appears to play a unique role in cognitive dysfunction risk in LMIC.

Weaknesses
• None noted

Strengths
• This is an excellent study team with experience to carry out the studies as proposed and a track record of work together.
• The schematic in the budget justification is incredibly useful in determining how these investigators will interact.
• The team has been very productive during the previous grant period.

Weaknesses
• None noted

Strengths
• The study of MCR and its risk factors in LMIC is highly innovative.
• The study of TBI as it relates to cognitive risk specific to LMIC is also highly innovative.

Weaknesses
• The proposal of a mechanism related to vascular disease is not novel.

Strengths
• The description of the interactions between the study team are fantastic.
• The description of the study sites is also very helpful.
• The existing infrastructure suggest a high likelihood for success.
• The potential for longitudinal imaging in an LMIC is exciting and important.

Weaknesses
• Are there differences in exposures in the urban and rural populations (i.e., pesticides, pollutants) that could bias any potential differences observed.
• Further, wouldn't one expect differences in PA between rural and urban residents just given lifestyle differences.
• What QC methods will be performed on neuroimaging data, motion often increases with cognitive impairment and could potentially systematically bias the data.

Strengths
• Environments are excellent.

Capacity Building:
• Significant opportunity for capacity building with exploration of new prodromal cognitive syndrome and expansion of neuroimaging and genetics capacities.

Protections for Human Subjects:
• Acceptable Risks and/or Adequate Protections Data and Safety Monitoring Plan (Applicable for Clinical Trials Only): • Not Applicable (No Clinical Trials)

Inclusion of Women, Minorities and Children:
• Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: • Inclusion/Exclusion of Children under 18: Excluding ages <18; justified scientifically Vertebrate Animals: • Not Applicable (No Vertebrate Animals) Footnotes for 2 R01 AG039330-07; PI Name: VERGHESE, JOE # Ad hoc or special section application percentiled against "Total CSR" base.
NIH has modified its policy regarding the receipt of resubmissions (amended applications).See Guide Notice NOT-OD-14-074 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-074.html.The impact/priority score is calculated after discussion of an application by averaging the overall scores (1-9) given by all voting reviewers on the committee and multiplying by 10.The criterion scores are submitted prior to the meeting by the individual reviewers assigned to an application, and are not discussed specifically at the review meeting Trials) Inclusion of Women, Minorities and Children: • Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: Not applicable • Inclusion/Exclusion of Children under 18: Excluding ages <18; justified scientifically Biological and/or Chemical Resources: • Not Applicable (No Relevant Resources)

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Joe Verghese, MBBS, MRCPI is the Principal Investigator.He is currently a Professor of Neurology and Medicine at Albert Einstein College of Medicine.Dr. Verghese has previously served as the Principal Investigator of the initial Kerala-Einstein Aging Study and, as a result, has extensive experience with epidemiological techniques, clinical trial experiences, experimental test development, neuroimaging, and investigations of biomarkers as well as genetic markers in the context of aging and dementia.He is joined by and Dr. who will serve as co-Principal Investigator of the study.Dr. Mathuranath is an Additional Professor at the National Institute of Mental Health and Neurosciences in Bangalore, India, and a visiting professor at Albert Einstein College of Medicine.Other co-investigators are Dr. Helena Blumen, Dr. Cuiling Wang, and Dr. Mirnova Ceide, all of Albert Einstein College of Medicine.They are also joined by Dr. Anne Ambrose.Dr. Anne Ambrose is the Co-Director of Department of Physical Medicine at the Winifred Masterson Burke Medical Research Institute.Drs.Ambrose and Mathuranath have both previously participated in the Kerala-Einstein Aging Study and their varied sets of expertise complement each other, and their synergistic efforts ensure that the renewal will be just as successful as the initial study.

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Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: Not applicable • Inclusion/Exclusion of Children under 18: Excluding ages <18; justified scientifically