Clarifying the relationships between neuropsychiatric symptoms and Alzheimer's disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC‐CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence‐based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.

Introduction: Sleep-wake disturbances are a common and early feature in Alzheimer's disease (AD). The impact of early tau pathology in wake-promoting neurons (WPNs) remains unclear. Methods: We performed stereology in postmortem brains from AD individuals and healthy controls to identify quantitative differences in morphological metrics in WPNs. Progressive supranuclear palsy (PSP) and corticobasal degeneration were included as disease-specific controls. Results: The three nuclei studied accumulate considerable amounts of tau inclusions and showed a decrease in neurotransmitter-synthetizing neurons in AD, PSP, and corticobasal degeneration. However, substantial neuronal loss was exclusively found in AD. Discussion: WPNs are extremely vulnerable to AD but not to 4 repeat tauopathies. Considering that WPNs are involved early in AD, such degeneration should be included in the models explaining sleep-wake disturbances in AD and considered when designing a clinical intervention. Sparing of WPNs in PSP, a condition featuring hyperinsomnia, suggest that interventions to suppress the arousal system may benefit patients with PSP.

The clinical spectrum of Alzheimer's disease (AD) extends well beyond the classic amnesticpredominant syndrome. The previous studies have suggested differential neurofibrillary tangle (NFT) burden between amnestic and logopenic primary progressive aphasia presentations of AD. In this study, we explored the regional distribution of NFT pathology and its relationship to AD presentation across five different clinical syndromes. We assessed NFT density throughout six selected neocortical and hippocampal regions using thioflavin-S fluorescent microscopy in a wellcharacterized clinicopathological cohort of pure AD cases enriched for atypical clinical presentations. Subjects underwent apolipoprotein E genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established composite z score. Our results showed that NFT regional burden aligns with the clinical presentation and region-specific cognitive scores. Cortical, but not hippocampal, NFT burden was higher among atypical clinical variants relative to the amnestic syndrome. In analyses of specific clinical variants, logopenic primary progressive aphasia showed higher NFT density in the superior temporal gyrus (p = 0.0091), and corticobasal syndrome showed higher NFT density in the primary motor cortex (p = 0.0205) relative to the amnestic syndrome. Higher NFT burden in the angular gyrus and CA1 sector of the hippocampus were independently associated with

Population aging will lead to a dramatic increase in dementia prevalence across the world. Dementia is the most costly illness in the United States, with an estimated yearly expenditure around $200 billion. 1 Differences in rates of dementia among diverse populations have garnered recent attention, and it is now accepted that health and socioeconomic disparities are stronger determinants than race or cultural identifiers of the differences in dementia prevalence. 2 While the leading risk factors for dementia, including age and genetic risk, are not yet modifiable, a reasonable proportion of risks are attributable to conditions that can be changed across an individual's life span. 3 Dementia prevention depends on actions that promote brain health. Access to quality education, healthy diet, and the treatment of conditions (such as diabetes, hypertension, and smoking) that are major risk factors for developing dementia are not equally available across different countries or even between different regions of the same country. Therefore, health and socioeconomic disparities are contributors to brain health.Dementia is more prevalent and occurs 10 years earlier in low-and middle-income countries than in highincome countries, 4 an example of disparities in socioeconomic conditions across countries contributing to brain health. It is believed that this difference is a consequence of a higher vulnerability to dementia of the population living in low-and middle-income countries because of conditions associated with low socioeconomic status, such as barriers in access to formal education and leisure activities, poor nutrition, poor living conditions, and stress, that can negatively affect brain health. Low educational attainment, for instance, is associated with higher risk of developing symptoms of dementia and earlier symptom onset by up to 8 years. 5 In turn, lower educational attainment has been linked to poor diabetes control and worse cognitive performance in the context of cerebrovascular lesions. Low socioeconomic status in childhood is associated with smaller hippocampal volumes, a higher burden of cerebrovascular lesions, 6 and a higher prevalence of smoking and obesity in adulthood.Further examples of socioeconomic conditions contributing to brain health include access to quality diet, protection against head injuries, and exposure to stressful situations. Consuming a healthy diet, for instance, is implicated in preserving cognition. 7 A healthy diet, rich in fruits, vegetables, whole grains, fish, and nuts, is not easily accessible for people from a low socioeconomic background because of its expense. Processed foods high in sugar and saturated fats are cheaper and more accessible. Head trauma is also linked to dementia risk. Such injuries can be prevented with use of helmets that

Trends in Psychiatry and Psychotherapy Brief CommunicationResumo Introdução: A depressão geriátrica (DG) é um transtorno prevalente que permanece sendo subdiagnosticado. Ferramentas validadas para rastreio de DG em idosos muito idosos na prática clínica são necessárias, especialmente em países em desenvolvimento. Objetivos: Avaliar a acurácia diagnóstica da Escala de Depressão Geriátrica (Geriatric Depression Scale, GDS-15) em uma população de idosos muito idosos residentes na comunidade. Métodos: Foram avaliados, com a GDS-15, 457 indivíduos não-demenciados, residentes na comunidade, com idade ≥75 anos. O diagnóstico definitivo de depressão maior foi realizado através da entrevista semiestruturada Mini International Neuropsychiatric Interview (MINI), de acordo com os critérios do DSM-IV. Resultados: Cinquenta e dois indivíduos (11,4%) foram diagnosticados com episódio depressivo maior. A área sob a curva receiver operating characteristic (ROC) foi de 0,908 (p<0,001). Utilizando-se o ponto de corte 5/6 (não-deprimido/deprimido), 84 (18,4%) indivíduos foram considerados deprimidos pela GDS-15 (coeficiente de kappa = 53,8%, p<0,001). O ponto de corte 4/5 atingiu a melhor combinação entre sensibilidade (86,5%) e especificidade (82,7%) (índice de Youden = 0,692), com valor preditivo negativo robusto (0,9802) e razoável valor preditivo positivo (0,3819). Conclusão: A GDS-15 demonstrou boa acurácia para o rastreio de depressão maior nesta amostra de base populacional de idosos muito idosos com baixa escolaridade. Os resultados do presente estudo indicam que o ponto de corte 4/5 mostrou-se mais adequado para utilização nesta população. Descritores: Depressão, psiquiatria geriátrica, avaliação geriátrica. AbstractIntroduction: Late-life depression (LLD) is common, but remains underdiagnosed. Validated screening tools for use with the oldest-old in clinical practice are still lacking, particularly in developing countries. Objectives: To evaluate the accuracy of a screening tool for LLD in a community-dwelling oldest-old sample. Methods: We evaluated 457 community-dwelling elderly subjects, aged ≥75 years and without dementia, with the Geriatric Depression Scale (GDS-15). Depression diagnosis was established according to DSM-IV criteria following a structured psychiatric interview with the Mini International Neuropsychiatric Interview (MINI). Results: Fifty-two individuals (11.4%) were diagnosed with major depression. The area under the receiver operating characteristic (ROC) curve was 0.908 (p<0.001). Using a cut-off score of 5/6 (not depressed/depressed), 84 (18.4%) subjects were considered depressed by the GDS-15 (kappa coefficient = 53.8%, p<0.001). The 4/5 cut-off point achieved the best combination of sensitivity (86.5%) and specificity (82.7%) (Youden's index = 0.692), with robust negative (0.9802) and reasonable positive predictive values (0.3819). Conclusion: GDS-15 showed good accuracy as a screening tool for major depression in this community-based sample of low-educated oldest-old individuals. Our findings sup...

ObjectivesAlzheimer disease (AD) shows a broad array of clinical presentations, but the mechanisms underlying these phenotypic variants remain elusive. Aging-related astrogliopathy (ARTAG) is a relatively recent term encompassing a broad array of tau deposition in astroglia outside the range of traditional tauopathies. White matter thorn-shaped astrocyte (WM-TSA) clusters, a specific ARTAG subtype, has been associated with atypical language presentation of AD in a small study lacking replication. To interrogate the impact of WM-TSA in modifying clinical phenotype in AD, we investigated a clinicopathologic sample of 83 persons with pure cortical AD pathology and heterogeneous clinical presentations.MethodsWe mapped WM-TSA presence and density throughout cortical areas and interrogated whether WM-TSA correlated with atypical AD presentation or worse performance in neuropsychological testing.ResultsWM-TSA was present in nearly half of the cases and equally distributed in typical and atypical AD presentations. Worsening language and visuospatial functions were correlated with higher WM-TSA density in language-related and visuospatial-related regions, respectively. These findings were unrelated to regional neurofibrillary tangle burden. Next, unsupervised clustering divided the participants into 2 groups: a high–WM-TSA (n = 9) and low–WM-TSA (n = 74) pathology signature. The high–WM-TSA group scored significantly worse in language but not in other cognitive domains.ConclusionsThe negative impact of WM-TSA pathology to language and possibly visuospatial networks suggests that WM-TSA is not as benign as other ARTAG types and may be explored as a framework to understand the mechanisms and impact of astrocytic tau deposition in AD in humans.

According to the cognitive reserve theory, intellectual stimuli acquired during life can prevent against developing cognitive impairment. The underlying cognitive reserve mechanisms were underexplored in low-educated individuals. Because episodic memory impairment due to hippocampal dysfunction is a key feature of Alzheimer’s dementia (AD), we sought to look at a possible cognitive reserve mechanism by determining whether few years of education moderated the relationship between the hippocampal volumes and the episodic-memory scores. The sample was composed by 183 older adults, 40.1% male, with the median age of 78[76,82] years and the median years of education of 4[2,10] who had undergone an episodic-memory test and a 3-Tesla MRI scan to access the hippocampal volumes. Overall, 112 were cognitively healthy, 26 had cognitive impairment-no dementia (CIND) and 45 had dementia. We used multiple linear regression to assess whether the interaction between years of education and each hippocampal volume significantly predicted the episodic-memory scores’ variance, controlling for cognitive diagnosis and nuisance variables. The interaction term with the left hippocampus (ß = 0.2, p = 0.043, CI = 1.0, 1.4), but not with the right (ß = 0.1, p = 0.218, CI = 0.9, 1.2) significantly predicted the variation on memory scores. The mechanism by which the left hippocampus seems to play a more important role on memory processing in more educated individuals needs to be further investigated and might be associated with a better use of mnemonic strategies or higher hippocampal connectivity. Because the sample’s median years of education was four, which corresponds to primary school, we may infer that this level might be sufficient to contribute for building cognitive reserve.