Genes critical for development and differentiation of dopaminergic neurons are downregulated in Parkinson's disease.

We performed transcriptome analysis using RNA sequencing on substantia nigra pars compacta (SNpc) from mice after acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment and from Parkinson's disease (PD) patients. Acute and chronic exposure to MPTP resulted in decreased expression of genes involved in sodium channel regulation. However, upregulation of pro-inflammatory pathways was seen after single dose but not after chronic MPTP treatment. Dopamine biosynthesis and synaptic vesicle recycling pathways were downregulated in PD patients and after chronic MPTP treatment in mice. Genes essential for midbrain development and determination of dopaminergic phenotype such as, LMX1B, FOXA1, RSPO2, KLHL1, EBF3, PITX3, RGS4, ALDH1A1, RET, FOXA2, EN1, DLK1, GFRA1, LMX1A, NR4A2, GAP43, SNCA, PBX1, and GRB10 were downregulated in human PD and overexpression of GFP tagged LMX1B rescued MPP+ induced death in SH-SY5Y neurons. Downregulation of gene ensemble involved in development and differentiation of dopaminergic neurons indicate their potential involvement in pathogenesis and progression of human PD.

Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) study: Study protocol.

INTRODUCTION: Prospective, population-based, aging, and cognition studies are an important approach to understand normal and pathological aging processes. METHODS: This is a longitudinal, community-based cohort study (n = 10,000) in rural India, with long-term follow-up for comprehensive evaluation of risk and protective factors associated with cognitive changes during aging. All participants will undergo comprehensive clinical, neurocognitive, and biochemical assessments. Genotyping using genome-wide association studies will be done for all participants. Whole genome sequencing and brain imaging (magnetic resonance imaging) will be done in a subset. RESULTS: This study will generate a rich database of clinical, neurocognitive, biochemical, neuroimaging, and genetic data that can help identify risk and protective factors for dementia and other related disorders. DISCUSSION: This longitudinal study is first of its kind, involving comprehensive evaluations, spanning phenotype to genotype, in a rural Indian cohort, and has major public health implications.

Comparison of risk factors for dementia among rural and urban elderly adults-data from two cohort studies in India.

INTRODUCTION: Studies on risk factors for dementia in India, especially rural India, are sparse and therefore we aimed to assess risk factors in a rural cohort on aging and compare it with an urban cohort. METHODS: We are presenting baseline data on proportion of hypertension, diabetes, obesity, physical inactivity, and Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) scores in both cohorts. RESULTS: The rural cohort is younger and less educated than the urban cohort. The chi-square test showed that the proportion of participants with hypertension, diabetes, and obesity was lower in the rural cohort, whereas physical inactivity was higher in comparison with the urban cohort; however, the proportion of high-risk CAIDE scores was higher in the rural cohort. DISCUSSION: Despite the rural cohort having a smaller proportion of participants with hypertension, diabetes, and obesity, the overall CAIDE score was higher-the main reason for this is low educational level.

Prevalence of neuropsychiatric conditions and cognitive impairment in two parallel, aging study cohorts from rural and urban India.

INTRODUCTION: With the rising proportion of the elderly in India, the burden of neuropsychiatric conditions and cognitive impairment is escalating. METHODS: Baseline data of cognitively healthy subjects ≥45 years of age, from two longitudinal, aging cohorts in rural (n = 3262) and urban (n = 693) India, were used to calculate prevalence of depression, early-life stressful events, stroke, head injury, and cognitive impairment. RESULTS: Depression prevalence was significantly higher in rural than urban subjects, with female preponderance in both groups. Early life stressor (parental death) and head injury were significantly more common in rural than in urban India, whereas stroke was more in urban India. There was no significant difference in overall prevalence of cognitive impairment between the rural and urban cohorts; however, women had higher prevalence than men in rural, whereas this was reverse in urban subjects. Depression and stroke were significantly associated with cognitive impairment in the rural cohort. DISCUSSION: Longitudinal assessment of these neuropsychiatric conditions, with parallel cognitive monitoring, will help identify their causal relationship with dementia.

COGNITO (Computerized assessment of adult information processing): Normative scores for a rural Indian population from the SANSCOG study.

INTRODUCTION: Neuropsychological assessments are inexpensive and efficient methods to understand the cognitive abilities of individuals in research studies and clinical settings. Normative scores for such measures are crucial in serving as a reference standard for identifying cognitively healthy and impaired individuals belonging to similar sociodemographic characteristics. METHODS: Study subjects in rural India recruited into the Srinivaspura Aging, Neuro Senescence and Cognition (SANSCOG) study were administered the COGNITO battery of tests, which traverse cognitive domains of attention, memory, language, and visuospatial abilities. Percentile norms based on age and education stratification were derived for the above cohort. RESULTS: Percentile norms are commensurate with literacy levels in this population. The percentile scores for the cognitive tests show a decline for the individuals aged 75 years and above indicating lower cognitive functioning in this age group. DISCUSSION: This is the first-ever study reporting norms for diverse cognitive domains for illiterate, literate, low-literate individuals enrolled in a large-scale community-based cohort study in rural India.

Approaches to engage an aging, rural cohort in southern India during the COVID-19 crisis and the psychological impact of COVID-19 in this cohort.

INTRODUCTION: The COVID-19 pandemic produced an unprecedented crisis across the world. Long-term cohort studies were stalled, including our longitudinal aging cohort study in rural India. METHODS: We describe approaches undertaken to engage with our cohort (n = 1830) through multiple rounds of calls and how we provided useful services to our subjects during the lockdown period. Consenting subjects also underwent telephonic assessments for depression and anxiety using validated, self-report questionnaires. RESULTS: Subjects reported benefitting from our telephonic engagement strategies, including the COVID-related safety awareness and counselling service. The proportion of subjects with depression increased from 7.42% pre-COVID to 28.97% post-COVID. DISCUSSION: We envisage that such engagement strategies would improve subject rapport and cohort retention, and thus, could be adopted by similar cohort studies across the world. This marginalized, rural Indian community had severe, adverse psychological impact in this pandemic. Urgent public health measures are needed to mitigate this impact and develop appropriate preventive strategies.

Regional research priorities in brain and nervous system disorders.

The characteristics of neurological, psychiatric, developmental and substance-use disorders in low- and middle-income countries are unique and the burden that they have will be different from country to country. Many of the differences are explained by the wide variation in population demographics and size, poverty, conflict, culture, land area and quality, and genetics. Neurological, psychiatric, developmental and substance-use disorders that result from, or are worsened by, a lack of adequate nutrition and infectious disease still afflict much of sub-Saharan Africa, although disorders related to increasing longevity, such as stroke, are on the rise. In the Middle East and North Africa, major depressive disorders and post-traumatic stress disorder are a primary concern because of the conflict-ridden environment. Consanguinity is a serious concern that leads to the high prevalence of recessive disorders in the Middle East and North Africa and possibly other regions. The burden of these disorders in Latin American and Asian countries largely surrounds stroke and vascular disease, dementia and lifestyle factors that are influenced by genetics. Although much knowledge has been gained over the past 10 years, the epidemiology of the conditions in low- and middle-income countries still needs more research. Prevention and treatments could be better informed with more longitudinal studies of risk factors. Challenges and opportunities for ameliorating nervous-system disorders can benefit from both local and regional research collaborations. The lack of resources and infrastructure for health-care and related research, both in terms of personnel and equipment, along with the stigma associated with the physical or behavioural manifestations of some disorders have hampered progress in understanding the disease burden and improving brain health. Individual countries, and regions within countries, have specific needs in terms of research priorities.

Glutaredoxin 1 Downregulation in the Substantia Nigra Leads to Dopaminergic Degeneration in Mice.

BACKGROUND: Parkinson's disease (PD) is characterized by a severe loss of the dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Perturbation of protein thiol redox homeostasis has been shown to play a role in the dysregulation of cell death and cell survival signaling pathways in these neurons. Glutaredoxin 1 (Grx1) is a thiol/disulfide oxidoreductase that catalyzes the deglutathionylation of proteins and is important for regulation of cellular protein thiol redox homeostasis. OBJECTIVES: We evaluated if the downregulation of Grx1 could lead to dopaminergic degeneration and PD-relevant motor deficits in mice. METHODS: Grx1 was downregulated unilaterally through viral vector-mediated transduction of short hairpin RNA against Grx1 into the SNpc. Behavioral assessment was performed through rotarod and elevated body swing test. Stereological analysis of tyrosine hydroxylase-positive and Nissl-positive neurons was carried out to evaluate neurodegeneration. RESULTS: Downregulation of Grx1 resulted in contralateral bias of elevated body swing and reduced latency to fall off, accelerating rotarod. This was accompanied by a loss of tyrosine hydroxylase-positive neurons in the SNpc and their DA projections in the striatum. Furthermore, there was a loss Nissl-positive neurons in the SNpc, indicating cell death. This was selective to the SNpc neurons because DA neurons in the ventral tegmental area were unaffected akin to that seen in human PD. Furthermore, Grx1 mRNA expression was substantially decreased in the SNpc from PD patients. CONCLUSIONS: Our study indicates that Grx1 is critical for the survival of SNpc DA neurons and that it is downregulated in human PD. © 2020 International Parkinson and Movement Disorder Society.

Aß mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease.

Dendritic spine loss is recognized as an early feature of Alzheimer's disease (AD), but the underlying mechanisms are poorly understood. Dendritic spine structure is defined by filamentous actin (F-actin) and we observed depolymerization of synaptosomal F-actin accompanied by increased globular-actin (G-actin) at as early as 1 month of age in a mouse model of AD (APPswe/PS1ΔE9, male mice). This led to recall deficit after contextual fear conditioning (cFC) at 2 months of age in APPswe/PS1ΔE9 male mice, which could be reversed by the actin-polymerizing agent jasplakinolide. Further, the F-actin-depolymerizing agent latrunculin induced recall deficit after cFC in WT mice, indicating the importance of maintaining F-/G-actin equilibrium for optimal behavioral response. Using direct stochastic optical reconstruction microscopy (dSTORM), we show that F-actin depolymerization in spines leads to a breakdown of the nano-organization of outwardly radiating F-actin rods in cortical neurons from APPswe/PS1ΔE9 mice. Our results demonstrate that synaptic dysfunction seen as F-actin disassembly occurs very early, before onset of pathological hallmarks in AD mice, and contributes to behavioral dysfunction, indicating that depolymerization of F-actin is causal and not consequent to decreased spine density. Further, we observed decreased synaptosomal F-actin levels in postmortem brain from mild cognitive impairment and AD patients compared with subjects with normal cognition. F-actin decrease correlated inversely with increasing AD pathology (Braak score, Aß load, and tangle density) and directly with performance in episodic and working memory tasks, suggesting its role in human disease pathogenesis and progression.SIGNIFICANCE STATEMENT Synaptic dysfunction underlies cognitive deficits in Alzheimer's disease (AD). The cytoskeletal protein actin plays a critical role in maintaining structure and function of synapses. Using cultured neurons and an AD mouse model, we show for the first time that filamentous actin (F-actin) is lost selectively from synapses early in the disease process, long before the onset of classical AD pathology. We also demonstrate that loss of synaptic F-actin contributes directly to memory deficits. Loss of synaptosomal F-actin in human postmortem tissue correlates directly with decreased performance in memory test and inversely with AD pathology. Our data highlight that synaptic cytoarchitectural changes occur early in AD and they may be targeted for the development of therapeutics.

Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, caused by the degeneration of the dopaminergic neurons in the substantia nigra. Mutations in PARK7 (DJ-1) result in early onset autosomal recessive PD, and oxidative modification of DJ-1 has been reported to regulate the protective activity of DJ-1 in vitro. Glutathionylation is a prevalent redox modification of proteins resulting from the disulfide adduction of the glutathione moiety to a reactive cysteine-SH, and glutathionylation of specific proteins has been implicated in regulation of cell viability. Glutaredoxin 1 (Grx1) is the principal deglutathionylating enzyme within cells, and it has been reported to mediate protection of dopaminergic neurons in Caenorhabditis elegans; however many of the functional downstream targets of Grx1 in vivo remain unknown. Previously, DJ-1 protein content was shown to decrease concomitantly with diminution of Grx1 protein content in cell culture of model neurons (SH-SY5Y and Neuro-2A lines). In the current study we aimed to investigate the regulation of DJ-1 by Grx1 in vivo and characterize its glutathionylation in vitro. Here, with Grx(-/-) mice we provide show that Grx1 regulates protein levels of DJ-1 in vivo. Furthermore, with model neuronal cells (SH-SY5Y) we observed decreased DJ-1 protein content in response to treatment with known glutathionylating agents, and with isolated DJ-1 we identified two distinct sites of glutathionylation. Finally, we found that overexpression of DJ-1 in the dopaminergic neurons partly compensates for the loss of the Grx1 homologue in a C. elegans in vivo model of PD. Therefore, our results reveal a novel redox modification of DJ-1 and suggest a novel regulatory mechanism for DJ-1 content in vivo.

Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver.

A 30-d course of oral administration of a semipurified extract of the root of Withania somnifera consisting predominantly of withanolides and withanosides reversed behavioral deficits, plaque pathology, accumulation of ß-amyloid peptides (Aß) and oligomers in the brains of middle-aged and old APP/PS1 Alzheimer's disease transgenic mice. It was similarly effective in reversing behavioral deficits and plaque load in APPSwInd mice (line J20). The temporal sequence involved an increase in plasma Aß and a decrease in brain Aß monomer after 7 d, indicating increased transport of Aß from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Aß-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain Aß levels. However, significant increase in liver LRP and NEP occurred much earlier, at 7 d, and were accompanied by a rise in plasma sLRP, a peripheral sink for brain Aß. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain Aß, indicating that increase in liver LRP and sLRP occurring independent of Aß concentration could result in clearance of Aß. Selective down-regulation of liver LRP, but not NEP, abrogated the therapeutic effects of the extract. The remarkable therapeutic effect of W. somnifera mediated through up-regulation of liver LRP indicates that targeting the periphery offers a unique mechanism for Aß clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models.

Gulf war toxicant-induced effects on the hippocampal dendritic arbor are reversed by treatment with a Withania somnifera extract.

Gulf War Illness (GWI) is a multi-symptom disorder that manifests with fatigue, sleep disturbances, mood-cognition pathologies, and musculoskeletal symptoms. GWI affects at least 25% of the military personnel that served in Operations Desert Shield and Desert Storm from 1990 to 1991. We modeled Gulf War toxicant exposure in C57BL/6J mice by combined exposure to pyridostigmine bromide (an anti-sarin drug), chlorpyrifos (an organophosphate insecticide), and DEET (an insect repellent) for 10 days followed by oral treatment with Withania somnifera root extract for 21 days beginning at 12 weeks post-exposure. W. somnifera, commonly referred to as ashwagandha, has been used in traditional Ayurvedic medicine for centuries to improve memory and reduce inflammation, and its roots contain bioactive molecules which share functional groups with modern pain, cancer, and anti-inflammatory drugs. Previously, we observed that GWI mice displayed chronic reductions in dendritic arbor and loss of spines in granule cells of the dentate gyrus of the hippocampus at 14 weeks post-exposure. Here, we examined the effects of treatment with W. somnifera root extract on chronic dendrite and spine morphology in dentate granule cells of the mouse hippocampus following Gulf War toxicant exposure. GWI mice showed approximately 25% decreases in dendritic length (p < 0.0001) and overall dendritic spine density with significant reductions in thin and mushroom spines. GWI mice treated with the Ayurvedic W. somnifera extract exhibited dendritic lengths and spine densities near normal levels. These findings demonstrate the efficacy of the Ayurvedic treatment for neuroprotection following these toxic exposures. We hope that the extract and the neuronal processes influenced will open new avenues of research regarding treatment of Gulf War Illness and neurodegenerative disorders.

Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down-regulation of pAkt.

Impairment of Akt phosphorylation, a critical survival signal, has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. However, the mechanism underlying pAkt loss is unclear. In the current study, we demonstrate pAkt loss in ventral midbrain of mice treated with dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), when compared to ventral midbrain of control mice treated with vehicle alone. Thiol residues of the critical cysteines in Akt are oxidized to a greater degree in mice treated with MPTP, which is reflected as a 40% loss of reduced Akt. Association of oxidatively modified Akt with the phosphatase PP2A, which can lead to enhanced dephosphorylation of pAkt, was significantly stronger after MPTP treatment. Maintaining the protein thiol homeostasis by thiol antioxidants prevented loss of reduced Akt, decreased association with PP2A, and maintained pAkt levels. Overexpression of glutaredoxin, a protein disulfide oxidoreductase, in human primary neurons helped sustain reduced state of Akt and abolished MPP(+)-mediated pAkt loss. We demonstrate for the first time the selective loss of Akt activity, in vivo, due to oxidative modification of Akt and provide mechanistic insight into oxidative stress-induced down-regulation of cell survival pathway in mouse midbrain following exposure to MPTP.

Impact of the COVID-19 pandemic on some modifiable risk factors of dementia in an aging, rural Indian population.

Introduction: The impact of the COVID-19 pandemic and associated lockdowns is likely to have caused adverse changes in lifestyle-related/cardiovascular risk factors and other such modifiable risk factors of dementia. We aimed to examine the pandemic's impact on some modifiable risk factors of dementia among rural Indians belonging to a large, prospective aging cohort-Srinivaspura Aging, NeuoSenescence, and COGnition (SANSCOG). Methods: This was a cross-sectional study among adults aged ≥ 45 years (n = 3,148; 1,492 males and 1,656 females) residing in the villages of Srinivaspura in Karnataka state, India. SANSCOG study data (clinical and biochemical assessments) of these participants were obtained from three distinct periods: (i) the "pre-COVID period"-before India's nationwide lockdown on 24 March 2020, (ii) the "COVID period"-during the first and second waves of the pandemic, wherein the social restrictions were prominent (25 March 2020 to 30 September 2021), and (iii) the "post-COVID period"-after easing of restrictions (from 1 October 2021 onward). Proportions of participants with diabetes, hypertension, obesity, dyslipidemia (diagnosed using standard criteria), and depression (diagnosed using the Geriatric Depression Scale) were compared between the above three periods. Results: The odds of having obesity, abnormal triglycerides, and depression among individuals in the COVID period were 1.42 times, 1.38 times, and 2.65 times more than the odds in the pre-COVID period, respectively. The odds of having hypertension, obesity, abnormal total cholesterol, abnormal triglycerides, abnormal LDL, and depression among individuals in the post-COVID period were 1.27 times, 1.32 times, 1.58 times, 1.95, 1.23, and 3.05 times more than the odds in the pre-COVID period, respectively. The odds of diabetes did not differ between any of the three periods. Discussion: We found significantly higher odds of some of the studied risk factors in the COVID and post-COVID periods compared to the pre-COVID period, suggesting that the pandemic adversely impacted the physical and psychological health of this marginalized, rural Indian population. We call for urgent public health measures, such as multimodal, lifestyle-based, and psychosocial interventions, to mitigate this negative impact and reduce the future risk of dementia.

Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort.

Women carry a higher burden of Alzheimer's disease (AD) compared to men, which is not accounted entirely by differences in lifespan. To identify the mechanisms underlying this effect, we investigated sex-specific differences in the progression of familial AD in humans and in APPswe/PS1ΔE9 mice. Activity dependent protein translation and associative learning and memory deficits were examined in APPswe/PS1ΔE9 mice and wild-type mice. As a human comparator group, progression of cognitive dysfunction was assessed in mutation carriers and non-carriers from DIAN (Dominantly Inherited Alzheimer Network) cohort. Female APPswe/PS1ΔE9 mice did not show recall deficits after contextual fear conditioning until 8 months of age. Further, activity dependent protein translation and Akt1-mTOR signaling at the synapse were impaired in male but not in female mice until 8 months of age. Ovariectomized APPswe/PS1ΔE9 mice displayed recall deficits at 4 months of age and these were sustained until 8 months of age. Moreover, activity dependent protein translation was also impaired in 4 months old ovariectomized APPswe/PS1ΔE9 mice compared with sham female APPswe/PS1ΔE9 mice. Progression of memory impairment differed between men and women in the DIAN cohort as analyzed using linear mixed effects model, wherein men showed steeper cognitive decline irrespective of the age of entry in the study, while women showed significantly greater performance and slower decline in immediate recall (LOGIMEM) and delayed recall (MEMUNITS) than men. However, when the performance of men and women in several cognitive tasks (such as Wechsler's logical memory) are compared with the estimated year from expected symptom onset (EYO) we found no significant differences between men and women. We conclude that in familial AD patients and mouse models, females are protected, and the onset of disease is delayed as long as estrogen levels are intact.

Protein Glutathionylation and Glutaredoxin: Role in Neurodegenerative Diseases.

Oxidative stress has been implicated in the pathogenesis and progression of many neurodegenerative disorders including Parkinson's disease and Alzheimer's disease. One of the major enzyme systems involved in the defense against reactive oxygen species are the tripeptide glutathione and oxidoreductase glutaredoxin. Glutathione and glutaredoxin system are very important in the brain because of the oxidative modification of protein thiols to protein glutathione mixed disulfides with the concomitant formation of oxidized glutathione during oxidative stress. Formation of Pr-SSG acts as a sink in the brain and is reduced back to protein thiols during recovery, thus restoring protein functions. This is unlike in the liver, which has a high turnover of glutathione, and formation of Pr-SSG is very minimal as liver is able to quickly quench the prooxidant species. Given the important role glutathione and glutaredoxin play in the brain, both in normal and pathologic states, it is necessary to study ways to augment the system to help maintain the protein thiol status. This review details the importance of glutathione and glutaredoxin systems in several neurodegenerative disorders and emphasizes the potential augmentation of this system as a target to effectively protect the brain during aging.

Rural-urban and gender differences in metabolic syndrome in the aging population from southern India: Two parallel, prospective cohort studies.

Background: Despite the growing evidence of metabolic syndrome as a major risk factor for cardiovascular and cerebrovascular disease, there are limited studies from India on its prevalence, especially in the aging population. We aimed to estimate the prevalence of metabolic syndrome and associated comorbidities in two prospective, aging cohorts from rural and urban India. Methods: In these two parallel, prospective, aging (≥ 45 years) cohorts, the samples included 2171 people from rural India (Srinivaspura Aging, Neuro Senescence and COGnition, SANSCOG cohort; April 23, 2018 to Sept 25, 2021) and 332 people from urban India (Tata Longitudinal Study on Aging, TLSA cohort; July 8, 2015 to Oct 23, 2021). Using cross-sectional data from baseline clinical and biochemical assessments, we calculated metabolic syndrome prevalence using two well established criteria, namely consensus criteria and National Cholesterol Education Program - Adult Treatment Panel III (NCEP-ATP III) criteria; further, rural-urban, gender, and age-wise differences were compared. Findings: Proportions of metabolic syndrome were 46.2 and 54.8% as per consensus criteria in rural and urban participants, respectively; corresponding numbers using NCEP-ATP III criteria were 40.3 and 45.1%. Rural-dwelling older adults had a significantly lesser prevalence of all individual metabolic syndrome parameters except impaired triglycerides and high-density lipoprotein levels. Rural women had a significantly higher prevalence of metabolic syndrome than rural men, whereas there was no significant difference among urban participants. We did not observe any consistent age-wise trend when comparing both cohorts. There was high burden of comorbidities among both groups, mostly undiagnosed in rural participants. Interpretation: Roughly one in two older adults had metabolic syndrome, urban significantly more than rural, reaching an alarming 63.1% among urban participants aged 65-74 years. The very high prevalence of undiagnosed co-morbidities among rural adults is extremely concerning, calling for urgent public health measures in this marginalised and health-disparate population. Funding: SANSCOG study is funded through the Centre for Brain Research (CBR), Indian Institute of Science (IISc) by Pratiksha Trust, the philanthropic arm of Mr. Kris Gopalakrishnan. TLSA is funded by Tata Trusts.

Normative data for three physical frailty parameters in an aging, rural Indian population.

Introduction: Physical frailty is associated with multiple adverse health outcomes. Since physical characteristics markedly vary with different populations, population-specific norms for physical frailty parameters are necessary. Such norms are lacking for the Indian population, especially for older, rural Indians. We aimed to develop normative values for three quantitative, frailty parameters-handgrip strength, "Timed Up-and-Go" (TUG) test time, and physical activity in an aging, rural Indian population. Methods: The study sample is from an ongoing, prospective, cohort (Srinivaspura NeuoSenescence and COGnition, SANSCOG) comprised of rural, community-dwelling, cognitively healthy, aging Indians. Subjects are recruited through area sampling strategy, from villages of Srinivaspura, Kolar district, Karnataka state, India. Three physical frailty parameters of Fried's phenotype-handgrip strength (n = 1787), TUG time (n = 1863), and physical activity (n = 1640) were assessed using digital hand dynamometry, TUG test, and General Physical Activity Questionnaire (GPAQ), respectively. Results: The 10th, 25th, 50th, 75th, 90th percentiles for the three frailty parameters were: right-hand grip strength (kg): males-13.9, 18.6, 23.8, 28.7, 33.7 and females-7.8, 10.6, 14.2, 17.9, 21.3; left-hand grip strength (kg): males-13.3, 18.3, 23.6, 28.9, 32.9 and females-7.9, 10.5, 14.3, 17.8, 21.2; TUG time (s): males-9.1, 10.1, 11.4, 13.4, 15.5 and females-9.5, 10.7, 12.4, 14.5, 16.6; physical activity (MET-minutes/week): males-1680; 4320; 8880; 15,840; 23,352 and females-1680; 4320; 9240; 15,120; 20,160. Discussion: Our findings show that from 45 years onwards, overall grip strength decreases and TUG time increases, with women performing significantly poorer than men across all age groups, except >75 years, where no differences were seen. Physical activity did not show any consistent trend according to age or gender. Reference values for this aging, rural Indian population were substantially lower for grip strength and higher for TUG time than aging populations in several Western and other Asian countries.

Depression and anxiety during the first and second waves of the COVID-19 pandemic in two large, prospective, aging cohorts in rural and urban India.

Introduction: The COVID-19 pandemic resulted in a wide variety of adverse consequences, including disruption of long-term, human research studies globally. Two long-term, prospective, aging cohort studies, namely, Srinivaspura Aging, Neurosenescence and COGnition (SANSCOG) study and Tata Longitudinal Study of Aging (TLSA), conducted in rural and urban India, respectively, had to be suspended during first and second waves of COVID-19. Methods: We conducted telephonic assessments to screen for depression and anxiety in the above two cohorts comprising of adults ≥45 years, during the first wave (2020) and second wave (2021) lockdown periods in India. Further, we included depression assessments data from two additional time periods-pre-COVID (2019) and the "inter-wave" period (between the first and second waves) to compare proportions of depression in these cohorts, during four distinct time periods-(i) pre-COVID, (ii) COVID first wave lockdown, (iii) inter-wave period, and (iv) COVID second wave lockdown (rural: 684, 733, 458, 611 and urban: 317, 297, 204, 305 respectively). Results: During COVID first wave, 28.8% and 5.5% had depression and anxiety, respectively in the rural cohort. Corresponding figures in the urban cohort were 6.5% and 1.7%. During second wave, 28.8% of rural subjects had depression and 3.9% had anxiety, whereas corresponding figures in urban subjects were 13.1% and 0.66%. During the above-mentioned four time periods, proportions of depression were: rural-8.3%, 28.8%, 16.6%, 28.8%; urban-12%, 6.1%, 8.8%, 13.1%. Conclusions: Multi-fold increase in depression among aging, rural Indians during first and second waves, with high depression among subjects ≥65 years and those with comorbidities during the first wave, is concerning. Urgent public health measures are needed to address this added mental health burden and thereby, prevent further potential adverse consequences.