Larger Brain Volumes Research Articles

Historical skull illustrations: Parietal foramen

IntroductionAnatomical illustration has progressed historically to become a means of documentation. The representation of a particular anatomical structure in a drawing/painting meant the artist/anatomist was aware of its presence, position and relation to surrounding structures and can also be used as a primer for tracking the knowledge about such structure. Despite the detailed historical depictions of the skull, the parietal emissary foramen often went unillustrated.ObjectiveThis study focuses on the parietal foramen and its historical depiction.MethodsIt perused artistic illustrations of the skull to establish by whom and when this foramen was displayed. ResultsLocated in the posterior part of the parietal bone, the parietal foramen allows passage for the parietal emissary vein and other structures. Its presence varies among populations, which may explain its omission in some anatomical works. However, artists like Antonio de Pereda and anatomists like Bernhard Siegfried Albinus and John Bell did illustrate it. As other emissary foramina, the parietal emissary foramen has a role in helping regulate intracranial pressure and brain temperature. Its significance has increased throughout human evolution, particularly with the development of bipedalism and larger brain volumes. The foramen may also function as a path in the spread of infection and/or tumors. Recent studies using CT scans have emphasized the importance of recognizing the parietal foramen in imaging and surgical planning.ConclusionThis paper helps uncover part of the history of neuroanatomical illustration pertaining to the depiction of the parietal foramen and highlights its clinical and surgical importance.

A stealthy neural recorder for the study of behaviour in primates.

By monitoring brain neural signals, neural recorders allow for the study of neurological mechanisms underlying specific behavioural and cognitive states. However, the large brain volumes of non-human primates and their extensive range of uncontrolled movements and inherent wildness make it difficult to carry out covert and long-term recording and analysis of deep-brain neural signals. Here we report the development and performance of a stealthy neural recorder for the study of naturalistic behaviours in non-human primates. The neural recorder includes a fully implantable wireless and battery-free module for the recording of local field potentials and accelerometry data in real time, a flexible 32-electrode neural probe with a resorbable insertion shuttle, and a repeater coil-based wireless-power-transfer system operating at the body scale. We used the device to record neurobehavioural data for over 1 month in a freely moving monkey and leveraged the recorded data to train an artificial intelligence model for the classification of the animals' eating behaviours.

A scalable and modular computational pipeline for axonal connectomics: automated tracing and assembly of axons across serial sections.

Progress in histological methods and in microscope technology has enabled dense staining and imaging of axons over large brain volumes, but tracing axons over such volumes requires new computational tools for 3D reconstruction of data acquired from serial sections. We have developed a computational pipeline for automated tracing and volume assembly of densely stained axons imaged over serial sections, which leverages machine learning-based segmentation to enable stitching and alignment with the axon traces themselves. We validated this segmentation-driven approach to volume assembly and alignment of individual axons over centimeter-scale serial sections and show the application of the output traces for analysis of local orientation and for proofreading over aligned volumes. The pipeline is scalable, and combined with recent advances in experimental approaches, should enable new studies of mesoscale connectivity and function over the whole human brain.

Fast X-ray ptychography: towards nanoscale imaging of large volume of brain

X-ray ptychography, a scanning coherent diffraction imaging technique, is one of the most used techniques at synchrotron facilities for high resolution imaging, with applications spanning from life science to nano-electronics. In the recent years there has been a great effort to make the technique faster to enable high throughput nanoscale imaging. Here we apply a fast ptychography scanning method to image in 3D 106μm3\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$10^6\\upmu \\mathrm{{m}}^3$$\\end{document} of brain-like phantom at 3 kHz, in a 7 h acquisition with a resolution of 270 nm. We then present the latest advances in fast ptychography by showing 2D images acquired at 110 kHz by combining the fast-acquisition scheme with a high-acquisition rate prototype detector from DECTRIS Ltd. We finally review the experimental outcome and discuss the prospective use of fast ptychography schemes for the investigation of mm3\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{3}$$\\end{document} size samples of brain-like phantom, by extrapolating the current results to the high coherent flux scenario of diffraction limited storage rings.

Predicting the reversion from mild cognitive impairment to normal cognition based on magnetic resonance imaging, clinical, and neuropsychological examinations.

Predicting the reversion from mild cognitive impairment to normal cognition based on magnetic resonance imaging, clinical, and neuropsychological examinations.

Prenatal substance exposure and child health: Understanding the role of environmental factors, genetics, and brain development.

Prenatal substance exposure (PSE) has been linked to adverse health outcomes, but its interactions with environmental and genetic factors remain unclear. Using data from the adolescent brain cognitive development cohort (n = 9,838; baseline age: 9.92 ± 0.62 years), we tested for the robust associations of PSE-caffeine/alcohol/tobacco/marijuana with children's health, cognition, and brain metrics after controlling for the environmental and genetic contexts. The environmental context involved birth, familial, and societal risk factors, while the genetic context included family histories and polygenic risk scores (PRSs) of mental disorders. In this sample, PSE-caffeine was observed in 59.8%, PSE-alcohol in 25.7%, PSE-tobacco in 13.2%, and PSE-marijuana in 5.6% of children. PSE-tobacco/marijuana was associated with higher environmental risks, PSE-alcohol was associated with lower familial risks, and all PSEs were associated with higher genetic risks. Controlling for these contexts reduced the number of significant health associations by 100, 91, 84, and 18% for PSE-tobacco/marijuana/caffeine/alcohol. Compared to the baseline, PSE-alcohol had the most health associations that were persistent over a 2-year period from preadolescence to adolescence, including associations with more sleep and mental health problems, improved cognitive functions, and larger brain volumes. These persistent associations with mental health problems and crystallized cognition were mediated by the surface areas of the frontal and the parietal cortices, respectively. Lower risk scores of the familial contexts attenuated associations between PSE-alcohol/marijuana and mental health problems. Higher PRS for substance use disorders enhanced late-onset associations of PSE-marijuana with externalizing problems. Results support the "health in context" concept, emphasizing modifiable factors mitigating adverse PSE effects.

Participating in leisure time physical activity across adulthood and later‐life brain health: 30 years follow‐up in 1946 British Birth Cohort

AbstractBackgroundWe assess if, and at which ages during 30 years of adulthood, undertaking leisure time physical activity (LTPA) is associated with brain health at age 70, and to what extent brain health metrics explain the positive association between LTPA and later‐life cognition.MethodParticipants from the British 1946 birth cohort prospectively reported LTPA five times between ages 36 and 69. Metrics were categorised into: not active (no participation/month); active (participated once or more/month); and summed. Participants underwent 18F‐florbetapir Aβ‐PET and MRI at age 70 (n = 468, 49% female). Regression analyses examined associations between LTPA metrics and later‐life brain health including Aβ‐PET, TIV‐adjusted brain, hippocampal and log‐transformed‐white matter hyperintensity (WMH) volume, adjusting for sex, scan age, childhood cognition, education, and childhood socioeconomic position. Effect modification by sex and APOE‐ε4 were examined. The relationship between cumulative LPTA and later‐life cognition (Addenbrooke’s cognitive Examination (ACE‐III)) was assessed adjusting for brain health measures.ResultParticipation in LTPA was associated with better brain health at age 70. For brain volume and WMH volume, the strongest associations were with LTPA at age 69 (Figure 1). Being active in one or more period across adulthood was linked to larger hippocampal volume (Figure 1); this relationship was modified by APOE‐ε4 (p<0.01), with a stronger effect shown in ε4 carriers (Figure 2). LTPA at age 43 was also associated with larger hippocampal volumes. There was no evidence of associations with amyloid status. The positive association between cumulative LTPA and better cognition was not attenuated by any of the brain health measures (Figure 3).ConclusionWe provide evidence that LTPA across adulthood is linked to brain health at age 70; being active throughout adulthood was associated with larger hippocampal volume, particularly in APOE ε4 carriers; and being active in later‐life was linked to less WMH and larger brain volume at age 70. However, these brain health metrics did not explain the relationship between LPTA and better cognitive scores, suggesting that these pathways may not underlie the inferred cognitive benefit at this age. Our findings warrant further research to shed light on the mechanisms of physical activity as a potential disease‐modifying intervention of brain health.

Investigating associations of multiple common infections with brain structure and white matter lesions: findings from prospective neuroimaging studies

AbstractBackgroundEvidence for a role of common infections in neurodegenerative and cerebrovascular diseases is conflicting, and the extent to which pathogen exposure associates with subclinical imaging markers of these diseases is unclear. We aimed to investigate associations between a panel of serological measures characterising exposure to common pathogens – selected based on their relevance to public health – and brain volume, hippocampal volume, and white matter lesions in two population‐based cohorts in the UK.MethodSerology and imaging data were available for 1371 participants across two studies: the UK Biobank (N = 935, mean age(SD)[years] = 55.3(7.7) at serology; 63.8(7.7) at imaging) and the Medical Research Council National Survey of Health and Development [N = 436, mean age(SD) [years] = 63.3(1.1) years at serology; 70.7(0.7) years at imaging). Serology measures included a) serostatuses of 17 pathogens, b) total proportion of 17 pathogens exposed to, and c) total proportion of 11 neurotropic pathogens exposed to (Table 1). Associations between serology measures and outcomes (brain volume, hippocampal volume, and white matter lesion volume) were tested using linear regression. Regression models included adjustments for total intracranial volume and clinic information (basic models), and age, sex, ethnicity, education, socioeconomic position and lifestyle factors (Figure 1). Findings across cohorts were meta‐analysed using random‐effects models. The present study will be expanded to include an additional cohort (Southall and Brent Revisited,N≤1200) to add more precision for identifying associations.ResultSeropositivity to seven pathogens associated with an outcome in basic models, and four in fully‐adjusted models: seropositivity to JC virus was associated with smaller brain volumes, Epstein‐Barr virus with larger brain volumes, Merkel cell virus with larger hippocampal volumes and fewer white matter lesions, and C.trachomatis with fewer white matter lesions (Figure 2). Neurotropic pathogen burden scores associated with smaller hippocampal volumes in basic models, but no associations were seen for either pathogen burden score in fully‐adjusted models.ConclusionWe found some evidence of both positive and negative associations between common infections and imaging markers of subclinical cerebrovascular disease and neurodegeneration, with no evidence of relationships with pathogen burden. This work highlights key relationships for further investigation, which may reveal novel pathways associated with brain structure and cerebrovascular pathology.

A global multicohort study to map subcortical brain development and cognition in infancy and early childhood

The human brain grows quickly during infancy and early childhood, but factors influencing brain maturation in this period remain poorly understood. To address this gap, we harmonized data from eight diverse cohorts, creating one of the largest pediatric neuroimaging datasets to date focused on birth to 6 years of age. We mapped the developmental trajectory of intracranial and subcortical volumes in ∼2,000 children and studied how sociodemographic factors and adverse birth outcomes influence brain structure and cognition. The amygdala was the first subcortical volume to mature, whereas the thalamus exhibited protracted development. Males had larger brain volumes than females, and children born preterm or with low birthweight showed catch-up growth with age. Socioeconomic factors exerted region- and time-specific effects. Regarding cognition, males scored lower than females; preterm birth affected all developmental areas tested, and socioeconomic factors affected visual reception and receptive language. Brain–cognition correlations revealed region-specific associations.

Lower Intelligence Quotient and Larger Brain Volume in the Precuneus among Patients with Graves’ Disease

Abstract Objectives: Neuropsychiatric symptoms are related to hyperthyroidism. Whether global cognitive function is impaired is unclear. In this study, we intended to investigate whether patients with Graves’ disease (GD) are characterized by a lower intelligence quotient (IQ) and gray matter volume loss. Methods: We enrolled 36 patients with GD and 36 healthy controls. Intelligence quotient and other cognitive functions, such as memory and attention, were assessed. Magnetic resonance imaging (MRI) study was used to measure the gray matter volume for those study participants. Results: Significantly lower IQ scores (p < 0.001) and poor memory function (p < 0.05) were found among the patients with GD. We also found that patients with GD had a nonsignificant larger gray matter volume in the precuneus compared with that in healthy controls. Conclusion: The deficits on global and complex cognitive testing among patients with GD should be noted. We speculate that the larger gray matter volume in the precuneus might be due to compensation.

Acoustically targeted noninvasive gene therapy in large brain volumes.

Focused Ultrasound Blood-Brain Barrier Opening (FUS-BBBO) can deliver adeno-associated viral vectors (AAVs) to treat genetic disorders of the brain. However, such disorders often affect large brain regions. Moreover, the applicability of FUS-BBBO in the treatment of brain-wide genetic disorders has not yet been evaluated. Herein, we evaluated the transduction efficiency and safety of opening up to 105 sites simultaneously. Increasing the number of targeted sites increased gene delivery efficiency at each site. We achieved transduction of up to 60% of brain cells with comparable efficiency in the majority of the brain regions. Furthermore, gene delivery with FUS-BBBO was safe even when all 105 sites were targeted simultaneously without negative effects on animal weight or neuronal loss. To evaluate the application of multi-site FUS-BBBO for gene therapy, we used it for gene editing using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system and found effective gene editing, but also a loss of neurons at the targeted sites. Overall, this study provides a brain-wide map of transduction efficiency, shows the synergistic effect of multi-site targeting on transduction efficiency, and is the first example of large brain volume gene editing after noninvasive gene delivery with FUS-BBBO.

Ensemble method employing quantitative biomarkers and deep learning approach from structural magnetic resonance imaging to diagnose Alzheimer’s disease

Abstract Introduction: Alzheimer’s disease (AD) is a neurodegenerative condition that impairs activities of daily living and sharply declines gross cognitive ability. Over 152 million individuals worldwide will live with the dreaded consequence of a longer lifespan by the year 2050, making it a pressing public health issue. Magnetic resonance imaging (MRI) provides excellent soft tissue contrast and helps image the brain in vivo, non-invasively. Aims and Objectives: To summarize AD’s anatomical, physiological, and pathophysiological changes and derivation of quantifiable biomarkers from MRI to develop artificial intelligence (AI) based computer-aided detection (CAD) system to classify subjects among AD, mild cognitive impairment (MCI), and cognitively normal (CN). Materials and Methods: This retrospective study uses clinical and standardized, pre-processed, quality-controlled, and quality-checked—structural MRI imaging (diagnosed/labeled) data of 1069 subjects, age, gender, and class matched, taken from Alzheimer’s disease neuroimaging initiative. A pipeline is developed to get quantified biomarkers from the assessment of (1) cortical thickness, (2) volumetric segmentation for whole brain volumes, and (3) region of interest (ROI) areas most affected in AD. A gradient boosting method is used to predict class labels. The second approach implements a convolution neural network (CNN) model comprising 3D ROI. Results: Implemented CAD system using an ensemble gradient boosting approach has demonstrated good receiver operating characteristics characteristic and yielded balanced accuracy (BA) of 82.31%, 78.52%, and 72.73%, and the CNN approach has given better results 88.44%, 82.96%, and 74.34% for classification task AD versus CN, AD versus MCI, and MCI versus CN, respectively. Conclusion: This study has used a substantially large dataset of 1069 subjects. The deep learning-based efficient and optimal CNN model has used significantly large ROI-based 3-Dimentional volume, resulting in impressive performance improvements over comparable methods. The CNN model had given higher accuracy (6.13% for AD vs. CN, 4.44% for AD vs. MCI and 1.61% for MCI vs. CN) over gradient boosting, as the model uses significantly large ROI-based 3D brain volume and an inherent capability of it in learning most discriminative features automatically. However, quantitative biomarkers derived from brain morphometry, which accesses structural changes, yield reasonable estimates over pathophysiological alterations across the brain and augment a clinician with insightful and a holistic view, resulting in higher confidence over predicated class label by CNN and is a step closer to explainable AI. Accuracy for MCI versus CN drops as these classes share similar features and characteristics and can be improved by integrating biomarkers from other MRI modalities.

Associations of Midlife Dietary Patterns with Incident Dementia and Brain Structure: Findings from the UK Biobank Study

Associations of Midlife Dietary Patterns with Incident Dementia and Brain Structure: Findings from the UK Biobank Study

Train Smart Study: protocol for a randomised trial investigating the role of exercise training dose on markers of brain health in sedentary middle-aged adults

IntroductionRegular aerobic exercise is associated with improved cognitive function, implicating it as a strategy to reduce dementia risk. This is reinforced by the association between greater cardiorespiratory fitness and larger...

Dietary magnesium intake is related to larger brain volumes and lower white matter lesions with notable sex differences

PurposeTo examine the association between dietary magnesium (Mg) intake and brain volumes and white matter lesions (WMLs) in middle to early old age.MethodsParticipants (aged 40–73 years) from UK Biobank (n = 6001) were included and stratified by sex. Dietary Mg was measured using an online computerised 24 h recall questionnaire to estimate daily Mg intake. Latent class analysis and hierarchical linear regression models were performed to investigate the association between baseline dietary Mg, Mg trajectories, and brain volumes and WMLs. Associations between baseline Mg, and baseline blood pressure (BP) measures, and baseline Mg, Mg trajectories and BP changes (between baseline and wave 2) were also investigated to assess whether BP mediates the link between Mg intake and brain health. All analyses controlled for health and socio-demographic covariates. Possible interactions between menopausal status and Mg trajectories in predicting brain volumes and WMLs were also investigated.ResultsOn average, higher baseline dietary Mg intake was associated with larger brain volumes (gray matter [GM]: 0.001% [SE = 0.0003]; left hippocampus [LHC]: 0.0013% [SE = 0.0006]; and right hippocampus [RHC]: 0.0023% [SE = 0.0006]) in both men and women. Latent class analysis of Mg intake revealed three classes: “high-decreasing” (men = 3.2%, women = 1.9%), “low-increasing” (men = 1.09%, women = 1.62%), and “stable normal” (men = 95.71%, women = 96.51%). In women, only the “high-decreasing” trajectory was significantly associated with larger brain volumes (GM: 1.17%, [SE = 0.58]; and RHC: 2.79% [SE = 1.11]) compared to the “normal-stable”, the “low-increasing” trajectory was associated with smaller brain volumes (GM: − 1.67%, [SE = 0.30]; white matter [WM]: − 0.85% [SE = 0.42]; LHC: − 2.43% [SE = 0.59]; and RHC: − 1.50% [SE = 0.57]) and larger WMLs (1.6% [SE = 0.53]). Associations between Mg and BP measures were mostly non-significant. Furthermore, the observed neuroprotective effect of higher dietary Mg intake in the “high-decreasing” trajectory appears to be greater in post-menopausal than pre-menopausal women.ConclusionsHigher dietary Mg intake is related to better brain health in the general population, and particularly in women.

Regular physical activity moderates the adverse impact of type 2 diabetes on brain atrophy independently from HbA1c.

Brain atrophy has been consistently associated with type 2 diabetes, beginning in early stages of dysglycemia, independently from micro and macrovascular complications. On the contrary, physical activity relates with larger brain volumes. Our aim is to assess the influence of regular physical activity on brain volumes in people with type 2 diabetes. A cross-sectional multimodal evaluation with 3T MRI was performed on 170 individuals: 85 individuals with type 2 diabetes and 85 controls. They underwent clinical examination, blood sampling and 3T MRI. Brain volumes (mm3) were estimated using FreeSurfer 7. Physical activity duration was self-reported by the participants as the number of hours of physical activity per week for at least the previous 6 months. Statistical analysis was performed with IBM SPSS 27. People with type 2 diabetes had significantly lower cortical and subcortical volumes, adjusted for age and individual intracranial volume, comparing to controls. Regression analysis showed that within type 2 diabetes group, lower gray matter volumes were associated with lesser physical activity duration (hours/week), independently from HbA1c. Moreover, there were significant moderate positive correlations between regular physical activity duration and gray matter volumes of cortical and subcortical subregions, specifically in the diabetes group. This study reveals a putative beneficial effect of regular physical activity independently of glycemic control, as assessed by HbA1c, which might contribute to reduce the negative impact of type 2 diabetes in the brain.

Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort

BackgroundThe risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT.MethodsThe analysis used baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes.ResultsAPOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6–10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= −0.555, p=0.035) and left hippocampal volumes (standardized β= −0.577, p=0.028) only in APOE4 carriers.ConclusionHRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.

A conventional fixation volume electron microscopy protocol for plants.

A conventional fixation volume electron microscopy protocol for plants.

Association between reproductive factors in women and risk of brain ageing and dementia

AbstractBackgroundWomen have a higher prevalence of dementia than men. We determined the association between female reproductive factors and risk of cognitive outcomes, including incident dementia, in a community‐based sample of cognitively healthy individuals.MethodLifetime reproductive factors including age of menarche, age of menopause, reproductive lifespan (age of menopause minus age of menarche), number of live births, post‐menopausal hormone replacement therapy use, and serum estradiol and estrone concentrations were measured in 796 dementia‐free women [mean age 68.4 (SD 5.7) yr] from the Framingham Heart Study Offspring cohort at examination cycle seven (1998‐2001). We related reproductive factors to subsequent risk of incident dementia. Structural MRI brain measures and neurocognitive test performance were included as secondary outcomes.ResultDuring a median 10 [Q1‐Q3, 8.04‐10.0] year follow‐up, 138 participants developed dementia. On Cox proportional‐hazards analysis adjusting for age and education, a longer reproductive lifespan was associated with a reduced risk of incident dementia (HR 0.94, 95% CI 0.91‐0.98, p = 0.004) while earlier age of menopause of ≤49 vs 50‐51 years was associated with an increased dementia risk (HR 2.56, 95% CI 1.12‐5.88, p = 0.027). Earlier menopause (≤49 versus 50‐51 years) was cross‐sectionally associated with lower hippocampal volume (β±SE, ‐0.123±0.057, p = 0.03). Compared to no live births, 1‐2 live births (5.85±2.03, p = 0.004) and ≥3 live births (5.17±2.06, p = 0.01) were associated with greater total cerebral brain volume. Use of post‐menopausal HRT (0.15±0.055, p = 0.007) and elevated serum estradiol (0.058±0.027, p = 0.03) and estrone concentrations (0.078±0.029, p = 0.006) were cross‐sectionally associated with improved abstract reasoning (Similarities test). Compared to no live births, 1‐2 live births (0.20±0.08, p = 0.018) and ≥3 live births (0.25±0.08, p = 0.003) were also associated with superior visuospatial performance.ConclusionGreater exposure to estrogen throughout a woman’s reproductive life was associated with a lower risk of incident dementia and cross‐sectionally associated with larger brain volumes and enhanced cognitive performance. Our results suggest positive cognitive benefits of greater lifetime estrogen exposure and highlight the potential role of estrogen exposure in modifying the risk of dementia.

Three-Dimensional Imaging of Fibrinogen and Neurovascular Alterations in Alzheimer's Disease.

Cerebrovascular dysfunction is a hallmark of Alzheimer's disease (AD) that is linked to cognitive decline. However, blood-brain barrier (BBB) disruption in AD is focal and requires sensitive methods to detect extravasated blood proteins and vasculature in large brain volumes. Fibrinogen, a blood coagulation factor, is deposited in AD brains at sites of BBB disruption and cerebrovascular damage. This chapter presents the methodology of fibrinogen immunolabeling-enabled three-dimensional (3D) imaging of solvent-cleared organs (iDISCO) which, when combined with immunolabeling of amyloid β (Aβ) and vasculature, enables sensitive detection of focal BBB vascular abnormalities, and reveals the spatial distribution of Aβ plaques and fibrin deposits, in large tissue volumes from cleared human brains. Overall, fibrinogen iDISCO enables the investigation of neurovascular and neuroimmune mechanisms driving neurodegeneration in disease.