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.

Attentional ERPs in consumers of smoked and insufflated cocaine associated with neuropsychological performance.

BACKGROUND: Cocaine consumption is associated with reduced attentional event-related potentials (ERPs), namely P3a and P3b, indicating bottom-up and top-down deficits respectively. At cognitive level, these impairments are larger for faster routes of administration (e.g., smoked cocaine [SC]) than slower routes (e.g., insufflated cocaine [IC]). Here we assess these ERPs considering the route of cocaine administration. We hypothesized that SC dependent (SCD) would exhibit reduced amplitude of the P3a, while both SCD and IC dependent (ICD) would show reduced amplitude of the P3b. METHODS: We examined 25 SCD, 22 ICD matched by poly-consumption profiles, and 25 controls matched by demographic variables. We combined EEG data from the Global-Local task with behavioral data from attentional cognitive tasks. RESULTS: At the behavioral level, SCD exhibited attentional deficits in both bottom-up and top-down processes, while ICD only showed a tendency for top-down deficits. The amplitude of P3a and P3b was lower in Users groups. We observed subtle route-based differences, with larger differences in the P3a for SCD and in the P3b for ICD. Neurophysiological and behavioral data converged, with the P3a associated to bottom-up performance and P3b to top-down. CONCLUSIONS: Different routes of administration lead to distinct attentional neurocognitive profiles. Specifically, SCD showed greater attentional impairment, mainly at bottom-up/P3a, while ICD showed a trend of top-down/P3b deficits. These findings emphasize the crucial role of considering the route of administration in both clinical and research settings and support the use of attentional ERPs as valid measures for assessing attentional deficits in substance Dependence.

The Brain Economy: Advancing Brain Science to Better Understand the Modern Economy.

The coming years are likely to be turbulent due to a myriad of factors or polycrisis, including an escalation in climate extremes, emerging public health threats, weak productivity, increases in global economic instability and further weakening in the integrity of global democracy. These formidable challenges are not exogenous to the economy but are in some cases generated by the system itself. They can be overcome, but only with far-reaching changes to global economics. Our current socio-economic paradigm is insufficient for addressing these complex challenges, let alone sustaining human development, well-being and happiness. To support the flourishing of the global population in the age of polycrisis, we need a novel, person-centred and collective paradigm. The brain economy leverages insights from neuroscience to provide a novel way of centralising the human contribution to the economy, how the economy in turn shapes our lives and positive feedbacks between the two. The brain economy is primarily based on Brain Capital, an economic asset integrating brain health and brain skills, the social, emotional, and the diversity of cognitive brain resources of individuals and communities. People with healthy brains are essential to navigate increasingly complex systems. Policies and investments that improve brain health and hence citizens' cognitive functions and boost brain performance can increase productivity, stimulate greater creativity and economic dynamism, utilise often underdeveloped intellectual resources, afford social cohesion, and create a more resilient, adaptable and sustainability-engaged population.

Investing in Late-Life Brain Capital.

Within many societies and cultures around the world, older adults are too often undervalued and underappreciated. This exacerbates many key challenges that older adults may face. It also undermines the many positive aspects of late life that are of tremendous value at both an individual and societal level. We propose a new approach to elevate health and well-being in late life by optimizing late-life Brain Capital. This form of capital prioritizes brain skills and brain health in a brain economy, which the challenges and opportunities of the 21st-century demands. This approach incorporates investing in late-life Brain Capital, developing initiatives focused on building late-life Brain Capital.

Psychological symptoms, mental fatigue and behavioural adherence after 72 continuous days of strict lockdown during the COVID-19 pandemic in Argentina.

BACKGROUND: An early and prolonged lockdown was adopted in Argentina during the first wave of COVID-19. Early reports evidenced elevated psychological symptoms. AIMS: To explore if the prolonged lockdown was associated with elevated anxiety and depressive symptoms; if mental fatigue was associated with lockdown adherence (a phenomenon called 'behavioural fatigue'); and if financial concerns were associated with lockdown adherence and emotional symptoms. METHOD: The survey included standardised questionnaires to assess depressive (PHQ-9) and anxious (GAD-7) symptoms, mental fatigue, risk perception, lockdown adherence, financial concerns, daily stress, loneliness, intolerance to uncertainty, negative repetitive thinking and cognitive problems. LASSO regression analyses were carried out to predict depression, anxiety and lockdown adherence. RESULTS: The survey reached 3617 adults (85.2% female) from all provinces of Argentina after 72 days of lockdown. Data were collected between 21 May 2020 and 4 June 2020. In that period, Argentina had an Oxford stringency index of 85/100. Of those surveyed, 45.6% and 27% met the cut-offs for depression and anxiety, respectively. Mental fatigue, cognitive failures and financial concerns were correlated with psychological symptoms, but not with adherence to lockdown. In regression models, mental fatigue, cognitive failures and loneliness were the most important variables to predict depression, intolerance to uncertainty and lockdown difficulty were the most important for anxiety, and perceived threat was the most important for predicting lockdown adherence. CONCLUSIONS: During the extended lockdown, psychological symptoms increased, being enhanced by mental fatigue, cognitive difficulties and financial concerns. We found no evidence of behavioural fatigue. Thus, feeling mentally fatigued is not the same as being behaviourally fatigued.

Early onset consumption of coca paste associated with executive-attention vulnerability markers linked to caudate-frontal structural and functional abnormalities.

Coca paste is the most popular form of smoked cocaine (SC) in Latin America and also the most widespread among adolescents in vulnerable sectors of society, thus representing a significant public health concern. Despite evidence suggesting that abnormal executive-attention function is predictive of addiction to stimulant drugs, no study to date has compared clinically relevant neuropsychological (NPS) and physiological variables between individuals with histories of smoked cocaine dependence (SCD) and insufflated cocaine hydrochloride dependence (ICD). In this study we evaluated 25 SCD and 22 ICD subjects matched by poly-consumption profiles, and 25 healthy controls (CTR) matched by age, gender, education, and socioeconomic status. An exhaustive NPS battery was used to assess cognitive domains (attention, executive functions, fluid intelligence, memory, language and social cognition). We complemented this assessment with structural (MRI) and functional (fMRI) neuroimaging data. We found that executive function and attention impairments could be explained by the administration route of cocaine, with strongest impairments for the SCD group. SCD also presented reduced grey matter density relative to ICD and CTR in the bilateral caudate, a key area for executive and attentional function. Functional connectivity between left caudate and inferior frontal regions mediated the association between brain structure and behavioral performance. Our results highlight the relevance of assessing the route of administration of stimulants, both in clinical and research settings.

Building brain capital.

Brains are indispensable drivers of human progress. Why not invest more heavily in them? We seek to place Brain Capital at the center of a new narrative to fuel economic and societal recovery and resilience.

The relationship between executive functions and fluid intelligence in multiple sclerosis.

BACKGROUND & OBJECTIVE: Deficits in cognitive functions dependent upon the integrity of the prefrontal cortex have been described in Multiple Sclerosis (MS). In a series of studies we have shown that fluid intelligence (g) is a substantial contributor to frontal deficits and that, for some classical "executive" tasks, frontal deficits were entirely explained by g. However, for another group of frontal tasks deficits remained once g was introduced as a covariate. This second set of tests included multitasking and theory of mind tasks. In the present study, we aimed at determining the role of fluid intelligence in frontal deficits seen in patients with MS. METHODS: A group of patients with Relapsing Remitting MS (n = 36) and a group of control subjects (n = 42) were assessed with a battery of classical executive tests (which included the Wisconsin Card Sorting Test, Verbal Fluency, and Trail Making Test B), a multitasking test, a theory of mind test and a fluid intelligence test. RESULTS: MS patients showed significant deficits in the fluid intelligence task. We found differences between patients and control subjects in all tests except for the multitasking test. The differences in the classical executive tests became non-significant once fluid intelligence was introduced as a covariate, but differences in theory of mind remained. CONCLUSIONS: The present results suggest that fluid intelligence can be affected in MS and that this impairment can play a role in the executive deficits described in MS.

Evaluating the reliability of neurocognitive biomarkers of neurodegenerative diseases across countries: A machine learning approach.

Accurate early diagnosis of neurodegenerative diseases represents a growing challenge for current clinical practice. Promisingly, current tools can be complemented by computational decision-support methods to objectively analyze multidimensional measures and increase diagnostic confidence. Yet, widespread application of these tools cannot be recommended unless they are proven to perform consistently and reproducibly across samples from different countries. We implemented machine-learning algorithms to evaluate the prediction power of neurocognitive biomarkers (behavioral and imaging measures) for classifying two neurodegenerative conditions -Alzheimer Disease (AD) and behavioral variant frontotemporal dementia (bvFTD)- across three different countries (>200 participants). We use machine-learning tools integrating multimodal measures such as cognitive scores (executive functions and cognitive screening) and brain atrophy volume (voxel based morphometry from fronto-temporo-insular regions in bvFTD, and temporo-parietal regions in AD) to identify the most relevant features in predicting the incidence of the diseases. In the Country-1 cohort, predictions of AD and bvFTD became maximally improved upon inclusion of cognitive screenings outcomes combined with atrophy levels. Multimodal training data from this cohort allowed predicting both AD and bvFTD in the other two novel datasets from other countries with high accuracy (>90%), demonstrating the robustness of the approach as well as the differential specificity and reliability of behavioral and neural markers for each condition. In sum, this is the first study, across centers and countries, to validate the predictive power of cognitive signatures combined with atrophy levels for contrastive neurodegenerative conditions, validating a benchmark for future assessments of reliability and reproducibility.

Explicit and implicit monitoring in neurodegeneration and stroke.

Monitoring is a complex multidimensional neurocognitive phenomenon. Patients with fronto-insular stroke (FIS), behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) show a lack of self-awareness, insight, and self-monitoring, which translate into anosognosia and daily behavioural impairments. Notably, they also present damage in key monitoring areas. While neuroscientific research on this domain has accrued in recent years, no previous study has compared monitoring performance across these brain diseases and none has applied a multiple lesion model approach combined with neuroimaging analysis. Here, we evaluated explicit and implicit monitoring in patients with focal stoke (FIS) and two types of dementia (bvFTD and AD) presenting damage in key monitoring areas. Participants performed a visual perception task and provided two types of report: confidence (explicit judgment of trust about their performance) and wagering (implicit reports which consisted in betting on their accuracy in the perceptual task). Then, damaged areas were analyzed via structural MRI to identify associations with potential behavioral deficits. In AD, inadequate confidence judgments were accompanied by poor wagering performance, demonstrating explicit and implicit monitoring impairments. By contrast, disorders of implicit monitoring in FIS and bvFTD patients occurred in the context of accurate confidence reports, suggesting a reduced ability to turn self-knowledge into appropriate wagering conducts. MRI analysis showed that ventromedial compromise was related to overconfidence, whereas fronto-temporo-insular damage was associated with excessive wagering. Therefore, joint assessment of explicit and implicit monitoring could favor a better differentiation of neurological profiles (frontal damage vs AD) and eventually contribute to delineating clinical interventions.

Robust automated computational approach for classifying frontotemporal neurodegeneration: Multimodal/multicenter neuroimaging.

INTRODUCTION: Timely diagnosis of behavioral variant frontotemporal dementia (bvFTD) remains challenging because it depends on clinical expertise and potentially ambiguous diagnostic guidelines. Recent recommendations highlight the role of multimodal neuroimaging and machine learning methods as complementary tools to address this problem. METHODS: We developed an automatic, cross-center, multimodal computational approach for robust classification of patients with bvFTD and healthy controls. We analyzed structural magnetic resonance imaging and resting-state functional connectivity from 44 patients with bvFTD and 60 healthy controls (across three imaging centers with different acquisition protocols) using a fully automated processing pipeline, including site normalization, native space feature extraction, and a random forest classifier. RESULTS: Our method successfully combined multimodal imaging information with high accuracy (91%), sensitivity (83.7%), and specificity (96.6%). DISCUSSION: This multimodal approach enhanced the system's performance and provided a clinically informative method for neuroimaging analysis. This underscores the relevance of combining multimodal imaging and machine learning as a gold standard for dementia diagnosis.

More than words: Social cognition across variants of primary progressive aphasia.

Although primary progressive aphasia (PPA) is clinically typified by linguistic impairments, emerging evidence highlights the presence of early deficits in social cognition. This review systematically describes the latter patterns, specifying their relation to the characteristic linguistic dysfunctions and atrophy patterns of non-fluent, semantic, and logopenic variants of the disease (nfvPPA, svPPA, and lvPPA, respectively), relative to closely related dementia types. Whereas the evidence on lvPPA proves scant, studies on nfvPPA and svPPA patients show consistent deficits in emotion recognition, theory of mind, and empathy. Notably, these seem to be intertwined with language impairments in nfvPPA, but they prove primary and independent of language disturbances in svPPA. Also, only the profile of svPPA resembles that of behavioral variant frontotemporal dementia, probably reflecting the overlap of fronto-temporal disruptions in both conditions. In short, the neurocognitive relationship between linguistic and socio-cognitive deficits cannot be precisely predicated for PPA as a whole; instead, specific links must be acknowledged in each variant. These emergent patterns pave the way for fruitful dimensional research in the field.

Reading Shakespearean tropes in a foreign tongue: Age of L2 acquisition modulates neural responses to functional shifts.

Functional shifts (FSs) - morphosyntactically marked words evoking coherent but novel meanings - are ubiquitous in English and, specially, in Shakespearean literature. While their neural signatures have been explored in native speakers, no study has targeted foreign-language users, let alone comparing early and late bilinguals. Here, we administered a validated FS paradigm to subjects from both populations and evaluated time-frequency modulations evoked by FS and control sentences. Early bilinguals exhibited greater sensitivity towards FSs, indexed by reduced fronto-posterior theta-band oscillations across semantic- and structural-integration windows. Such oscillatory modulations may represent a key marker of age-of-acquisition effects during foreign-language wordplay processing.

Brain structural correlates of executive and social cognition profiles in behavioral variant frontotemporal dementia and elderly bipolar disorder.

An early stage of behavioral variant frontotemporal dementia (bvFTD) often displays a mix of behavioral disturbances and personality changes hindering a differential diagnosis from elderly bipolar disorder (BD), making this process a big challenge. However, no studies have compared these pathologies from neuropsychological and neuroanatomical perspectives. The aim of the present study was to compare the executive functions (EF) and social cognition profiles as well as the structural neuroimaging of bvFTD and elderly patients with BD. First, we compared the executive and social cognition performances of 16 bvFTD patients, 13 BD patients and 22 healthy controls. Second, we compared grey matter volumes in both groups of patients and controls using voxel-based morphometry. Lastly, we examined the brain regions where atrophy might be associated with specific impairments in bvFTD and BD patients. Compared to controls, bvFTD patients showed deficits in working memory, abstraction capacity, inhibitory control, cognitive flexibility, verbal fluency and theory of mind (ToM). Patients with BD showed lower performance than controls in terms of abstraction capacity and verbal inhibitory control. In bvFTD patients, atrophy of frontal, temporal and insular cortices was related to EF deficits. Atrophy of the amygdala, the hippocampus, the parahippocampal gyrus, the putamen, the insula, the precuneus, the right temporo-parietal junction and superior temporal pole was associated to ToM impairments. No significant associations between atrophy and EF performance were observed in BD patients. BvFTD patients showed greater EF and ToM deficits than BD patients. Moreover, compared to BD, bvFTD patients exhibited a significant decrease in GM volume in frontal, temporal and parietal regions. Our results provide the first comparison of EF, social cognition and neuroanatomical profiles of bvFTD and elderly BD patients. These findings shed light on differential diagnosis of these disorders and may have important clinical implications.

The IFS (INECO Frontal Screening) and level of education: Normative data.

Level of education is known to confound neuropsychological test performance. The INECO Frontal Screening (IFS) is an easy-to-use and brief measure of several domains of executive function, which has previously shown reliably clinical usefulness and superior psychometric performance when compared to other frontal screening instruments. However, previous studies with the IFS have been limited to participants with high levels of education, preventing its generalizability to populations with less than 12 years of formal education. This is crucial, as less than half of the Latin American population and a large percentage of immigrants in developed countries attain high school education. The aim of this study was to generate IFS normative data in a sample stratified by age and education levels. One hundred and sixty one healthy adults were assessed with the IFS as well as measures of global cognitive screening, namely, the Addenbrooke Cognitive Examination Revised and the Mini-Mental State Examination. Multiple lineal regression analysis showed significant effects for education and nonsignificant effects for age. A correction grid for IFS raw scores was developed and cut-off scores were calculated. The correction grid and cut-off scores may be useful in the interpretation of IFS scores in participants with low education.

Performance of Patients with Early Parkinson Disease on an Executive and Social Cognition Battery.

OBJECTIVE: To demonstrate the usefulness of incorporating the Executive and Social Cognition Battery (ESCB) to detect executive and social cognition deficits, which are otherwise not captured by more "classical" executive tests in early Parkinson disease (PD). BACKGROUND: PD is a neurodegenerative disorder that includes executive and social cognition deficits. While cognitive assessment in PD still relies on classical executive tasks to detect frontal deficits, these traditional tests often fail to uncover subtle, yet relevant, frontal impairment. METHODS: We evaluated 39 PD patients and 47 controls with a battery of classical executive tests and the ESCB. The ESCB includes a series of tasks that more closely resemble real-life activities and have been previously shown to be useful in detecting executive deficits in other neuropsychiatric disorders with frontal involvement. RESULTS: We observed that both batteries used in a complementary way yielded better results, as 15 of the 39 patients presented deficits only on some of the ESCB tests, but not on the classical battery, while 5 patients presented deficits only on some tests of the classical battery, but not on the ESCB. Fourteen patients presented deficits on some tests of either battery, and 5 patients did not present deficits on any of the tests. CONCLUSIONS: We found that, used along with traditional neuropsychological tasks, the ESCB may be useful in providing a more comprehensive evaluation of frontal dysfunction among patients with PD, thus contributing to the early diagnosis of cognitive disorders in this patient population.

Weighted Symbolic Dependence Metric (wSDM) for fMRI resting-state connectivity: A multicentric validation for frontotemporal dementia.

The search for biomarkers of neurodegenerative diseases via fMRI functional connectivity (FC) research has yielded inconsistent results. Yet, most FC studies are blind to non-linear brain dynamics. To circumvent this limitation, we developed a "weighted Symbolic Dependence Metric" (wSDM) measure. Using symbolic transforms, we factor in local and global temporal features of the BOLD signal to weigh a robust copula-based dependence measure by symbolic similarity, capturing both linear and non-linear associations. We compared this measure with a linear connectivity metric (Pearson's R) in its capacity to identify patients with behavioral variant frontotemporal dementia (bvFTD) and controls based on resting-state data. We recruited participants from two international centers with different MRI recordings to assess the consistency of our measure across heterogeneous conditions. First, a seed-analysis comparison of the salience network (a specific target of bvFTD) and the default-mode network (as a complementary control) between patients and controls showed that wSDM yields better identification of resting-state networks. Moreover, machine learning analysis revealed that wSDM yielded higher classification accuracy. These results were consistent across centers, highlighting their robustness despite heterogeneous conditions. Our findings underscore the potential of wSDM to assess fMRI-derived FC data, and to identify sensitive biomarkers in bvFTD.