The 2022 symposium on dementia and brain aging in low- and middle-income countries: Highlights on research, diagnosis, care, and impact.

Two of every three persons living with dementia reside in low- and middle-income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high-income countries (HICs), with dementia research predominantly focusing on HICs. This imbalance necessitates LMIC-focused research to ensure that characterization of dementia accurately reflects the involvement and specificities of diverse populations. Development of effective preventive, diagnostic, and therapeutic approaches for dementia in LMICs requires targeted, personalized, and harmonized efforts. Our article represents timely discussions at the 2022 Symposium on Dementia and Brain Aging in LMICs that identified the foremost opportunities to advance dementia research, differential diagnosis, use of neuropsychometric tools, awareness, and treatment options. We highlight key topics discussed at the meeting and provide future recommendations to foster a more equitable landscape for dementia prevention, diagnosis, care, policy, and management in LMICs. HIGHLIGHTS: Two-thirds of persons with dementia live in LMICs, yet research and costs are skewed toward HICs. LMICs expect dementia prevalence to more than double, accompanied by socioeconomic disparities. The 2022 Symposium on Dementia in LMICs addressed advances in research, diagnosis, prevention, and policy. The Nairobi Declaration urges global action to enhance dementia outcomes in LMICs.

Commonality and variation in mental representations of music revealed by a cross-cultural comparison of rhythm priors in 15 countries.

Music is present in every known society but varies from place to place. What, if anything, is universal to music cognition? We measured a signature of mental representations of rhythm in 39 participant groups in 15 countries, spanning urban societies and Indigenous populations. Listeners reproduced random 'seed' rhythms; their reproductions were fed back as the stimulus (as in the game of 'telephone'), such that their biases (the prior) could be estimated from the distribution of reproductions. Every tested group showed a sparse prior with peaks at integer-ratio rhythms. However, the importance of different integer ratios varied across groups, often reflecting local musical practices. Our results suggest a common feature of music cognition: discrete rhythm 'categories' at small-integer ratios. These discrete representations plausibly stabilize musical systems in the face of cultural transmission but interact with culture-specific traditions to yield the diversity that is evident when mental representations are probed across many cultures.

The Most Difficult Question in a Cognitive Disorders Clinic.

This essay describes the difficulty in diagnosing dementia and the experiences and questions caregivers have regarding its diagnosis.

Clinicoradiological Features and Long-term Cognitive and Functional Outcome in Patients with Deep Cerebral Venous Thrombosis.

Background: Deep cerebral venous thrombosis (DCVT) can have long-term functional and cognitive sequelae. Although literature exists on cognitive impairment after arterial stroke, cognitive sequelae after cerebral venous thrombosis (CVT) are much less studied. Methods: Clinical records of 29 patients diagnosed with DCVT were reviewed. The Modified Telephonic Interview for Cognitive Status (TICS-M) was adapted and validated in the regional language (Kannada) and applied to 18 patients with DCVT, at a mean follow-up duration of 5.32 years. Screening for depression was done via telephonic Patient Health Questionnaire-9 (PHQ-9)-Kannada version, and functional status was screened by applying the modified Rankin Scale (mRS). Results: DCVT had a mortality rate of 10.34% due to acute complications. mRS scores of 0-1 were achieved at follow-up in all patients who survived. Receiver operating characteristic (ROC) analysis revealed a cutoff of ≤44.5 (maximum score of 49) for the diagnosis of cognitive impairment via TICS-M (Kannada version) in DCVT patients. Evidence of cognitive dysfunction was seen in eight patients (42.10%), and three patients (16.66%) had evidence of depression. Conclusions: Survivors of acute DCVT can potentially have long-term cognitive sequelae. Screening for cognitive dysfunction, depression, and functional status can be effectively done using telephonically applied scales that are adapted to the local language. Neuropsychological evaluation and early cognitive rehabilitation can be initiated for patients in whom deficits are identified on cognitive screening.

Protective effect of bilingualism on aging, MCI, and dementia: A community-based study.

INTRODUCTION: Lifelong bilingualism is associated with a delayed age at onset of dementia, but evidence from community-based studies is limited. We investigated the relationship between bilingualism and the prevalence of cognitive impairment in a linguistically diverse community. METHODS: A door-to-door community study was conducted from January to December 2021 in urban Bengaluru, India. 1234 individuals aged ≥60 years participated in the study. Participants were diagnosed with no cognitive impairment (NCI), mild cognitive impairment (MCI), or dementia using established diagnostic criteria. RESULTS: Dementia prevalence was higher in monolinguals (4.9%) than bilinguals (0.4%) (P = .001). The prevalence of MCI was also higher in monolinguals (8.5%) than bilinguals (5.3%) (P = .001). The study also revealed better cognitive function in bilinguals than monolinguals with NCI, after controlling for confounding variables. DISCUSSION: The current study provides significant support for the protective effect of bilingualism on cognitive impairment in an urban community with extensive bilingual interactional contexts in everyday life. HIGHLIGHTS: Bilingualism has been demonstrated to protect against dementia and mild cognitive impairment in a linguistically diverse community with extensive code-switching contexts. Bilingual older individuals had superior baseline cognitive performance compared to monolingual older individuals. Bilingualism was found to have an independent effect on general cognition after adjusting for major social determinants of health in the group without cognitive impairment.

Illiterate Addenbrooke's Cognitive Examination-III in Three Indian Languages: An Adaptation and Validation Study.

BACKGROUND: Literacy is an important factor that predicts cognitive performance. Existing cognitive screening tools are validated only in educated populations and are not appropriate for older adults with little or no education leading to poor performance on these tests and eventually leading to misdiagnosis. This challenge for clinicians necessitates a screening tool suitable for illiterate or low-literate older individuals. OBJECTIVES: The objective was to adapt and validate Addenbrooke's Cognitive Examination-III (ACE-III) for screening general cognitive functions in illiterate and low-literate older populations in the Indian context in three languages. METHOD: The Indian illiterate ACE-III was systematically adapted by modifying the original items of the Indian literate ACE-III to assess the cognitive functions of illiterates and low-literates with the consensus of an expert panel of professionals working in the area of dementia and related disorders. A total of 180 illiterate or low-literate participants (84 healthy-controls, 50 with dementia, and 46 with mild cognitive impairment [MCI]) were recruited from three different centers speaking Bengali, Hindi, and Kannada to validate the adapted version. RESULTS: The optimal cut-off score for illiterate ACE-III to distinguish controls from dementia in all 3 languages was 75. The optimal cut-off scores in distinguishing between controls and MCI ranged from 79 to 82, with a sensitivity ranging from 93% to 99% and a specificity ranging from 72% to 99%. CONCLUSION: The test is found to have good psychometric properties and is a reliable cognitive screening tool for identifying dementia and MCI in older adults with low educational backgrounds in the Indian context.

Alzheimer's Disease Is Associated with Increased Network Assortativity: Evidence from Metabolic Connectivity.

Introduction: Unraveling the network pathobiology in neurodegenerative disorders is a popular and promising field in research. We use a relatively newer network measure of assortativity in metabolic connectivity to understand network differences in patients with Alzheimer's Disease (AD), compared with those with mild cognitive impairment (MCI). Methods: Eighty-three demographically matched patients with dementia (56 AD and 27 MCI) who underwent positron emission tomography-magnetic resonance imaging (PET-MRI) study were recruited for this exploratory study. Global and nodal network measures obtained using the BRain Analysis using graPH theory toolbox were used to derive group-level differences (corrected p < 0.05). The methods were validated in age, and gender-matched 23 cognitively normal, 25 MCI, and 53 AD patients from the publicly available Alzheimer's Disease Neuroimaging Initiative (ADNI) data. Regions that revealed significant differences were correlated with the Addenbrooke's Cognitive Examination-III (ACE-III) scores. Results: Patients with AD revealed significantly increased global assortativity compared with the MCI group. In addition, they also revealed increased modularity and decreased participation coefficient. These findings were validated in the ADNI data. We also found that the regional standard uptake values of the right superior parietal and left superior temporal lobes were proportional to the ACE-III memory subdomain scores. Conclusion: Global errors associated with network assortativity are found in patients with AD, making the networks more regular and less resilient. Since the regional measures of these network errors were proportional to memory deficits, these measures could be useful in understanding the network pathobiology in AD.

Pathways to care for people with dementia in India: An exploratory study using case vignettes.

BACKGROUND: Limited evidence exists on how people living with dementia and their family/unpaid carers navigate care and support in India. AIM: This study used case vignettes to illustrate likely pathways to care for dementia, from receiving a diagnosis to long-term support, in India and to highlight gaps and challenges associated with current care provision for persons living with dementia. METHODS: As part of the Strengthening Responses to Dementia in Developing Countries (STRiDE) project, and to contribute to an analysis of dementia care policies and systems in India, case vignettes were used to illustrate the diverse situations that people with dementia and their families may experience when seeking care in the Indian context. Eight hypothetical, but realistic cases of people with dementia were created by a multi-disciplinary team with experience in dementia care in India, to map out the likely care journeys of each case. RESULTS: Investigating eight diverse care trajectories of people living with dementia highlighted important patterns relevant to the Indian context. We identified delays in dementia diagnosis to be attributed to low awareness of dementia among the general public and medical professionals in addition to a critical shortage of specialist services involved in facilitating dementia diagnosis. Post-diagnosis, support was recognized as limited and associated with considerable out-of-pocket (OOP) costs. Families primarily provide long-term care for people with dementia till end of life. CONCLUSIONS AND RECOMMENDATIONS: Several steps need to be taken in order to improve dementia care in India. Increasing dementia awareness among both medical professionals and general public is essential. Shortages in dementia specialists can be addressed in part through appropriate task shifting. Lastly, more research is needed to develop evidence-based community interventions to support informal care provision for persons with dementia in India.

Estimating the number of people living with dementia at different stages of the condition in India: A Delphi process.

INTRODUCTION: Numerous studies have previously estimated the dementia prevalence in India. However, as these estimates use different methodologies and sampling strategies, generating definitive prevalence estimates can be difficult. METHODS: A Delphi process involving eight clinical and academic experts provided prevalence estimates of dementia within India, split by sex and age. The experts were also asked to estimate the number of people potentially living at different stages of the condition. A priori criteria were used to ascertain the point in which consensus was achieved. RESULTS: Our consensus estimates generated a dementia prevalence of 2.8% (95% CI = 1.9 to 3.6) for those aged 60 years and above in India. Consensus was achieved across age and sex prevalence estimates, with the exception of one (females aged 60-64). Our experts estimated that 42.9% of people living with dementia in India had a mild severity. CONCLUSIONS: The findings indicate that there could be approximately 3.9 million people living with dementia in India, of which 1.7 million could be living with dementia of mild severity. Such estimates can better help researchers and policy makers to estimate the true cost and impact of dementia in India and can inform resource allocation decisions.

Gaps in clinical research in frontotemporal dementia: A call for diversity and disparities-focused research.

Frontotemporal dementia (FTD) is one of the leading causes of dementia before age 65 and often manifests as abnormal behavior (in behavioral variant FTD) or language impairment (in primary progressive aphasia). FTD's exact clinical presentation varies by culture, language, education, social norms, and other socioeconomic factors; current research and clinical practice, however, is mainly based on studies conducted in North America and Western Europe. Changes in diagnostic criteria and procedures as well as new or adapted cognitive tests are likely needed to take into consideration global diversity. This perspective paper by two professional interest areas of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment examines how increasing global diversity impacts the clinical presentation, screening, assessment, and diagnosis of FTD and its treatment and care. It subsequently provides recommendations to address immediate needs to advance global FTD research and clinical practice.

Clinical trials in vascular cognitive impairment following SPRINT-MIND: An international perspective.

A large interventional trial, the Systolic Blood Pressure Intervention Trial sub-study termed Memory and Cognition in Decreased Hypertension (SPRINT-MIND), found reduced risk of cognitive impairment in older adults with intensive, relative to standard, blood-pressure-lowering targets (systolic BP < 120 vs. <140 mm Hg). In this perspective, we discuss key questions and make recommendations for clinical practice and for clinical trials, following SPRINT-MIND. Future trials should embody cognitive endpoints appropriate to the participant group, ideally with adaptive designs that ensure robust answers for cognitive and cardiovascular endpoints. Reliable data from diverse populations, including the oldest-old (age > 80 years), will maximize external validity and global implementation of trial findings. New biomarkers will improve phenotyping to stratify patients to optimal treatments. Currently no antihypertensive drug class stands out for dementia risk reduction. Multi-domain interventions, incorporating lifestyle change (exercise, diet) alongside medications, may maximize global impact. Given the low cost and wide availability of antihypertensive drugs, intensive BP reduction may be a cost-effective means to reduce dementia risk in diverse, aging populations worldwide.

A call for clinical trial globalization in Alzheimer's disease and related dementia.

BACKGROUND: The burden of Alzheimer's disease and related dementia (ADRD) is projected to disproportionally impact low-middle-income countries (LMICs). However, there is a systematic under-representation of LMICs in ADRD clinical trial platforms. METHODS: We aimed to determine the global distribution of ADRD clinical trials and identify existing barriers for conducting clinical trials in LMICs. Primary data sources to identify trial distribution in LMICs included ClinicalTrials.gov and the International Trials Registry Platform. An additional systematic review and expert consensus interviews were conducted to identify barriers for conducting clinical trials in LMICs. FINDINGS: Among 1237 disease-modifying therapies tested in ADRD clinical trials, only 11.6% have been or are conducted in emerging economies (upper-middle income [9.6%] and low-middle income [2.0%]). We identified several limitations for trial implementation including a lack of financial resources, low industry presence, regulatory obstacles, and operational barriers INTERPRETATION: Although LMICs bear the greatest burden of ADRD globally, substantial development of clinical trial platforms to address this inequity and health disparity is lacking.

Pathological (Dis)Similarities in Neuronal Exosome-Derived Synaptic and Organellar Marker Levels Between Alzheimer's Disease and Frontotemporal Dementia.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are pathologically distinct neurodegenerative disorders with certain overlap in cognitive and behavioral symptoms. Both AD and FTD are characterized by synaptic loss and accumulation of misfolded proteins, albeit, in different regions of the brain. OBJECTIVE: To investigate the synaptic and organellar markers in AD and FTD through assessment of the levels of synaptic protein, neurogranin (Ng) and organellar proteins, mitofusin-2 (MFN-2), lysosomal associated membrane protein-2 (LAMP-2), and golgin A4 from neuronal exosomes. METHODS: Exosomes isolated from the plasma of healthy controls (HC), AD and FTD subjects were characterized using transmission electron microscopy. Neurodegenerative status was assessed by measurement of neurofilament light chain (NfL) using Simoa. The pooled exosomal extracts from each group were analyzed for Ng, MFN-2, LAMP-2, and golgin A4 by western blot analysis using enhanced chemiluminescence method of detection. RESULTS: The densitometric analysis of immunoreactive bands demonstrated a 65% reduction of Ng in AD and 53% in FTD. Mitochondrial protein MFN-2 showed a significant reduction by 32% in AD and 46% in FTD. Lysosomal LAMP-2 and Golgi complex associated golgin A4 were considerably increased in both AD and FTD. CONCLUSION: Changes in Ng may reflect the ongoing synaptic degeneration that are linked to cognitive disturbances in AD and FTD. Importantly, the rate of synaptic degeneration was more pronounced in AD. Changes to a similar extent in both the dementia groups in organellar proteins indicates shared mechanisms of protein accumulation/degradation common to both AD and FTD.