Apolipoprotein E ε2 allele is associated with lower risk of carotid artery obstruction in a population-based autopsy study.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The Potential Role of Selection Bias in the Association Between Coronary Atherosclerosis and Cognitive Impairment.

BACKGROUND: Coronary atherosclerosis assessed in vivo was associated with cognitive impairment; however, conflicting findings have been reported in autopsy samples. OBJECTIVE: Our aims were to assess the association between atherosclerotic stenosis in the coronary arteries and cognitive impairment and to investigate the possibility of selection bias in an autopsy study. METHODS: Coronary arteries were collected, and the largest luminal stenosis was measured. Sociodemographic, clinical, and cognitive information were reported by a reliable next-of-kin. The association was tested using logistic and linear regressions adjusted for sociodemographic and clinical variables. We restricted the sample to individuals that were born in 1935 or earlier and stratified the analysis by cause of death to investigate the role of selection bias. RESULTS: In 253 participants (mean age = 78.0±8.5 years old, 48% male), stenosis was not associated with cognitive impairment (OR = 0.85, 95% CI = 0.69; 1.06, p = 0.15). In individuals who were born before 1936 in the absence of cardiovascular disease as the cause of death, greater stenosis was associated with cognitive impairment (OR = 4.02, 95% CI = 1.39; 11.6, p = 0.01). On the other hand, this association was not present among those born in 1935 or earlier who died of cardiovascular diseases (OR = 0.83, 95% CI = 0.60; 1.16, p = 0.28). CONCLUSION: We found that higher coronary stenosis was associated with cognitive impairment only in individuals born in 1935 or earlier and who had not died from cardiovascular diseases. Selection bias may be an important issue when investigating risk factors for chronic degenerative diseases in older individuals using autopsy samples.

Social Isolation, Loneliness, and Cognitive Performance in Older Adults: Evidence From the ELSI-Brazil Study.

BACKGROUND: The association between social isolation and cognitive performance has been less investigated in low-to-middle-income countries (LMIC) and the presence of depression as a moderator on this association has not been examined. The authors examined the associations of social isolation and perceived loneliness with cognitive performance in the Brazilian Longitudinal Study of Aging. METHODS: In this cross-sectional analysis, social isolation was evaluated by a composite score including marital status, social contact, and social support. The dependent variable was global cognitive performance, which considered memory, verbal fluency, and temporal orientation tests. Linear and logistic regressions were adjusted for sociodemographic and clinical variables. The authors added interaction terms of depressive symptoms with social isolation and loneliness to examine whether depression, measured through the Center for Epidemiologic Studies-Depression Scale, modified these associations. RESULTS: Among 6,986 participants (mean age = 62.1 ± 9.2 years), higher levels of social connections were associated with better global cognitive performance (B = 0.02, 95%CI: 0.02; 0.04). Perceived loneliness was associated with worse cognition (B = -0.26, 95%CI = -0.34; -0.18). Interactions of depressive symptoms with social connections scores were found on memory z-score and with loneliness on global and memory z-scores, suggesting a weaker association between social isolation or loneliness and cognition among those with depressive symptoms. CONCLUSION: In a large sample from an LMIC, social isolation and loneliness were associated with worse cognitive performance. Surprisingly, depressive symptoms decrease the strength of these associations. Future longitudinal studies are important to assess the direction of the association between social isolation and cognitive performance.

Potentially inappropriate medications and cognitive performance: cross-sectional results from the ELSA-Brasil study.

OBJECTIVES: Potentially inappropriate medications (PIM), especially those with potential effects on the central nervous system, can increase the risk of cognitive impairment. We investigated the association of the use of PIM and PIM that may impair cognition (PIM-Cog) with cognitive performance among older adults. METHODS: In this cross-sectional study with 2,626 participants, PIM and PIM-Cog were defined by the 2019 American Geriatrics Society Beers criteria. We calculated global cognition and memory, verbal fluency, and Trail Making Test B version (TMT-B) z-scores. Linear regression models adjusted for sociodemographic and clinical variables were used to investigate the association between PIM and cognition. RESULTS: 27% and 7% of the sample (mean age = 65.1 ± 4.1 years old, 54% women, and 61% White) used at least one PIM and PIM-cog, respectively. PIM was associated with poor performance in the TMT-B (ß = -0.17, 95% Cl = -0.29; -0.05, p = 0.007). PIM-Cog was also associated with poor TMT-B performance (ß = -0.08, 95% Cl = -0.15; -0.01, p = 0.025). CONCLUSION: The use of PIM and PIM-Cog was associated with poor executive function among older adults. The review of PIM use and the deprescription of these drugs may be an effective way to improve cognitive function.

The action of phosphodiesterase-5 inhibitors on ß-amyloid pathology and cognition in experimental Alzheimer's disease: A systematic review.

Alzheimer's disease (AD) is the most frequent cause of dementia worldwide. The etiology of AD is partially explained by the deposition of ß-amyloid in the brain. Despite extensive research on the pathogenesis of AD, the current treatments are ineffective. Here, we systematically reviewed studies that investigated whether phosphodiesterase 5 inhibitors (PDE5i) are efficient in reducing the ß-amyloid load in hippocampi and improving cognitive decline in rodent models with ß-amyloid accumulation. We identified ten original studies, which used rodent models with ß-amyloid accumulation, were treated with PDE5i, and ß-amyloid was measured in the hippocampi. PDE5i was efficient in reducing the ß-amyloid levels, except for one study that exclusively used female rodents and the treatment did not affect ß-amyloid levels. Interestingly, PDE5i prevented cognitive decline in all studies. This study supports the potential therapeutic use of PDE5i for the reduction of the ß-amyloid load in hippocampi and cognitive decline. However, we highlight the importance of conducting additional experimental studies to evaluate the PDE5i-related molecular mechanisms involved in ß-amyloid removal in male and female animals.

Apolipoprotein E genotypes were not associated with intracranial atherosclerosis: a population-based autopsy study.

BACKGROUND: Apolipoprotein E gene (APOE) ε4 allele is associated with a higher risk of carotid atherosclerosis, but less is known about the association of APOE with intracranial atherosclerotic disease (IAD). We aimed to investigate the association of APOE alleles with IAD in a cross-sectional autopsy study. METHODS: We measured the stenosis in the 12 arteries of the Circle of Willis using postmortem morphometric measurements. The APOE polymorphism was determined by real-time polymerase chain reaction. We assessed the association between APOE polymorphism and IAD using regression models adjusted for sociodemographic and clinical variables. We also verified the modifier effect of age, sex, and race on this association. We stratified the analysis by age group to investigate the possibility of attrition bias. RESULTS: In 400 participants (mean age=73.2±12.3 years old, 51% female, and 64% White), IAD was evaluated in 4,504 artery segments. APOE-ε4 was not associated with IAD nor with the number of artery stenosis compared to non-APOE-ε4 carriers. Sociodemographic variables did not modify this relationship. Among participants older than 70 years, there was a trend towards an association between APOE allele ε4 and a lower stenosis index in the middle cerebral artery, suggesting attrition bias related to the APOE-ε4 effect on mortality. CONCLUSIONS: APOE alleles were not associated with IAD in this population-based autopsy study. Lower stenosis in older participants suggests the possibility of attrition bias.

Macrophage Polarization in the Perivascular Fat Was Associated With Coronary Atherosclerosis.

Background Inflammation of the perivascular adipose tissue (PvAT) may be related to atherosclerosis; however, the association of polarized macrophages in the pericoronary PvAT with measurements of atherosclerosis components in humans has not been fully investigated. Methods and Results Coronary arteries were dissected with surrounding PvAT. We evaluated the percentage of arterial obstruction, intima-media thickness, fibrous cap thickness, plaque components, and the number of vasa vasorum. The number of proinflammatory (M1) and anti-inflammatory (M2) macrophages in the periplaque and control PvAT were evaluated using immunohistochemistry. Regression models adjusted for sociodemographic and clinical variables were used. In 319 segments from 82 individuals, we found a correlation of the M1/M2 macrophage density ratio with an increase in arterial obstruction (P=0.02) and lipid content (P=0.01), and a decrease in smooth muscle cells (P=0.02). M1 and the ratio of M1/M2 macrophages were associated with an increased risk of thrombosis (P=0.03). In plaques with thrombosis, M1 macrophages were correlated with a decrease in fibrous cap thickness (P=0.006), an increase in lipid content (P=0.008), and the number of vasa vasorum in the adventitia layer (P=0.001). M2 macrophages were correlated with increased arterial obstruction (P=0.01), calcification (P=0.02), necrosis (P=0.03) only in plaques without thrombosis, and decrease of the number of vasa vasorum in plaques with thrombosis (P=0.003). Conclusions M1 macrophages in the periplaque PvAT were associated with a higher risk of coronary thrombosis and were correlated with histological components of plaque progression and destabilization. M2 macrophages were correlated with plaque size, calcification, necrotic content, and a decrease in the number of vasa vasorum in the adventitia layer.

B Lymphocytes and Macrophages in the Perivascular Adipose Tissue Are Associated With Coronary Atherosclerosis: An Autopsy Study.

Background Macrophages and T lymphocytes in the perivascular adipose tissue (PvAT) were previously linked to coronary artery disease. However, the role of these cells and B lymphocytes in the human PvAT adjacent to unstable atherosclerotic plaques has not been investigated. Moreover, previous studies were inconclusive on whether PvAT inflammation was restricted to the surroundings of the atheroma plaque. Methods and Results Coronary arteries were freshly dissected with the surrounding PvAT. Atherosclerotic plaques were classified according to the internationally accepted anatomopathological criteria. Immune cells in the PvAT were detected using immunohistochemistry and then quantified. We used linear and logistic regressions with robust standard errors, adjusted for possible confounding factors. In 246 atherosclerotic plaques (205 stable and 41 unstable plaques) from 82 participants (mean age=69.0±14.4 years; 50% men), the percentage of arterial obstruction was positively correlated with the densities of CD68+ macrophages (P=0.003) and CD20+ B lymphocytes (P=0.03) in the periplaque PvAT. The number of cells was greater in the periplaque PvAT than in the distal PvAT (macrophages, P<0.001; B lymphocytes, P=0.04). In addition, the density of macrophages in the periplaque PvAT was greater in the presence of unstable plaques (P=0.03) and was also greater near unstable plaques than in the distal PvAT (P=0.001). CD3+ T lymphocytes were not associated with percentage of obstruction and stable/unstable plaque composition. Conclusions The density of CD20+ B lymphocytes and CD68+ macrophages in periplaque PvAT was increased with plaque size, and the CD68+ macrophages were greater near unstable atherosclerotic plaques than near stable lesions. This inflammation was more intense in the periplaque PvAT than in the PvAT distal to the atherosclerotic plaques.

Perivascular Adipose Tissue Inflammation and Coronary Artery Disease: An Autopsy Study Protocol.

BACKGROUND: Perivascular adipose tissue (PAT) inflammation may have a role in coronary artery disease (CAD) pathophysiology. However, most evidence has come from samples obtained during surgical procedures that may imply in some limitations. Moreover, the role of B lymphocytes and inflammation in PAT that is adjacent to unstable atheroma plaques has not been investigated in humans using morphometric measurements. OBJECTIVE: The objective of this study is to investigate the inflammation in PAT, subcutaneous, and perirenal adipose tissues (SAT and PrAT) among chronic CAD, acute CAD, and control groups in an autopsy study. METHODS: Heart, SAT, and PrAT samples are collected from autopsied subjects in a general autopsy service, with the written informed consent of the next-of-kin (NOK). Sociodemographic and clinical data are obtained from a semistructure interview with the NOK. Coronary arteries are dissected and PAT are removed. Sections with the greatest arterial obstruction or unstable plaques, and the local with absence of atherosclerosis in all coronary arteries are sampled. PAT are represented adjacent to these fragments. Adipose tissues are fixed in 4% buffered paraformaldehyde solution and analyzed immunohistochemically for macrophages (CD68), macrophage polarization (CD11c for proinflammatory and CD206 for anti-inflammatory), B lymphocytes (CD20), and T lymphocytes (CD3). Slides will be scanned, and inflammatory cells will be quantified in 20 random fields. Participants will be categorized in CAD groups, after morphometric measurement of arterial obstruction and plaque composition analysis in accordance with American Heart Association classification. Three study groups will be investigated: acute CAD (at least one unstable plaque); chronic CAD (≥50% arterial obstruction); and controls (<50% arterial obstruction). Inflammatory cells in PAT, SAT, and PrAT will be counted and compared between groups using multivariate linear regression, adjusted for age, body mass index, hypertension, diabetes, alcohol use, and smoking. RESULTS: We present the methods of our study that was developed from 2 pilots. Currently, data collection and tissue processing are ongoing. Data collection, histology and immunochemistry procedures, and quantification of all inflammatory cells are expected to be concluded within 1 year. CONCLUSIONS: This study will contribute for the understanding of the mechanisms of CAD pathophysiology because it will help to clarify the role of inflammation both in chronic and acute CAD.