Morphometric measurements of extracranial and intracranial atherosclerotic disease: A population-based autopsy study

BACKGROUND AND AIMS:Intracranial (IAD) and extracranial atherosclerotic diseases (EAD) have been mostly investigated using imaging methods. Autopsy studies allow for a direct and complete evaluation of the atherosclerotic disease. We aimed to investigate the frequency of IAD and EAD, their association, and related risk profiles in a large cross-sectional autopsy study. METHODS:We measured the intima-media thickness and stenosis of the common (CCA) and internal carotid arteries (ICA), using morphometric measurements. The main outcome was stenosis (≥50%) in the artery with the largest obstruction among the 12 cerebral arteries. We used multivariable logistic regression models to investigate the association between EAD and IAD. RESULTS:In 661 participants (mean age = 71.3 ± 11.7 y, 51% male), stenosis was more common in IAD than in EAD (59% vs. 51%). EAD was associated with Caucasian race, hypertension, and smoking, while IAD was associated with older age, less years of education, hypertension, diabetes, and a previous history of stroke. Stenosis in CCA and ICA was associated with more than two times the odds of having stenosis in the intracranial arteries (CCA: OR = 2.32, 95% CI = 1.64; 3.28; ICA: OR = 2.51, 95% CI = 1.76; 3.57). CONCLUSIONS:In this population-based autopsy study, IAD was common, even more common than EAD, but correlated with EAD

Neuropathological lesions in the very old: results from a large Brazilian autopsy study

ObjectiveTo compare neuropathological correlates of cognitive impairment between very old and younger individuals from a Brazilian clinicopathological study.MethodsWe assessed the frequency of neuropathological lesions and their association with cognitive impairment (Clinical Dementia Rating scale ≥0.5) in the 80 or over age group compared to younger participants, using logistic regression models adjusted for sex, race and education.ResultsExcept for infarcts and siderocalcinosis, all neuropathological lesions were more common in the 80 or over age group (n = 412) compared to 50-79 year olds (n = 677). Very old participants had more than twice the likelihood of having ≥2 neuropathological diagnoses than younger participants (OR = 2.66, 95% CI = 2.03-3.50). Neurofibrillary tangles, infarcts and hyaline arteriolosclerosis were associated with cognitive impairment in the two age groups. Siderocalcinosis was associated with cognitive impairment in the younger participants only, while Lewy body disease was associated with cognitive impairment in the very old only. In addition, we found that the association of infarcts and multiple pathologies with cognitive impairment was attenuated in very old adults (Infarcts: P for interaction = 0.04; and multiple pathologies: P = 0.05). However, the predictive value for the aggregate model with all neuropathological lesions showed similar discrimination in both age groups [Area under Receiver Operating Characteristic curve (AUROC) = 0.778 in younger participants and AUROC = 0.765 in the very old].Conclusion and relevanceDespite a higher frequency of neuropathological findings in the very old group, as found in studies with high-income populations, we found attenuation of the effect of infarcts rather than neurofibrillary tangles and plaques as reported previously

Direct Measurements of Abdominal Visceral Fat and Cognitive Impairment in Late Life: Findings From an Autopsy Study.

Background: The relationship between cognitive impairment and abdominal visceral is controversial. Moreover, all studies so far used imaging studies to evaluate visceral fat and this association has not been described yet using autopsy material, which allows the direct quantification of abdominal fat. We aimed to investigate the association between direct measurements of abdominal visceral fat and cognitive impairment in an autopsy study. Methods: In this cross-sectional study, we collected information on sociodemographics, cardiovascular risk factors, and cognitive status from subjects aged 50 or older at time of death in a general autopsy service in Brazil. Abdominal visceral fat was obtained in natura by the dissection of perirenal, mesenteric, omental, and mesocolon fat. The associations of total abdominal visceral fat with cognitive impairment [clinical dementia rating (CDR) score ≥0.5] and CDR-sum of boxes (CDR-SB) were evaluated using logistic regression and negative binomial regression models, respectively. All analyses were adjusted for height, age, sex, education, hypertension, diabetes mellitus, stroke, smoking, alcohol use, and physical inactivity. In addition, we compared the discrimination of visceral fat, body mass index (BMI), and waist circumference (WC) measurements in predicting cognitive impairment. Results: We evaluated 234 participants (mean age = 71.2 ± 12.9 years old, 59% male). Abdominal visceral fat was inversely associated with cognitive impairment (OR = 0.46, CI = 0.30; 0.70, p < 0.0001) and with CDR-SB scores (β = -0.85, 95% CI = -1.28; -0.43, p < 0.0001). When we compared the area under the ROC curve (AUC), visceral fat (AUC = 0.754), BMI (AUC = 0.729), and WC (AUC = 0.720) showed similar discrimination in predicting cognitive impairment (p = 0.38). Conclusion: In an autopsy study, larger amount of directly measured abdominal visceral fat was associated with lower odds of cognitive impairment in older adults

Similar Microglial Cell Densities across Brain Structures and Mammalian Species: Implications for Brain Tissue Function

Microglial cells play essential volume-related actions in the brain that contribute to the maturation and plasticity of neural circuits that ultimately shape behavior. Microglia can thus be expected to have similar cell sizes and even distribution both across brain structures and across species with different brain sizes. To test this hypothesis, we determined microglial cell densities (the inverse of cell size) using immunocytochemistry to Iba1 in samples of free cell nuclei prepared with the isotropic fractionator from brain structures of 33 mammalian species belonging to males and females of five different clades. We found that microglial cells constitute ∼7% of non-neuronal cells in different brain structures as well as in the whole brain of all mammalian species examined. Further, they vary little in cell density compared with neuronal cell densities within the cerebral cortex, across brain structures, across species within the same clade, and across mammalian clades. As a consequence, we find that one microglial cell services as few as one and as many as 100 neurons in different brain regions and species, depending on the local neuronal density. We thus conclude that the addition of microglial cells to mammalian brains is governed by mechanisms that constrain the size of these cells and have remained conserved over 200 million years of mammalian evolution. We discuss the probable consequences of such constrained size for brain function in health and disease.SIGNIFICANCE STATEMENT Microglial cells are resident macrophages of the CNS, with key functions in recycling synapses and maintaining the local environment in health and disease. We find that microglial cells occur in similar densities in the brains of different species and in the different structures of each individual brain, which indicates that these cells maintain a similar average size in mammalian evolution, suggesting in turn that the volume monitored by each microglial cell remains constant across mammals. Because the density of neurons is highly variable across the same brain structures and species, our finding implies that microglia-dependent functional recovery may be particularly difficult in those brain structures and species with high neuronal densities and therefore fewer microglial cells per neuron

Cell number changes in Alzheimer's disease relate to dementia, not to plaques and tangles.

Alzheimer's disease is the commonest cause of dementia in the elderly, but its pathological determinants are still debated. Amyloid-β plaques and neurofibrillary tangles have been implicated either directly as disruptors of neural function, or indirectly by precipitating neuronal death and thus causing a reduction in neuronal number. Alternatively, the initial cognitive decline has been attributed to subtle intracellular events caused by amyloid-β oligomers, resulting in dementia after massive synaptic dysfunction followed by neuronal degeneration and death. To investigate whether Alzheimer's disease is associated with changes in the absolute cell numbers of ageing brains, we used the isotropic fractionator, a novel technique designed to determine the absolute cellular composition of brain regions. We investigated whether plaques and tangles are associated with neuronal loss, or whether it is dementia that relates to changes of absolute cell composition, by comparing cell numbers in brains of patients severely demented with those of asymptomatic individuals-both groups histopathologically diagnosed as Alzheimer's-and normal subjects with no pathological signs of the disease. We found a great reduction of neuronal numbers in the hippocampus and cerebral cortex of demented patients with Alzheimer's disease, but not in asymptomatic subjects with Alzheimer's disease. We concluded that neuronal loss is associated with dementia and not the presence of plaques and tangles, which may explain why subjects with histopathological features of Alzheimer's disease can be asymptomatic; and exclude amyloid-β deposits as causes for the reduction of neuronal numbers in the brain. We found an increase of non-neuronal cell numbers in the cerebral cortex and subcortical white matter of demented patients with Alzheimer's disease when compared with asymptomatic subjects with Alzheimer's disease and control subjects, suggesting a reactive glial cell response in the former that may be related to the symptoms they present

Cell number changes in Alzheimer's disease relate to dementia, not to plaques and tangles.

Alzheimer's disease is the commonest cause of dementia in the elderly, but its pathological determinants are still debated. Amyloid-β plaques and neurofibrillary tangles have been implicated either directly as disruptors of neural function, or indirectly by precipitating neuronal death and thus causing a reduction in neuronal number. Alternatively, the initial cognitive decline has been attributed to subtle intracellular events caused by amyloid-β oligomers, resulting in dementia after massive synaptic dysfunction followed by neuronal degeneration and death. To investigate whether Alzheimer's disease is associated with changes in the absolute cell numbers of ageing brains, we used the isotropic fractionator, a novel technique designed to determine the absolute cellular composition of brain regions. We investigated whether plaques and tangles are associated with neuronal loss, or whether it is dementia that relates to changes of absolute cell composition, by comparing cell numbers in brains of patients severely demented with those of asymptomatic individuals-both groups histopathologically diagnosed as Alzheimer's-and normal subjects with no pathological signs of the disease. We found a great reduction of neuronal numbers in the hippocampus and cerebral cortex of demented patients with Alzheimer's disease, but not in asymptomatic subjects with Alzheimer's disease. We concluded that neuronal loss is associated with dementia and not the presence of plaques and tangles, which may explain why subjects with histopathological features of Alzheimer's disease can be asymptomatic; and exclude amyloid-β deposits as causes for the reduction of neuronal numbers in the brain. We found an increase of non-neuronal cell numbers in the cerebral cortex and subcortical white matter of demented patients with Alzheimer's disease when compared with asymptomatic subjects with Alzheimer's disease and control subjects, suggesting a reactive glial cell response in the former that may be related to the symptoms they present