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Background: Sleep/wake disturbance is a common and debilitating symptom of Alzheimer's disease (AD) that precedes cognitive loss. The lateral hypothalamic area (LHA) is critical in orchestrating the sleep/wake cycle through the neuropeptide orexin and melanin‐concentrating hormone. We previously demonstrated that LHA neurons accumulate AD‐tau from Braak stage (BB) 0 and losses ∼72% of neurons by BB6. Little is known about the molecular changes underlying LHA vulnerability during AD progression. We investigated RNA expression changes in LHA across Braak stages to close this gap. Method: We dissected LHA from 30um‐thick sections of the brain from healthy control (HC) and subjects at progressive AD stages and extracted RNA using conventional techniques. We ran RNA transcriptomic assay using customized and neuropathology nCounter® (Nanostring) panels. The Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when log2 fold‐change was > = |1| and the p‐value was <0.05. Result: We found an upregulation of HCRTR1, LDHC, NKX6, and SLC11A1 from early stages (BB2‐3), whereas HCRTR2 RNA levels remained stable. Circadian gene PER2 was downregulated from the intermediate stages (BB4). Gene Ontology analyses detected dysregulation of neuropeptide‐ligand interaction pathways from early AD. Linoleic acid metabolism, fat digestion and absorption, and immune pathways became dysregulated at intermediate stages, while glycolysis and gluconeogenesis pathways were in late stages (BB5‐6). Of note, it is critical to consider that the massive LHA neuronal loss during AD progression may confound the interpretation of changes in late stages because of the few remaining neurons. Conclusion: nCounter® is suitable for identifying transcriptome changes in LHA, even at early AD stages. Molecular profiling of LHA across the Braak stage revealed that the earliest changes are associated with an imbalance in neurotransmitter receptors, while the decline in metabolism and increased inflammation marked the intermediate stage. The late‐stage AD is characterized by hypoglycemia and energy deficit. Notably, discrepancies in receptor behavior can inform more effective symptomatic treatment for sleep dysfunction in AD. [ABSTRACT FROM AUTHOR]

Background: Sleep/wake disturbance is a common and debilitating symptom of Alzheimer's disease (AD) that precedes cognitive loss. The lateral hypothalamic area (LHA) is critical in orchestrating the sleep/wake cycle through the neuropeptide orexin and melanin‐concentrating hormone. We previously demonstrated that LHA neurons accumulate AD‐tau from Braak stage (BB) 0 and losses ∼72% of neurons by BB6. Little is known about the molecular changes underlying LHA vulnerability during AD progression. We investigated RNA expression changes in LHA across Braak stages to close this gap. Method: We dissected LHA from 30um‐thick sections of the brain from healthy control (HC) and subjects at progressive AD stages and extracted RNA using conventional techniques. We ran RNA transcriptomic assay using customized and neuropathology nCounter® (Nanostring) panels. The Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when log2 fold‐change was > = |1| and the p‐value was <0.05. Result: We found an upregulation of HCRTR1, LDHC, NKX6, and SLC11A1 from early stages (BB2‐3), whereas HCRTR2 RNA levels remained stable. Circadian gene PER2 was downregulated from the intermediate stages (BB4). Gene Ontology analyses detected dysregulation of neuropeptide‐ligand interaction pathways from early AD. Linoleic acid metabolism, fat digestion and absorption, and immune pathways became dysregulated at intermediate stages, while glycolysis and gluconeogenesis pathways were in late stages (BB5‐6). Of note, it is critical to consider that the massive LHA neuronal loss during AD progression may confound the interpretation of changes in late stages because of the few remaining neurons. Conclusion: nCounter® is suitable for identifying transcriptome changes in LHA, even at early AD stages. Molecular profiling of LHA across the Braak stage revealed that the earliest changes are associated with an imbalance in neurotransmitter receptors, while the decline in metabolism and increased inflammation marked the intermediate stage. The late‐stage AD is characterized by hypoglycemia and energy deficit. Notably, discrepancies in receptor behavior can inform more effective symptomatic treatment for sleep dysfunction in AD. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive impairment is common after severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. However, associations between post‐hospital discharge risk factors and cognitive trajectories have not been explored. Methods: A total of 1105 adults (mean age ± SD 64.9 ± 9.9 years, 44% women, 63% White) with severe coronavirus disease 2019 (COVID‐19) were evaluated for cognitive function 1 year after hospital discharge. Scores from cognitive tests were harmonized, and clusters of cognitive impairment were defined using sequential analysis. Results: Three groups of cognitive trajectories were observed during the follow‐up: no cognitive impairment, initial short‐term cognitive impairment, and long‐term cognitive impairment. Predictors of cognitive decline after COVID‐19 were older age (β = −0.013, 95% CI = −0.023;−0.003), female sex (β = −0.230, 95% CI = −0.413;−0.047), previous dementia diagnosis or substantial memory complaints (β = −0.606, 95% CI = −0.877;−0.335), frailty before hospitalization (β = −0.191, 95% CI = −0.264;−0.119), higher platelet count (β = −0.101, 95% CI = −0.185;−0.018), and delirium (β = −0.483, 95% CI = −0.724;−0.244). Post‐discharge predictors included hospital readmissions and frailty. Discussion: Cognitive impairment was common and the patterns of cognitive trajectories depended on sociodemographic, in‐hospital, and post‐hospitalization predictors. Highlights: Cognitive impairment after coronavirus disease 2019 (COVID‐19) hospital discharge was associated with higher age, less education, delirium during hospitalization, a higher number of hospitalizations post discharge, and frailty before and after hospitalization.Frequent cognitive evaluations for 12‐month post‐COVID‐19 hospitalization showed three possible cognitive trajectories: no cognitive impairment, initial short‐term impairment, and long‐term impairment.This study highlights the importance of frequent cognitive testing to determine patterns of COVID‐19 cognitive impairment, given the high frequency of incident cognitive impairment 1 year after hospitalization. [ABSTRACT FROM AUTHOR]

Background: Dementia has been associated with increased risk of hospital mortality (1). However, predictors of hospital mortality for patients with dementia have not been widely addressed. We aimed to investigate predictors of hospital mortality according to preexisting clinical dementia in older adults. Methods: We analyzed data from a prospective cohort study in Sao Paulo, Brazil. We included acutely ill patients aged ≥60 years admitted to a tertiary university hospital between 2009 and 2020. Candidates underwent comprehensive geriatric assessments in the first 24 hours of hospitalization. Preexisting clinical dementia (after this, referred to as dementia) was determined by a Clinical Dementia Rating (CDR) ≥1 (2). We investigated independent predictors of hospital mortality according to dementia using multivariable Poisson regressions. We further analyzed our multivariable models' accuracy in predicting hospital mortality using area under the ROC curves (AUC). Results: We included 3,863 participants (mean age = 80; female = 62%). Overall, 1,761 participants (46%) had dementia. Mortality was 11% in participants without dementia and 21% in those with dementia (p<0.001). In participants without dementia, mortality was independently predicted by age, multimorbidity, functional status, delirium, nutritional status, and serum albumin (Table 1). However, in participants with dementia, mortality was also predicted by illness acuity and creatinine. Finally, we observed that our multivariable model had an AUC = 0.88 (95%CI = 0.86‐0.90) in participants without dementia and 0.80 (0.78‐0.83) in those with dementia (Figure 1). Conclusion: Older adults with dementia were twice as likely to die in the hospital than those without dementia. Moreover, independent predictors of hospital mortality were not necessarily shared between patients with and without dementia. Given the importance of prognostic assessments for decision‐making processes, researchers should consider exploring new algorithms that differ according to baseline cognition. References: 1. Bouza C, Martínez‐Alés G, López‐Cuadrado T. The impact of dementia on hospital outcomes for elderly patients with sepsis: A population‐based study. PLoS One. 2019;14(2):e0212196. Published 2019 Feb 19. https://doi.org/10.1371/journal.pone.0212196 2. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia.Br J Psychiatry. 1982;140:566‐572. https://doi.org/10.1192/bjp.140.6.566 [ABSTRACT FROM AUTHOR]

Background: Although Alzheimer's disease (AD) etiology is partially explained by the deposition of aggregated forms of β‐amyloid proteins and neurofibrillary tangles in the brain, the process that triggers the deposition of these proteins is still unknown. The neural (nNOS), endothelial (eNOS), and inducible nitric oxide synthases (iNOS) may play an important role in AD pathophysiology according to previous studies in animals. However, studies on humans are scarce. Therefore, we aimed to quantify the expression of NOS enzymes in the hippocampus of individuals with AD compared to individuals without the disease and investigate the association of NOS expression with cognition and AD‐related pathology. Method: We evaluated the nNOS, eNOS, and iNOS expressions using immunohistochemistry in the cornu ammonis (CA) and the dentate gyrus (DG) from hippocampi from subjects with pure AD and sex‐matched controls. Cognitive abilities were evaluated using the Clinical Dementia Rating (CDR) and AD pathology using Braak staging for neurofibrillary tangles and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) for neuritic plaque. We used linear regression to examine the association of NOS with cognition and AD pathology. Results: Sociodemographic and clinical variables were similar between the control and AD groups (Table 1). In individuals with AD, nNOS was overexpressed in the CA (β = 23.62, IC95% = 5.13;42.10, p = 0.01) and DG (β = 16.76, IC95% = 0.35;3.18, p = 0.01), while eNOS and iNOS were increased only in the CA (β = 0.93, IC95% = 0.02;1.84, p = 0.04; β = 0.19, IC95% = 0.09;0.90, p = 0.01, respectively) (Figure 1). Larger nNOS levels in the CA and DG were associated with worse cognitive abilities, higher Braak and CERAD scores (Table 2). Conclusion: The nNOS, eNOS, and iNOS were increased in the hippocampi of subjects with AD. However, only nNOS overexpression was associated with cognitive impairment and AD‐related pathology. [ABSTRACT FROM AUTHOR]

Background: The two main catecholaminergic members of the isodendritic core nuclei are the substantia nigra (SN) and the locus coeruleus (LC). Despite cytoarchitectural and neurochemical similarities between the two nuclei, the LC is significantly more vulnerable to early degenerative changes in tauopathies like Alzheimer's disease (AD) as compared to the SN. Here, we seek to use the gradient of vulnerability in these catecholaminergic nuclei to identify pathways associated with vulnerability in early AD pathological stages. Method: This cohort includes individuals with no neuropathologic entities and Alzheimer's disease proteinopathic stages. Individuals with TDP‐43, Lewy Body, or Chronic Traumatic Encephalopathy pathologic entities were excluded. The LC and SN was dissected from frozen human brainstem tissue using macroscopic anatomic features. To compare the LC and SN, only cases below Braak III with sufficient RNA from both nuclei were included. The Nanostring nCounter platform was used to probe specific pathways related to neurodegenerative processes. DBH and SLC6A3 served as confirmatory readouts of accurate anatomic sampling of the LC and SN. Differential gene expression analysis was used to evaluate patterns of gene expression that differentiate the two nuclei. Annotated gene sets were evaluated using global significance scores (GSS), a representation of cumulative t‐statistics for relevant genes. Result: The LC and SN were collected from 26 cases (Figure 1) eligible for this analysis. Accurate dissections were confirmed by differential expression of DBH (p = 1.38e‐9) and SLC6A3 (p = 4.5e‐16). Among the differentially expressed genes (Figure 2), genes associated with microglia activation (GSS = 2.35), oxidative stress (GSS = 2.17), and lipid metabolism (GSS = 2.00) significantly differentiated the LC and SN. Conclusion: The LC and SN serve as examples of differentially vulnerable nuclei at the earliest neuropathologic stages of AD. Cell intrinsic factors, physiological demands, vascular contributions, and exposure to extrinsic factors like toxins are thought to contribute to the LC's early vulnerability. Here, we show that neuroinflammation and oxidative stress pathways are likely central to differential vulnerability at the earliest stages of Alzheimer's disease and may represent targets for intervention in prodromal stages. [ABSTRACT FROM AUTHOR]

Background: Coronary heart disease (CHD) is the leading cause of mortality worldwide. Dementia is also among the ten most common causes of mortality, and it is one of the main causes of disability in older people. However, the association of direct morphometric percentage of obstruction in coronary arteries with Alzheimer's disease (AD) type‐pathology remains unclear. We investigated the association of the percentage of obstruction of coronary arteries with AD type‐pathology. Method: The heart and brain of participants 50 years or older, who underwent full‐body autopsy were collected. The main coronary arteries were dissected and the region with the largest luminal narrowing or with unstable plaques were sampled. The percentage of obstruction was calculated using the lumen and internal elastic lamina areas. The dependent variable was defined by the presence of at least moderate AD‐type pathology (Braak≥3 and CERAD≥B), according to the Braak staging for neurofibrillary tangles, and CERAD for neuritic plaques. Regression models were adjusted for sociodemographic and clinical factors, with robust standard error to account for repeated measures in the same individual. Result: The sample included 193 participants (mean age = 75±12 years old, 56% men, and 70% white). The percentage of obstruction of coronary arteries was not associated with the neuropathological diagnosis of AD (OR = 1.00, 95% CI = 0.99; 1.01, p = 0.52), Braak staging (β = ‐0.002, 95% CI = ‐0.009;0.003, p = 0.36) or CERAD (β = ‐0.0002; 95% CI = ‐0.005;0.004, p = 0.93). Conclusion: There is no association between coronary artery obstruction and AD type‐pathology in this autopsy study with morphometric measurements of atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: A biological mechanism in cancer promotion may have a protective role against AD1. Although disparities between the clinical and the anatomopathological postmortem diagnoses related to the etiology of dementia and cancer were described2, most previous studies were based only on the clinical diagnoses for both diseases. Therefore, we aimed to investigate the association between AD and cancer in a large autopsy study from a racially diverse sample. Method: This cross‐sectional study analyzed data with postmortem brain tissue from participants over 55 years of age from the Biobank for Aging Studies. Data from the full‐body autopsy reports and a Functional Clinical Questionnaire (FCQ) applied to an informant were used to determine the presence of cancer. The association between AD and cancer was investigated using logistic and linear models adjusted for sociodemographic and clinical variables and APOE allele 4. Result: 689 subjects were included (mean age 74.2 ± 10.8 years old, 47.5% women, 68% White) (Table 1). 18% of the sample had cancer. The frequencies of cancer types and neuropathological post‐mortem diagnoses are shown in Figure 1. Cancer was not associated with AD (OR = 0.56, 95% CI = 0.21;1.39), or CERAD neuritic plaque score [ b = 0.057, 95% CI = ‐0.31; 0.41], but was associated with lower Braak neurofibrillary tangle staging (b = ‐0.49, 95% CI = ‐0.98; ‐0.03] (Table 2). Conclusion: In a large autopsy study, we found an association between cancer and Braak neurofibrillary tangle staging, which is in accordance with previous research suggesting a protective role of cancer in AD risk3. 1. Ospina‐Romero M, Glymour MM, Hayes‐Larson E, Mayeda ER, Graff RE, Brenowitz WD, Ackley SF, Witte JS, Kobayashi LC. Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Metaanalysis. JAMA Netw Open. 2020 Nov 2;3(11):e2025515. 2. Landefeld CS, Chren MM, Myers A, et al. Diagnostic yield of the autopsy in a university hospital and a community hospital. The New England Journal of Medicine. 1988 May;318(19):1249‐1254. 3. Nakamura M, Kaneko S, Dickson DW, Kusaka H. Aberrant Accumulation of BRCA1 in Alzheimer Disease and Other Tauopathies. J Neuropathol Exp Neurol. 2020 Jan 1;79(1):22‐33. [ABSTRACT FROM AUTHOR]

Background: The association between moderate/severe dementia and lower Body Mass Index (BMI) is well described, but the weight decline seems to also occur in cognitively normal individuals with preclinical dementia. Considering that up to one‐fifth of individuals with normal cognition might meet the criteria for a neuropathological diagnosis, autopsy studies are key detecting neurodegenerative and cerebrovascular diseases that could be underlining weight changes during the life course. Therefore, we investigated the association between dementia‐related brain lesions and BMI and evaluated whether cognitive function was a mediator of this association. Method: Neuropathological study in a population‐based sample of 1,170 Brazilians. Clinical variables and cognition evaluation were obtained through a post mortem interview with a proxy. Linear regression adjusted models were used to investigate the association between each neuropathologic lesion (independent variable) and the BMI (dependent variable). The direct and indirect (considering a mediation by cognitive abilities) effects of each neuropathologic lesion on BMI were evaluated through a mediation model. Result: Individuals with lower body weight were more likely to have a higher burden of neuropathological lesions and worse cognitive abilities. Neurofibrillary tangles (NFT) and neuropathological comorbidity were associated with low BMI. Mediation analyses showed these lesions were directly associated with BMI and indirectly through cognitive abilities. Despite having normal cognitive abilities, 25% of the sample had at least one neuropathologic diagnosis. High NFT burden was associated with lower BMI even in these participants. Conclusion: Neurofibrillary tangles were associated with lower BMI independent of cognitive abilities. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) patients commonly experience sleep/wake (S/W) disturbances, such as sleep fragmentation and excessive daytime sleepiness. The S/W cycle is controlled by a complex system regulated by a master regulator, the suprachiasmatic nucleus (SCN) that controls wake‐ and sleep‐promoting nuclei. Despite its importance in orchestrating sleep architecture, little is known about the molecular changes that occur in the SCN during the progression of AD and how these changes contribute to S/W disturbances. Method: We used postmortem brain tissue of 10 controls without AD pathology and 32 subjects with progressive AD stages. Our approach included quantitative neuropathological assessments of AVP and VIP‐expressing neurons in SCN and its adjacent hypothalamic region, the supraoptic nucleus (SON). We also used an in‐situ cell‐specific spatial proteomics platform [GeoMx Digital Spatial Profiling (DSP)] to probe levels of different pathological tau species and proteins commonly dysregulated in AD. Result: Preliminary findings reveal a significant decrease in SCN volume (∼75%) (Fig.1) and a loss of ∼58% AVP neurons and ∼41% VIP neurons in Braak stage (Braak) VI compared to Braak 0. The DSP results indicate that both neurons in the SCN have twice the burden of p‐tau levels as the SON (Fig.2‐right), and neurofibrillary tanglesAdditionally, SCN shows an increase in proteins associated with glia and immune responses (Fig.2‐left). Furthermore, an increase in microglial proteins is observed in the SCN in Braak I (Fig.3‐left). In contrast, the SON displays a milder pattern of protein dysregulation in Braak I (Fig.3‐right), consistent with its lower tau expression observed in histology and DSP. Conclusion: SCN is vulnerable to AD pathology even in Braak I, which is characterized by volume loss, increased immune response protein dysregulation, and later neuronal loss, as well as p‐tau pathology. This pattern supports the idea that the SCN plays a role in S/W disturbances observed from early AD stages. Interestingly, its neighboring nucleus, SON, which also has AVP neurons, remained spared, providing opportunities for studies investigating factors related to selective vulnerability. Ongoing studies are addressing changes in the SCN and SON in intermediate AD stages. [ABSTRACT FROM AUTHOR]

Background: The two main catecholaminergic members of the isodendritic core nuclei are the substantia nigra (SN) and the locus coeruleus (LC). Despite cytoarchitectural and neurochemical similarities between the two nuclei, the LC is significantly more vulnerable to early degenerative changes in tauopathies like Alzheimer's disease (AD) as compared to the SN. Here, we seek to use the gradient of vulnerability in these catecholaminergic nuclei to identify pathways associated with vulnerability in early AD pathological stages. Method: This cohort includes individuals with no neuropathologic entities and Alzheimer's disease proteinopathic stages. Individuals with TDP‐43, Lewy Body, or Chronic Traumatic Encephalopathy pathologic entities were excluded. The LC and SN was dissected from frozen human brainstem tissue using macroscopic anatomic features. To compare the LC and SN, only cases below Braak III with sufficient RNA from both nuclei were included. The Nanostring nCounter platform was used to probe specific pathways related to neurodegenerative processes. DBH and SLC6A3 served as confirmatory readouts of accurate anatomic sampling of the LC and SN. Differential gene expression analysis was used to evaluate patterns of gene expression that differentiate the two nuclei. Annotated gene sets were evaluated using global significance scores (GSS), a representation of cumulative t‐statistics for relevant genes. Result: The LC and SN were collected from 26 cases (Figure 1) eligible for this analysis. Accurate dissections were confirmed by differential expression of DBH (p = 1.38e‐9) and SLC6A3 (p = 4.5e‐16). Among the differentially expressed genes (Figure 2), genes associated with microglia activation (GSS = 2.35), oxidative stress (GSS = 2.17), and lipid metabolism (GSS = 2.00) significantly differentiated the LC and SN. Conclusion: The LC and SN serve as examples of differentially vulnerable nuclei at the earliest neuropathologic stages of AD. Cell intrinsic factors, physiological demands, vascular contributions, and exposure to extrinsic factors like toxins are thought to contribute to the LC's early vulnerability. Here, we show that neuroinflammation and oxidative stress pathways are likely central to differential vulnerability at the earliest stages of Alzheimer's disease and may represent targets for intervention in prodromal stages. [ABSTRACT FROM AUTHOR]

Background: Coronary heart disease (CHD) is the leading cause of mortality worldwide. Dementia is also among the ten most common causes of mortality, and it is one of the main causes of disability in older people. However, the association of direct morphometric percentage of obstruction in coronary arteries with Alzheimer's disease (AD) type‐pathology remains unclear. We investigated the association of the percentage of obstruction of coronary arteries with AD type‐pathology. Method: The heart and brain of participants 50 years or older, who underwent full‐body autopsy were collected. The main coronary arteries were dissected and the region with the largest luminal narrowing or with unstable plaques were sampled. The percentage of obstruction was calculated using the lumen and internal elastic lamina areas. The dependent variable was defined by the presence of at least moderate AD‐type pathology (Braak≥3 and CERAD≥B), according to the Braak staging for neurofibrillary tangles, and CERAD for neuritic plaques. Regression models were adjusted for sociodemographic and clinical factors, with robust standard error to account for repeated measures in the same individual. Result: The sample included 193 participants (mean age = 75±12 years old, 56% men, and 70% white). The percentage of obstruction of coronary arteries was not associated with the neuropathological diagnosis of AD (OR = 1.00, 95% CI = 0.99; 1.01, p = 0.52), Braak staging (β = ‐0.002, 95% CI = ‐0.009;0.003, p = 0.36) or CERAD (β = ‐0.0002; 95% CI = ‐0.005;0.004, p = 0.93). Conclusion: There is no association between coronary artery obstruction and AD type‐pathology in this autopsy study with morphometric measurements of atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: A biological mechanism in cancer promotion may have a protective role against AD1. Although disparities between the clinical and the anatomopathological postmortem diagnoses related to the etiology of dementia and cancer were described2, most previous studies were based only on the clinical diagnoses for both diseases. Therefore, we aimed to investigate the association between AD and cancer in a large autopsy study from a racially diverse sample. Method: This cross‐sectional study analyzed data with postmortem brain tissue from participants over 55 years of age from the Biobank for Aging Studies. Data from the full‐body autopsy reports and a Functional Clinical Questionnaire (FCQ) applied to an informant were used to determine the presence of cancer. The association between AD and cancer was investigated using logistic and linear models adjusted for sociodemographic and clinical variables and APOE allele 4. Result: 689 subjects were included (mean age 74.2 ± 10.8 years old, 47.5% women, 68% White) (Table 1). 18% of the sample had cancer. The frequencies of cancer types and neuropathological post‐mortem diagnoses are shown in Figure 1. Cancer was not associated with AD (OR = 0.56, 95% CI = 0.21;1.39), or CERAD neuritic plaque score [ b = 0.057, 95% CI = ‐0.31; 0.41], but was associated with lower Braak neurofibrillary tangle staging (b = ‐0.49, 95% CI = ‐0.98; ‐0.03] (Table 2). Conclusion: In a large autopsy study, we found an association between cancer and Braak neurofibrillary tangle staging, which is in accordance with previous research suggesting a protective role of cancer in AD risk3. 1. Ospina‐Romero M, Glymour MM, Hayes‐Larson E, Mayeda ER, Graff RE, Brenowitz WD, Ackley SF, Witte JS, Kobayashi LC. Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Metaanalysis. JAMA Netw Open. 2020 Nov 2;3(11):e2025515. 2. Landefeld CS, Chren MM, Myers A, et al. Diagnostic yield of the autopsy in a university hospital and a community hospital. The New England Journal of Medicine. 1988 May;318(19):1249‐1254. 3. Nakamura M, Kaneko S, Dickson DW, Kusaka H. Aberrant Accumulation of BRCA1 in Alzheimer Disease and Other Tauopathies. J Neuropathol Exp Neurol. 2020 Jan 1;79(1):22‐33. [ABSTRACT FROM AUTHOR]

Background: The association between moderate/severe dementia and lower Body Mass Index (BMI) is well described, but the weight decline seems to also occur in cognitively normal individuals with preclinical dementia. Considering that up to one‐fifth of individuals with normal cognition might meet the criteria for a neuropathological diagnosis, autopsy studies are key detecting neurodegenerative and cerebrovascular diseases that could be underlining weight changes during the life course. Therefore, we investigated the association between dementia‐related brain lesions and BMI and evaluated whether cognitive function was a mediator of this association. Method: Neuropathological study in a population‐based sample of 1,170 Brazilians. Clinical variables and cognition evaluation were obtained through a post mortem interview with a proxy. Linear regression adjusted models were used to investigate the association between each neuropathologic lesion (independent variable) and the BMI (dependent variable). The direct and indirect (considering a mediation by cognitive abilities) effects of each neuropathologic lesion on BMI were evaluated through a mediation model. Result: Individuals with lower body weight were more likely to have a higher burden of neuropathological lesions and worse cognitive abilities. Neurofibrillary tangles (NFT) and neuropathological comorbidity were associated with low BMI. Mediation analyses showed these lesions were directly associated with BMI and indirectly through cognitive abilities. Despite having normal cognitive abilities, 25% of the sample had at least one neuropathologic diagnosis. High NFT burden was associated with lower BMI even in these participants. Conclusion: Neurofibrillary tangles were associated with lower BMI independent of cognitive abilities. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) patients commonly experience sleep/wake (S/W) disturbances, such as sleep fragmentation and excessive daytime sleepiness. The S/W cycle is controlled by a complex system regulated by a master regulator, the suprachiasmatic nucleus (SCN) that controls wake‐ and sleep‐promoting nuclei. Despite its importance in orchestrating sleep architecture, little is known about the molecular changes that occur in the SCN during the progression of AD and how these changes contribute to S/W disturbances. Method: We used postmortem brain tissue of 10 controls without AD pathology and 32 subjects with progressive AD stages. Our approach included quantitative neuropathological assessments of AVP and VIP‐expressing neurons in SCN and its adjacent hypothalamic region, the supraoptic nucleus (SON). We also used an in‐situ cell‐specific spatial proteomics platform [GeoMx Digital Spatial Profiling (DSP)] to probe levels of different pathological tau species and proteins commonly dysregulated in AD. Result: Preliminary findings reveal a significant decrease in SCN volume (∼75%) (Fig.1) and a loss of ∼58% AVP neurons and ∼41% VIP neurons in Braak stage (Braak) VI compared to Braak 0. The DSP results indicate that both neurons in the SCN have twice the burden of p‐tau levels as the SON (Fig.2‐right), and neurofibrillary tanglesAdditionally, SCN shows an increase in proteins associated with glia and immune responses (Fig.2‐left). Furthermore, an increase in microglial proteins is observed in the SCN in Braak I (Fig.3‐left). In contrast, the SON displays a milder pattern of protein dysregulation in Braak I (Fig.3‐right), consistent with its lower tau expression observed in histology and DSP. Conclusion: SCN is vulnerable to AD pathology even in Braak I, which is characterized by volume loss, increased immune response protein dysregulation, and later neuronal loss, as well as p‐tau pathology. This pattern supports the idea that the SCN plays a role in S/W disturbances observed from early AD stages. Interestingly, its neighboring nucleus, SON, which also has AVP neurons, remained spared, providing opportunities for studies investigating factors related to selective vulnerability. Ongoing studies are addressing changes in the SCN and SON in intermediate AD stages. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) are very common in Lewy body dementias (LBD), but their aetiology is poorly understood. In a post‐mortem study we aimed to characterise the contribution of neuropathological substrates to some of the most common NPS in dementia. Method: Participants who passed away between 2004 and 2021 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies. Neuropathological data was collected for Lewy body neuropathology (LBD Braak score), neurofibrillary tangles (NFT Braak score), amyloid‐β burden (CERAD‐NP), TDP‐43, lacunar infarcts, cerebral amyloid angiopathy and hyaline atherosclerosis. Post‐mortem interviews were used to collect information regarding neuropsychiatric and cognitive status using the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR). A total of 948 cases were classified according to neuropathological assessment: (1) No pathology (NP) (n = 678); (2) Alzheimer's Disease (AD) (n = 183); (3) LBD (n = 57); (4) AD+LBD (n = 30). Result: Multinomial logistic regression models comparing LBD, AD and AD+LBD to NP, adjusted for age, ethnicity, sex, and education level, showed significantly higher odds of hallucination and delusions across all groups compared to NP with the relative risk of hallucinations most elevated in AD+LBD cases (RRR = 19.3,[95%CI = 8.00‐46.3], p<0.001). All groups had increased risk of higher NPI scores relative to NP, but the greatest increase was for AD+LBD (RRR = 1.04, [95%CI = 1.02‐1.06], p<0.001). There were significantly greater risk of agitation and apathy in AD and AD+LBD groups relative to NP. (Table 1) Additionally, hallucinations were associated with higher Lewy body Braak scores (OR = 1.30, 95%CI = 1.13‐1.49, p<0.001). Higher NFT Braak scores were associated with depression (OR = 1.28, 95%CI = 1.09‐1.50, p<0.001), agitation (OR = 1.30, 95% CI = 1.07‐1.57, p = 0.009) and overall NPI score (IRR = 1.15, 95%CI = 1.05‐1.27, p = 0.004). Lacunar infarcts were associated with delusions (OR = 4.68, 95%CI = 1.12‐19.5, p = 0.03). More frequent neuritic plaques was inversely associated with apathy (OR = 0.70, 95%CI = 0.52‐0.93, p = 0.01). Cerebral amyloid angiopathy, hyaline atherosclerosis, and TDP‐43 did not associate with any of the neuropsychiatric symptoms in the multivariable logistic models. (Table 2) Conclusion: Lewy body pathology was the most significant contributor to the aetiology of hallucinations, while NFT were important contributors to depression and agitation in dementia. Supporting the dual importance of these pathologies, subjects with AD and LBD co‐pathology showed the greatest burden of NPS. [ABSTRACT FROM AUTHOR]

Introduction: Neuropsychiatric symptoms (NPS) are common in Lewy body disease (LBD), but their etiology is poorly understood. Methods: In a population‐based post mortem study neuropathological data was collected for Lewy body (LB) neuropathology, neurofibrillary tangles (NFT), amyloid beta burden, TDP‐43, lacunar infarcts, cerebral amyloid angiopathy (CAA), and hyaline atherosclerosis. Post mortem interviews collected systematic information regarding NPS and cognitive status. A total of 1038 cases were included: no pathology (NP; n = 761), Alzheimer's disease (AD; n = 189), LBD (n = 60), and AD+LBD (n = 28). Results: Hallucinations were associated with higher LB Braak stages, while higher NFT Braak staging was associated with depression, agitation, and greater number of symptoms in the Neuropsychiatric Inventory. Cases with dual AD+LBD pathology had the highest risk of hallucinations, agitation, apathy, and total symptoms but a multiplicative interaction between these pathologies was not significant. Discussion: LB and AD pathology contribute differentially to NPS likely with an additive process contributing to the increased burden of NPS. [ABSTRACT FROM AUTHOR]

Introduction: Education, and less frequently occupation, has been associated with lower dementia risk in studies from high‐income countries. We aimed to investigate the association of cognitive impairment with education and occupation in a low‐middle‐income country sample. Methods: In this cross‐sectional study, cognitive function was assessed by the Clinical Dementia Rating sum of boxes (CDR‐SOB). We investigated the association of occupation complexity and education with CDR‐SOB using adjusted linear regression models for age, sex, and neuropathological lesions. Results: In 1023 participants, 77% had < 5 years of education, and 56% unskilled occupations. Compared to the group without education, those with formal education had lower CDR‐SOB (1–4 years: β$\beta \;$= ‐0.99, 95% confidence interval [CI] = –1.85; –0.14, P =.02; ≥5 years: β$\beta \;$= –1.42, 95% CI = –2.47; –0.38, P =.008). Occupation complexity and demands were unrelated to cognition. Discussion: Education, but not occupation, was related to better cognitive abilities independent of the presence of neuropathological insults. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to compare causes of death in the most prevalent neuropathologically diagnosed dementias.Methods: We analyzed causes of death in a community-based cohort of participants aged 50 or older, submitted to full-body autopsy and a comprehensive neuropathologic examination of the brain. Individuals with Alzheimer disease (AD), vascular dementia (VaD), mixed dementia (AD+VaD), or dementia with Lewy bodies (DLBs) were compared with individuals with no dementia.Results: In a sample of 920 individuals, 456 had no dementia, 147 had AD, 120 had VaD, 53 had DLB, and 37 had AD+VaD. Pneumonia as the cause of death was more frequent in the AD (P=0.023), AD+VaD (P=0.046), and DLB (P=0.043) groups. In addition, VaD (P=0.041) and AD+VaD (P=0.028) groups had a higher frequency of atherosclerosis as detected by full-body autopsy.Conclusion: Our findings highlight the importance of preventive measures regarding atherosclerosis and pneumonia in patients with dementia. Moreover, because of cognitive impairment, these patients may not fully account for symptoms to make early detection and diagnosis possible. These results confirm findings from previous studies that were based on clinical data, with added accuracy provided by neuropathologic diagnosis and full-body autopsy reports. [ABSTRACT FROM AUTHOR]

Background: Dementia affects more Black individuals, likely due to a combination of environmental and biological factors1,2,3. APOE ε4 allele risk of dementia is different between individuals with European (EUR) and African (AFR) ancestries4,5,6. It is unclear what drives these differences in Alzheimer's disease (AD) neuropathology among patients with cognitive decline, both outcomes influenced by different sets of biological and environmental factors. We studied the interaction between global and local APOE African ancestry, e4 allele, burden of neuritic plaques (NP) and neurofibrillary tangles (NFT), and cognition in a postmortem sample of admixed individuals with AD pathology. Method: Community‐dwelling autopsied brains (n=400) without neuropathological changes or with NP scored using CERAD and NFT scored by Braak stage but lacking others comorbid neuropathologies. Subject's cognitive function prior to death as assessed using Clinical Dementia Rating sum of boxes (CDR‐SOB). APOE genotypes were assessed with allele‐specific amplification. Global ancestry was inferred using Admixture and local ancestry using RFMix, derived from panels of variants interrogated by microarray. Result: When dichotomously ascertained at 2% of AFR, and adjusting for age, sex, educational attainment and APOE ε4 carrier status, the admixed group is significantly protected of neuritic plaques (NP, beta=‐0.21, p=0.04) but not neurofibrillary tangles (NFT, beta=0.137, p=0.39). However, CDR‐SOB was associated with continuously distributed AFR (Table 1) only among individuals with severe levels of NFT (beta=7.04, p<0.001) and NP (beta=3.9, p<0.001). Stratifying the same analysis between APOE status, only APOE ε4 noncarriers presented significant associations between AFR and CDR‐SOB, but APOE ε4 carriers lost significance. APOE local ancestry inference of showed that non‐European admixed APOE ε4 noncarriers had lower NP burden outcomes (Table 2, beta=‐0.28, p=0.032 and beta=‐0.27, p=0.015 with and without adjusting for AFR, respectively), but worst cognitive decline compared to European APOE of the same genotype group when adjusting by NP levels (beta=1.01, p=0.041, without adjusting for AFR). Lastly, APOE ε has a significant effect on neuropathology, but not cognition, only within European local ancestry contexts (Table 3, beta=0.61, p<0.001). Conclusion: Our results demonstrate a complex relation between APOE genotypes and local ancestry, AFR global ancestry and AD‐related neuropathology and cognition outcomes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To establish a microcephaly cut-off size in adults using head circumference as an indirect measure of brain size, as well as to explore factors associated with microcephaly via data mining. METHODS: In autopsy studies, head circumference was measured with an inelastic tape placed around the skull. Total brain volume was also directly measured. A linear regression was used to determine the association of head circumference with brain volume and clinical variables. Microcephaly was defined as head circumference that were two standard deviations below the mean of significant clinical variables. We further applied an association rule mining to find rules associating microcephaly with several sociodemographic and clinical variables. RESULTS: In our sample of 2,508 adults, the mean head circumference was 55.3 ± 2.7cm. Head circumference was related to height, cerebral volume, and sex (p < 0.001 for all). Microcephaly was present in 4.7% of the sample (n = 119). Out of 34,355 association rules, we found significant relationships between microcephaly and a clinical dementia rating (CDR) > 0.5 with an informant questionnaire on cognitive decline in the elderly (IQCODE) = 3.4 (confidence: 100% and lift: 5.6), between microcephaly and a CDR > 0.5 with age over 70 years (confidence: 42% and lift: 2.4), and microcephaly and males (confidence: 68.1% and lift: 1.3). CONCLUSION: Head circumference was related to cerebral volume. Due to its low cost and easy use, head circumference can be used as a screening test for microcephaly, adjusting it for gender and height. Microcephaly was associated with dementia at old age. [ABSTRACT FROM AUTHOR]

Background: Cognitive reserve helps maintain cognitive function in the face of accumulating brain pathology and potentially delays the onset of clinical dementia. However, there is a lack of research examining the role of cognitive reserve in delirium, particularly in the context of preexisting neurocognitive disorders. We aimed to investigate the interaction between years of education and baseline cognition in their association with delirium occurrence in hospitalized older adults. Methods: Prospective cohort study including acutely ill patients aged ≥60 admitted to the geriatrics unit of a university hospital in Sao Paulo, Brazil (2009‐2020). Candidates underwent comprehensive geriatric assessments in the first 24 hours of hospitalization. Delirium occurrence was defined using the CAM, completed daily during the hospital stay. Baseline cognition was determined using the CDR and the CDR‐SB. Years of education were used as a proxy for cognitive reserve. We investigated the association between delirium occurrence and years of education using logistic regression models; we then completed interaction analyses exploring the effect of baseline cognition on that association. Results: We included 3,863 participants (mean age = 80; female = 62%; mean years of education = 6). Overall, 1,346 (35%) participants experienced delirium during hospitalization. Additionally, 777 (20%) participants had normal baseline cognition (CDR = 0), 2,068 (54%) had mild cognitive impairment or mild dementia (CDR = 0.5‐1), and 1,018 (26%) had moderate or severe dementia, with a median CDR‐SB of 4. After adjusting for age and sex, we found that participants with ≥12 years of education were less likely to experience delirium (OR = 0.75, 95%, 95%CI = 0.59‐0.96, p = 0.022). However, we found that the association was significantly modified by baseline cognition (p = 0.024) (Figure 1) and that having more years of education was protective against delirium only in the absence of preexisting cognitive impairment (Figure 2). Conclusion: More years of education were protective against delirium occurrence in hospitalized older adults, but only in the absence of preexisting cognitive impairment. Our results suggest that after the onset of clinical neurocognitive disorders, previous markers of cognitive reserve no longer contribute to a lower risk of delirium. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E ε4 allele (APOE‐ε4) is the main genetic risk factor for dementia. APOE‐ε4 is also associated with Alzheimer's disease (AD) pathology, cerebrovascular disease, and non‐AD neurodegenerative pathologies. Although APOE‐ε4 may influence cognitive impairment through these pathways, less evidence is available from diverse populations, considering that APOE genotype associations seem to vary by race. Therefore, we aimed to evaluate the pathways linking APOE‐ε4 to cognition through AD and non‐AD neuropathology in an autopsy study with an admixed sample. Method: We used data from the Biobank for Aging Studies of the University of Sao Paulo Medical School. Participants were classified into APOE‐ε4 carriers (at least one ε4 allele) and non‐carriers. Cognitive function was evaluated by the Clinical Dementia Rating Scale sum of boxes. Mediation analyses were conducted to assess the APOE‐ε4 association with cognition through direct and indirect pathways. Indirect pathways included the following mediators: AD‐type pathology, lacunar infarcts, hyaline arteriosclerosis, cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), and TAR DNA‐binding protein 43 (TDP‐43). We used immunohistochemistry to detect AD pathology, CAA, LBD, and TDP‐43. AD pathology was scored using the Braak staging for neurofibrillary tangles and the Consortium to Establish a Registry for AD criteria for β‐amyloid plaque. Lacunar infarcts and hyaline arteriosclerosis were evaluated microscopically using hematoxylin and eosin‐stained. All analyses were adjusted for demographic and clinical cofounders. Result: We included 648 participants (mean age 75±12 y, 52% women, 69% white, and 28% APOE‐ε4 carriers). The association between APOE‐ε4 and cognitive abilities was mediated by the burden of neurofibrillary tangles (β = 0.78, 95% CI = 0.39; 1.22, p<0.001) and β‐amyloid plaques (β = 0.87, 95% CI = 0.39; 1.40, p<0.001). Lacunar infarcts, hyaline arteriosclerosis, CAA, LBD, and TDP‐43 were not mediators in the pathway from APOE‐ε4 to cognitive function. Direct pathways remained significant in the presence of all mediators except TDP‐43 (p = 0.09) and β‐amyloid plaques (p = 0.07). Conclusion: The influence of APOE‐ε4 on cognitive abilities was partially mediated by AD pathology. However, cerebrovascular lesions and non‐AD pathologies were not mediators in the pathway linking APOE‐ε4 to cognition. [ABSTRACT FROM AUTHOR]

Background: Given the progressive nature of neurodegenerative pathologies, great effort has been made to create diagnostic tools for detecting neurodegenerative changes in their early stages. However, the lack of information about the frequency of neurodegenerative changes in mid‐age adults impacts biomarker interpretation and sensitivity improvement. In addition, recent clinicopathological studies have shown than even a low Alzheimer's disease (AD) neuropathological burden can significantly impact neuropsychiatric function. Finally, clinicopathological studies point to a role of small cerebrovascular changes in the cognitive decline of individuals with zero or low neurodegenerative burden; however, it remains unclear if small vascular brain lesions can impact cognition in younger mid‐age individuals. Method: We evaluated the presence of AD neuropathological changes and their relationship with cognitive impairment, neuropsychiatric symptoms and risk factors in a multiethnic and heterogeneous group under 65 years of age at the moment of death, most of them with low educational level (Table 1). A semi‐structured interview with an informant was performed to obtain socioeconomic and clinical data. Internationally accepted neuropathological criteria were used for pathologic diagnosis. Result: Some degree of neurofibrillary pathology was found in 53% (n = 145) of the individuals, while neuritic plaques were found in 10% (n = 26) of the cases, regardless of the presence of cognitive impairment or neuropsychiatric symptoms. AD‐type pathology burden was similar among individuals with and without cognitive impairment. However, a higher frequency of vascular pathology (p<0.001) was found in individuals with cognitive impairment (Table 2). Some degree of neuropsychiatric symptoms was noted in 59% (n = 160) of the cases. High frequency of cerebrovascular risk factors such as hypertension (63.9%), smoking (58.5%) and alcohol intake (27.5%) was also observed in the entire sample (n = 275) (Table 1). Conclusion: Our data shows that AD neuropathological changes can begin in mid‐age and corroborates findings from other series with predominantly older Caucasians of high scholarity that have demonstrated the role of vascular pathology in cognitive impairment. As vascular risks are preventable, aggressive measures to reduce these factors may impact the prevalence of cognition‐related dysfunction. [ABSTRACT FROM AUTHOR]

Background: The APOE gene is identified as a major risk factor for late onset Alzheimer's disease and has three alleles, ε2, ε3 and ε4, related to two non‐synonymous substitutions. The presence of the ε4 allele confers an increased risk for the disease in a dose dependent manner (odds ratio 12.9 for homozygous individuals and between 3.2 and 4.2 for heterozygous individuals). The most prevalent form of Alzheimer's disease has a multifactorial etiology, where several genetic and environmental factors influence its pathology. Factors such as age and sex are relevant in determining the risk for APOE, recent studies point out that the ancestry around the APOE gene is also relevant to the risk for the disease. Individuals of African‐American ancestry have a reduced risk of developing the disease compared to European and Asian whites. These regions may act in a cis‐regulatory manner in modulating gene expression. The Brazilian population results from miscegenation between indigenous, African and European populations, offering an opportunity to study the effects of different ancestries on the risk of Alzheimer's disease, fill the lack of genetic information about admixed groups and characterize the differential patterns of APOE's expression in Brazilian population. Method: This project aims to quantitatively characterize the role of different local ancestry in the different APOE genotypes using 36 post‐mortem brain tissue, with distinct genotypes and local ancestries combinations (33,34,44, European‐European, African‐African, European‐African, African‐European) and associating them with the expression of this gene through molecular marker genotyping and RT‐qPCR techniques. It is expected that the mRNA expression is differentially increased when European local ancestry is shown to be present, compared to non‐European ancestry and may explain, in part, the difference in risks observed in populations of different ancestries. Result: ongoing research Conclusion: ongoing research [ABSTRACT FROM AUTHOR]

Background: Given the progressive nature of neurodegenerative pathologies, great effort has been made to create diagnostic tools for detecting neurodegenerative changes in their early stages. However, the lack of information about the frequency of neurodegenerative changes in mid‐age adults impacts biomarker interpretation and sensitivity improvement. In addition, recent clinicopathological studies have shown than even a low Alzheimer's disease (AD) neuropathological burden can significantly impact neuropsychiatric function. Finally, clinicopathological studies point to a role of small cerebrovascular changes in the cognitive decline of individuals with zero or low neurodegenerative burden; however, it remains unclear if small vascular brain lesions can impact cognition in younger mid‐age individuals. Method: We evaluated the presence of AD neuropathological changes and their relationship with cognitive impairment, neuropsychiatric symptoms and risk factors in a multiethnic and heterogeneous group under 65 years of age at the moment of death, most of them with low educational level (Table 1). A semi‐structured interview with an informant was performed to obtain socioeconomic and clinical data. Internationally accepted neuropathological criteria were used for pathologic diagnosis. Result: Some degree of neurofibrillary pathology was found in 53% (n = 145) of the individuals, while neuritic plaques were found in 10% (n = 26) of the cases, regardless of the presence of cognitive impairment or neuropsychiatric symptoms. AD‐type pathology burden was similar among individuals with and without cognitive impairment. However, a higher frequency of vascular pathology (p<0.001) was found in individuals with cognitive impairment (Table 2). Some degree of neuropsychiatric symptoms was noted in 59% (n = 160) of the cases. High frequency of cerebrovascular risk factors such as hypertension (63.9%), smoking (58.5%) and alcohol intake (27.5%) was also observed in the entire sample (n = 275) (Table 1). Conclusion: Our data shows that AD neuropathological changes can begin in mid‐age and corroborates findings from other series with predominantly older Caucasians of high scholarity that have demonstrated the role of vascular pathology in cognitive impairment. As vascular risks are preventable, aggressive measures to reduce these factors may impact the prevalence of cognition‐related dysfunction. [ABSTRACT FROM AUTHOR]

Background: The APOE gene is identified as a major risk factor for late onset Alzheimer's disease and has three alleles, ε2, ε3 and ε4, related to two non‐synonymous substitutions. The presence of the ε4 allele confers an increased risk for the disease in a dose dependent manner (odds ratio 12.9 for homozygous individuals and between 3.2 and 4.2 for heterozygous individuals). The most prevalent form of Alzheimer's disease has a multifactorial etiology, where several genetic and environmental factors influence its pathology. Factors such as age and sex are relevant in determining the risk for APOE, recent studies point out that the ancestry around the APOE gene is also relevant to the risk for the disease. Individuals of African‐American ancestry have a reduced risk of developing the disease compared to European and Asian whites. These regions may act in a cis‐regulatory manner in modulating gene expression. The Brazilian population results from miscegenation between indigenous, African and European populations, offering an opportunity to study the effects of different ancestries on the risk of Alzheimer's disease, fill the lack of genetic information about admixed groups and characterize the differential patterns of APOE's expression in Brazilian population. Method: This project aims to quantitatively characterize the role of different local ancestry in the different APOE genotypes using 36 post‐mortem brain tissue, with distinct genotypes and local ancestries combinations (33,34,44, European‐European, African‐African, European‐African, African‐European) and associating them with the expression of this gene through molecular marker genotyping and RT‐qPCR techniques. It is expected that the mRNA expression is differentially increased when European local ancestry is shown to be present, compared to non‐European ancestry and may explain, in part, the difference in risks observed in populations of different ancestries. Result: ongoing research Conclusion: ongoing research [ABSTRACT FROM AUTHOR]

Current recommendations to assess sarcopenia requiring specialized equipment hinder its use as a prognostic tool in busy acute settings. To investigate the prognostic value of a rapid sarcopenia measure in acutely ill older outpatients for 1-year adverse outcomes. Prospective study with 665 acutely ill older adults (mean age 78.7 ± 8.3 years; 63% women) in need of intensive management to avoid hospital admission. Sarcopenia was screened upon admission, defined as the presence of both low muscle strength and low muscle mass. Low muscle strength was determined by handgrip strength according to the cutoffs of the Foundation for the National Institutes of Health (<16 kg for women and <26 kg for men). Low muscle mass was assessed by calf circumference, a validated surrogate measure of skeletal muscle mass, using previously established thresholds (≤33 cm for women and ≤34 cm for men). Outcomes were time to hospitalization, new dependence in basic activities of daily living (ADL), worsening walking ability, and death. To investigate the association of sarcopenia and its components with outcomes we used hazard models, considering death as a competing risk, adjusted for sociodemographic factors, Charlson comorbidity index, cognitive impairment, depressive symptoms, and weight loss. On admission, 203 (31%) patients had sarcopenia. Comparing 1-year adverse outcomes between older adults with and without sarcopenia, respectively, cumulative incidences for hospitalization were 46% vs 32% (adjusted sub-hazard ratio [sHR] = 1.53; 95% CI = 1.16–2.04), for new ADL dependence, 47% vs 24% (adjusted sHR = 1.78; 95% CI = 1.31–2.42), for worsening walking ability, 28% vs 13% (adjusted sHR = 1.93; 95% CI = 1.28–2.90), and for death, 22% vs 10% (adjusted HR = 1.69; 95% CI = 1.05–2.73). Low muscle strength alone was associated with all outcomes, and low muscle mass was associated with all outcomes except mortality. Sarcopenia was a strong predictor of 1-year adverse outcomes among acutely ill older outpatients. Combining handgrip strength with calf circumference may be a practical and efficient approach to screen for sarcopenia, and thereby identify high-risk older adults in busy clinical settings. • Sarcopenia can identify older people at risk of poor outcomes. • Time pressure and few resources hinder the assess of sarcopenia in busy settings. • Grip strength and calf circumference are measures quickly assessed in busy settings. • Handgrip strength and calf circumference captures the key elements of sarcopenia. • This practical sarcopenia screening predicts poor outcomes after acute care. [ABSTRACT FROM AUTHOR]

Background: The presence of aging‐related tau astrogliopathy (ARTAG) is highly frequent, but poorly characterized in aging brain and neurodegeneration. Over the abnormal tau accumulation processes, tau protein undergoes pathological modifications and the sequency of these pathological events can be associated with different levels of tau aggregation. Method: To evaluate the frequency of ARTAG in a large population‐based study, we analyzed brain sections immunostained with phosphor tau (AT8) of 1151 individuals with previous neuropathological evaluation. Further, to investigate early stages of tau protein aggregation in ARTAG, we performed additional immunohistochemistry in the amygdala of 32 cases with ARTAG pathology using the following tau antibodies: AT100 and Tau‐C3. Result: ARTAG was frequently observed in cognitively normal individuals independent of concomitant neurodegenerative disease. Higher burden of Alzheimer‐type pathology was observed in ARTAG compared to non‐ARTAG. Also, presence of more than one pathology (mixed pathology) was higher in ARTAG compared to non‐ARTAG (p<0.001). Additionally, AT100 immunoreactive ARTAG was found in overall cases, while Tau‐C3 immunoreactive ARTAG was not observed in 12 cases (36%), showing different mature stage for ARTAG compared to neurofibrillary tangles. Conclusion: Different immunological markers can be found in ARTAG and Alzheimer's neurofibrillary pathology in early stages of tau pathological processing, suggesting different levels of abnormal tau aggregates among cases with ARTAG pathology. [ABSTRACT FROM AUTHOR]

Background: Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease predominantly found in former athletes and associated with repetitive brain injury (TBI). Despite the increased number of studies, several questions about prevalence and risk factors for CTE in the general population remain unknown. Method: to investigate the presence of CTE pathology in a population‐based clinicopathological cohort, we analyzed brain sections immunostained with tau antibody (AT8) of 1151 individuals over 30 years of age with previous neuropathological assessment. The presence of CTE pathology was evaluated according to the current neuropathological consensus criteria. Demographic and clinical data were collected through interviews with a next‐of‐kin. All cases are from the Biobank for Aging Studies of the University of São Paulo University. Internationally accepted criteria were used to diagnose and stage the brain tissue pathologies. Result: Only 7 cases (0.6%) met neuropathological criteria for CTE, contrasting with the high frequency of aging‐related tau astrocyte pathology (ARTAG) (50%) The mean age of death was 73.4 12.5 and only one individual were female. Presence of co‐pathologies was observed in all cases, being the most frequent comorbidity AD‐type pathology, followed by argyrophilic grain disease. Dementia was present in 43%, meanwhile 57% had some degree of neuropsychiatric symptoms (NPS). The most frequent NPS was depression, followed by anxiety. The history of sport practice was complete only for two cases. Both played soccer, however only one semi‐professionally. Conclusion: The low frequency of CTE pathology corroborate findings from other studies that CTE is not a frequent finding in population‐based samples. The overlapping between CTE and ARTAG may contribute with the misclassification of ARTAG as CTE. [ABSTRACT FROM AUTHOR]

Background: The presence of aging‐related tau astrogliopathy (ARTAG) is highly frequent, but poorly characterized in aging brain and neurodegeneration. Over the abnormal tau accumulation processes, tau protein undergoes pathological modifications and the sequency of these pathological events can be associated with different levels of tau aggregation. Method: To evaluate the frequency of ARTAG in a large population‐based study, we analyzed brain sections immunostained with phosphor tau (AT8) of 1151 individuals with previous neuropathological evaluation. Further, to investigate early stages of tau protein aggregation in ARTAG, we performed additional immunohistochemistry in the amygdala of 32 cases with ARTAG pathology using the following tau antibodies: AT100 and Tau‐C3. Result: ARTAG was frequently observed in cognitively normal individuals independent of concomitant neurodegenerative disease. Higher burden of Alzheimer‐type pathology was observed in ARTAG compared to non‐ARTAG. Also, presence of more than one pathology (mixed pathology) was higher in ARTAG compared to non‐ARTAG (p<0.001). Additionally, AT100 immunoreactive ARTAG was found in overall cases, while Tau‐C3 immunoreactive ARTAG was not observed in 12 cases (36%), showing different mature stage for ARTAG compared to neurofibrillary tangles. Conclusion: Different immunological markers can be found in ARTAG and Alzheimer's neurofibrillary pathology in early stages of tau pathological processing, suggesting different levels of abnormal tau aggregates among cases with ARTAG pathology. [ABSTRACT FROM AUTHOR]

Background: Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease predominantly found in former athletes and associated with repetitive brain injury (TBI). Despite the increased number of studies, several questions about prevalence and risk factors for CTE in the general population remain unknown. Method: to investigate the presence of CTE pathology in a population‐based clinicopathological cohort, we analyzed brain sections immunostained with tau antibody (AT8) of 1151 individuals over 30 years of age with previous neuropathological assessment. The presence of CTE pathology was evaluated according to the current neuropathological consensus criteria. Demographic and clinical data were collected through interviews with a next‐of‐kin. All cases are from the Biobank for Aging Studies of the University of São Paulo University. Internationally accepted criteria were used to diagnose and stage the brain tissue pathologies. Result: Only 7 cases (0.6%) met neuropathological criteria for CTE, contrasting with the high frequency of aging‐related tau astrocyte pathology (ARTAG) (50%) The mean age of death was 73.4 12.5 and only one individual were female. Presence of co‐pathologies was observed in all cases, being the most frequent comorbidity AD‐type pathology, followed by argyrophilic grain disease. Dementia was present in 43%, meanwhile 57% had some degree of neuropsychiatric symptoms (NPS). The most frequent NPS was depression, followed by anxiety. The history of sport practice was complete only for two cases. Both played soccer, however only one semi‐professionally. Conclusion: The low frequency of CTE pathology corroborate findings from other studies that CTE is not a frequent finding in population‐based samples. The overlapping between CTE and ARTAG may contribute with the misclassification of ARTAG as CTE. [ABSTRACT FROM AUTHOR]

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Apolipoprotein E (APOE) ε4 allele has been associated with higher carotid atherosclerosis risk, while the APOE-ε2 seems to decrease this risk. Data from autopsy studies, where carotid arteries can be evaluated in their full extension, is scarce. Therefore, we investigated the association between APOE alleles and direct morphometric measurements of carotid atherosclerosis in an autopsy study with an admixed sample. We measured the intima-media thickness (IMT) and stenosis of the common (CCA) and internal carotid (ICA) arteries. The APOE polymorphisms were determined by real-time polymerase chain reaction. Participants were classified into three groups according to the APOE alleles (ε2, ε3, and ε4). We evaluated the association between APOE groups and carotid atherosclerosis using adjusted regression models and included interaction terms of APOE alleles with age, sex, and race. We evaluated 1,850 carotid artery samples from 185 participants (mean age=75±12 years old, 55% female, and 71% White). The APOE-ε2 group (n=17) had a lower carotid obstruction and a lower number of severe stenoses (≥ 70%). Having at least one ε4 allele (n=51) was not associated with carotid atherosclerosis. APOE alleles were also not associated with carotid IMT. Age, sex, and race did not modify these relationships. APOE-ε2 carriers had a lower percentage of carotid obstruction and less severe stenosis. APOE-ε4 was not related to a higher risk of carotid atherosclerosis in this cross-sectional population-based autopsy study. [ABSTRACT FROM AUTHOR]

Background: Most people with dementia already live in low‐ to middle‐income countries (LMIC). However, most evidence regarding dementia prevention comes from high‐income countries that have different socioeconomic status (SES) and risk factors prevalence than LMIC. In this session, we will present results on risk and protective factors for dementia from the Longitudinal Study of Adult Health (ELSA‐Brasil), the Brazilian Longitudinal Study of Aging (ELSI‐Brazil), and the Brazilian Biobank for Aging Studies (BAS). Method: The ELSA‐Brasil follows 15,105 public servants since 2008‐10. The ELSI‐Brazil is a nationally representative study with 9,412 adults aged 50 years and older, who were enrolled in 2015‐16. The BAS is a neuropathology study that started in 2004 and is the largest brain bank in Latin America with a collection of 1,441 brains. The focus of this presentation will be on the associations of education, SES, and cardiovascular factors with dementia using data from these three studies. Result: In the BAS, 77% of the sample has less than 5 years of education and 56% unskilled occupations. Compared to the group without education, those with formal education had better cognitive performance (1‐4 years: 훽 = ‐0.99, 95%CI = –1.85; –0.14, p = 0.02; ≥5 years: = –1.42, 95% CI = –2.47; –0.38, p = 0.008). On the other hand, occupation complexity and demands were unrelated to cognition. Similarly, we showed that education and early‐life SES were the main contributors to cognitive performance in the ELSA‐Brasil, while later SES had a lower influence on cognitive scores. Cardiovascular factors are also important contributors to brain health. Ideal vascular health was related to better cognitive function in the ELSA‐Brasil. Participants with intermediate (β = 0.064, 95%CI = 0.033; 0.096) and optimal health (β = 0.108, 95%CI = 0.052; 0.164) had better cognitive z‐scores. Moreover, carotid artery atherosclerosis evaluated by morphometric measurements was related to cognitive impairment in BAS and with cognitive decline in the ELSA‐Brasil after 8 years of follow‐up (β = ‐0.028, 95%CI = ‐0.036; ‐0.020, p<0.001). Finally, hypertension was related to worse cognition (β = ‐0.09; 95%CI = ‐0.15, ‐0.04; p = 0.001) in ELSI‐Brazil, mainly in non‐frail participants. Conclusion: Studies from LMIC regarding dementia risk factors are essential to implement tailored public policies for dementia primary prevention. [ABSTRACT FROM AUTHOR]

Copyright of Arquivos de Neuro-Psiquiatria is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction Alzheimer's disease (AD) progression follows a specific spreading pattern, emphasizing the need to characterize those brain areas that degenerate first. The brainstem's locus coeruleus (LC) is the first area to develop neurofibrillary changes (neurofibrillary tangles [NFTs]). Methods The methods include unbiased stereological analyses in human brainstems to estimate LC volume and neuronal population in controls and individuals across all AD stages. Results As the Braak stage increases by 1 unit, the LC volume decreases by 8.4%. Neuronal loss started only midway through AD progression. Age-related changes spare the LC. Discussion The long gap between NFT accumulation and neuronal loss suggests that a second trigger may be necessary to induce neuronal death in AD. Imaging studies should determine whether LC volumetry can replicate the stage-wise atrophy observed here and how these changes are specific to AD. LC volumetry may develop into a screening biomarker for selecting high-yield candidates to undergo expensive and less accessible positron emission tomography scans and to monitor AD progression from presymptomatic stages. [ABSTRACT FROM AUTHOR]

Multidisciplinary teams (MDTs) have been incorporated into the practical care of elderly patients with cancer. Several geriatric oncology centres have attempted to determine the best way to implement MDTs by using geriatric assessment (GA). Developing a geriatric oncology service is a feasible work, which requires significant resources. The challenges of MDTs must be known so that better care planning for elderly patients with cancer can be devised. The aim of this paper is to discuss the practical aspects of the multidisciplinary care of older adults with cancer by considering a geriatric point of view and the recent literature. Reviewing data from recent studies helps enumerate the major challenges in establishing collaboration in geriatric oncology: evaluating the resources of your centre, knowing the role of each member of the team, establishing good communication both within the team and with the patients, and determining referral criteria and using screening tests to select which patients can benefit the most from the multidisciplinary evaluation and a more thorough GA. [ABSTRACT FROM AUTHOR]

Background: Clinical Dementia Rating Scale (CDR) is one of the most used assessment scales in the care of dementia but it still lacks a detailed analysis of construct validity. We aimed to analyze evidences of construct validity of the CDR to assess the level of cognitive decline by informants. Method: We analyzed 650 records of elderly subjects belonging to the Brazilian Biobank for Aging Studies. A trained nurse fulfilled the CDR during the clinical interview with a knowledgeable next‐of‐kin, after informed consent. We considered each domain of the CDR as one item. Exploratory (EFA) and Confirmatory factor analysis (CFA) were performed. We used Robust Unweighted Least Squares with promax rotation, with a bootstrapping of 1.000 cases, and Parallel Analysis. Sample adequacy was tested by the Kaiser‐Meyer‐Olkin and Bartlett sphericity tests. UniCo, ECV and Mireal tested the dimensionality. Factor loading ≥ 0.50 and communalities ≥ 0.40 were indicators of good factor solution. In CFA we tested: Goodness of Fit Index (GFI), Adjusted Goodness of Fit Index (AGFI), Non‐Normed Fit Index (NNFI), Comparative Fit Index (CFI), and Weighted Root Mean Square Residual (WRMR). Reliability was tested by standardized Chronbach's Alpha, Ordinal McDonald's Ômega and GLB. For the analysis, we used Factor 10.10.3. Result: Sample was composed by 55.5% of females, the mean age of the sample was 68.7±11.3 years and 78.8% of the participants were cognitively normal (CDR = 0). KMO was 0.86 and Bartlett was <0.001. Total explained variance was 84.6%. Parallel analysis showed only one dimension and values of UniCo (0.994); ECV (0.919) and MIREAL (0.279) confirmed the unidimensionality of the structure. Factor loadings ranged from 0.846 to 0.945 and communalities from 0.716 to 0.894. Memory was the item with the higher factor loading and communality. All the goodness of fit indexes confirmed the structure of CDR. Indicators of reliability were also very good (Table 1). Conclusion: CDR is a unidimensional instrument composed by six items that together explain 84.6% of the 'level of cognitive decline'. Results indicated that the CDR has very good evidence of construct validity and reliability and can be used to assess the level of cognitive decline by informants. [ABSTRACT FROM AUTHOR]