Stereological Investigation of Regional Brain Volumes after Acute and Chronic Cuprizone-Induced Demyelination

Brain volume measurement is one of the most frequently used biomarkers to establish neuroprotective effects during pre-clinical multiple sclerosis (MS) studies. Furthermore, whole-brain atrophy estimates in MS correlate more robustly with clinical disability than traditional, lesion-based metrics. However, the underlying mechanisms leading to brain atrophy are poorly understood, partly due to the lack of appropriate animal models to study this aspect of the disease. The purpose of this study was to assess brain volumes and neuro-axonal degeneration after acute and chronic cuprizone-induced demyelination. C57BL/6 male mice were intoxicated with cuprizone for up to 12 weeks. Brain volume, as well as total numbers and densities of neurons, were determined using design-based stereology. After five weeks of cuprizone intoxication, despite severe demyelination, brain volumes were not altered at this time point. After 12 weeks of cuprizone intoxication, a significant volume reduction was found in the corpus callosum and diverse subcortical areas, particularly the internal capsule and the thalamus. Thalamic volume loss was accompanied by glucose hypermetabolism, analyzed by [18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography. This study demonstrates region-specific brain atrophy of different subcortical brain regions after chronic cuprizone-induced demyelination. The chronic cuprizone demyelination model in male mice is, thus, a useful tool to study the underlying mechanisms of subcortical brain atrophy and to investigate the effectiveness of therapeutic interventions.

Download Full-text

Relationship Between Verbal Fluency Performance, Fight Exposure, and Subcortical Region Brain Volumes in Professional Fighters

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acz026.05 ◽

2019 ◽

Vol 34 (5) ◽

pp. 735-735

Author(s):

L Bennett ◽

C Bernick ◽

S Banks

Keyword(s):

Verbal Fluency ◽

Brain Structures ◽

Brain Regions ◽

Health Study ◽

Semantic Fluency ◽

Cognitive Changes ◽

Brain Volumes ◽

Subcortical Brain ◽

Subcortical Region ◽

Subcortical Brain Structures

Abstract Purpose Verbal fluency performance has been shown to be sensitive to preclinical cognitive changes in neurodegenerative diseases and may detect early, trauma-related cognitive and volumetric changes amongst professional fighters. Baseline verbal fluency performance and volumes of relevant subcortical brain structures were expected to decline as number of professional fights (NoPF) increased, while controlling for education. Methods Baseline letter and semantic fluency performance, NoPF, and structural brain imaging from 548 active and retired fighters who participated in the Professional Fighters Brain Health Study were considered. ANCOVAs were conducted to assess differences in verbal fluency performance by NOPF, while controlling for years of education. Number of professional fights were stratified into low (0-20 fights), medium (21-40 fights), and high (41 or more fights). Results Semantic fluency performance differed across the three levels of NoPF (F(2, 542)=4.56; p<.02). In addition, significant positive correlations between semantic fluency performance and volumes in the following regions were observed: left thalamus, left putamen, left pallidum, bilateral caudates, bilateral amygdalae, bilateral hippocampi, and bilateral accumbens (all p’s<.05). In contrast, letter fluency performance was not significantly associated with NoPF or volumes of relevant subcortical brain structures (all p’s>.05). Conclusion Semantic fluency may be low-cost, easy-to-administer harbinger of emerging cognitive dysfunction and lower volumes in related subcortical brain regions. Additional assessment of clinical utility is necessary.

Download Full-text

Abstract 171: CRP, IL-18, and BNP are Associated with Regional Brain Atrophy: Results from the Dallas Heart Study

Stroke ◽

10.1161/str.44.suppl_1.a171 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Richard T Lucarelli ◽

Amit Khera ◽

Ronald M Peshock ◽

Roderick McColl ◽

Colby Ayers ◽

...

Keyword(s):

Brain Atrophy ◽

Linear Regression Analysis ◽

Brain Regions ◽

Population Based ◽

Multivariate Linear Regression Analysis ◽

Brain Images ◽

Brain Volumes ◽

Heart Study ◽

Total Brain ◽

Dallas Heart Study

Purpose: Multiple biomarkers have been associated with total brain atrophy. However, little is known about their relationship to segmental atrophy in a large, multi-ethnic, population-based sample. Materials and Methods: 3D-MPRAGE brain images obtained at 3T from 2082 participants of the Dallas Heart Study (DHS) 2 were analyzed with Freesurfer and outlier analysis was performed. Divisive eigenvalue clustering of 89 brain segments yielded 24 groups with linked atrophy patterns. Plasma C-reactive protein (CRP), IL-18, homocsysteine and B-type natriuretic peptide (BNP) obtained 7 years prior during DHS 1 were available for 1343, 840, 1333 and 1331 participants, respectively. Multivariate linear regression analysis with adjustments for age, ethnicity, and gender were used to demonstrate associations between biomarkers and atrophy clusters. Results: Nine atrophy clusters were associated with CRP, three atrophy clusters were associated with IL-18, and six atrophy clusters were associated with BNP (Table 1). Homocysteine did not have any significant correlations. Conclusions: The markers studied had associations with distinct patterns of segmental atrophy indicating they may have unique interactions in different brain regions. This suggests that distinct inflammatory and other pathways may be at work in specific regions of the brain and that their localized effects may be obscured by approaches evaluating solely total brain volumes. Table 1:

Download Full-text

Regional Brain Volumes and ADHD Symptoms in Middle-Aged Adults: The PATH Through Life Study

Journal of Attention Disorders ◽

10.1177/1087054714523316 ◽

2014 ◽

Vol 21 (13) ◽

pp. 1073-1086 ◽

Cited By ~ 3

Author(s):

Debjani Das ◽

Nicolas Cherbuin ◽

Kaarin J. Anstey ◽

Walter Abhayaratna ◽

Simon Easteal

Keyword(s):

Brain Volume ◽

Brain Regions ◽

Equation Modeling ◽

Depression Symptoms ◽

Middle Aged ◽

Brain Volumes ◽

Automated Method ◽

Inattention And Hyperactivity ◽

Middle Aged Adults ◽

Anxiety Depression

Objective: We investigated whether volumetric differences in ADHD-associated brain regions are related to current symptoms of inattention and hyperactivity in healthy middle-aged adults and whether co-occurring anxiety/depression symptoms moderate these relationships. Method: ADHD Self-Report Scale and Brief Patient Health Questionnaire were used to assess current symptoms of inattention, hyperactivity, anxiety, and depression in a population-based sample ( n = 269). Brain volumes, measured using a semi-automated method, were analyzed using multiple regression and structural equation modeling to evaluate brain volume–inattention/hyperactivity symptom relationships for selected regions. Results: Volumes of the left nucleus accumbens and a region overlapping the dorsolateral prefrontal cortex were positively associated with inattention symptoms. Left hippocampal volume was negatively associated with hyperactivity symptoms. The brain volume–inattention/hyperactivity symptom associations were stronger when anxiety/depression symptoms were controlled for. Conclusion: Inattention and hyperactivity symptoms in middle-aged adults are associated with different brain regions and co-occurring anxiety/depression symptoms moderate these brain–behavior relationships.

Download Full-text

Total Cerebral Blood Flow, White Matter Lesions and Brain Atrophy: The SMART-MR Study

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600563 ◽

2007 ◽

Vol 28 (3) ◽

pp. 633-639 ◽

Cited By ~ 53

Author(s):

Auke PA Appelman ◽

Yolanda van der Graaf ◽

Koen L Vincken ◽

Audrey M Tiehuis ◽

Theo D Witkamp ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

White Matter ◽

Magnetic Resonance ◽

Brain Atrophy ◽

Brain Volume ◽

White Matter Lesions ◽

Arterial Disease ◽

Subcortical Brain ◽

Mr Study

We investigated whether total cerebral blood flow (CBF) was associated with brain atrophy, and whether this relation was modified by white matter lesions (WML). Within the Second Manifestations of ARTerial disease-magnetic resonance (SMART-MR) study, a prospective cohort study among patients with arterial disease, cross-sectional analyses were performed in 828 patients (mean age 58±10 years, 81% male) with quantitative flow, atrophy, and WML measurements on magnetic resonance imaging (MRI). Total CBF was measured with MR angiography and was expressed per 100 mL brain volume. Total brain volume and ventricular volume were divided by intracranial volume to obtain brain parenchymal fraction (BPF) and ventricular fraction (VF). Lower BPF indicates more global brain atrophy, whereas higher VF indicates more subcortical brain atrophy. Mean CBF was 52.0±10.2 mL/min per 100 mL, mean BPF was 79.2±2.9%, and mean VF was 2.03±0.96%. Linear regression analyses showed that lower CBF was associated with more subcortical brain atrophy, after adjusting for age, sex, vascular risk factors, intima-media thickness, and lacunar infarcts, but only in patients with moderate to severe WML (upper quartile of WML): Change in VF per s.d. decrease in CBF 0.18%, 95% CI: 0.02 to 0.34%. Our findings suggest that cerebral hypoperfusion in the presence of WML may be associated with subcortical brain atrophy.

Download Full-text

Protein contributions to brain atrophy acceleration in Alzheimer’s disease and primary age-related tauopathy

Brain ◽

10.1093/brain/awaa299 ◽

2020 ◽

Vol 143 (11) ◽

pp. 3463-3476

Author(s):

Keith A Josephs ◽

Peter R Martin ◽

Stephen D Weigand ◽

Nirubol Tosakulwong ◽

Marina Buciuc ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Atrophy ◽

Neurofibrillary Tangle ◽

Amyloid Β ◽

Brain Regions ◽

Hippocampal Atrophy ◽

Brain Volumes ◽

Age Related ◽

Over Time

Abstract Alzheimer’s disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer’s disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer’s disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer’s disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer’s disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer’s disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0–16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer’s disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer’s disease and primary age-related tauopathy.

Download Full-text

Cortical and Subcortical Brain Volumes Partially Mediate the Association between Dietary Composition and Behavioral Disinhibition: A UK Biobank Study

Nutrients ◽

10.3390/nu13103542 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3542

Author(s):

Daan van Rooij ◽

Lizanne Schweren ◽

Huiqing Shi ◽

Catharina A Hartman ◽

Jan K Buitelaar

Keyword(s):

Brain Volume ◽

Adult Population ◽

Dietary Quality ◽

Outcome Variable ◽

Behavioral Disinhibition ◽

Dietary Composition ◽

Uk Biobank ◽

Brain Volumes ◽

Subcortical Brain ◽

Dietary Components

Behavioral disinhibition is observed to be an important characteristic of many neurodevelopmental and psychiatric disorders. Recent studies have linked dietary quality to levels of behavioral inhibition. However, it is currently unclear whether brain factors might mediate this. The current study investigates whether cortical and subcortical brain volumes mediate part of the association between dietary composition and behavioral disinhibition. A total of 15,258 subjects from the UK Biobank project were included in the current study. Dietary composition and behavioral disinhibition were based on Principle Component Analyses of self-reported dietary composition). As a further data reduction step, cortical and subcortical volume segmentations were input into an Independent Component Analysis. The resulting four components were used as mediator variables in the main mediation analyses, where behavioral disinhibition served as the outcome variable and dietary components as predictors. Our results show: (1) significant associations between all dietary components and brain volume components; (2) brain volumes are associated with behavioral disinhibition; (3) the mediation models show that part of the variance in behavioral disinhibition explained by dietary components (for healthy diet, restricted diet, and high-fat dairy diet) is mediated through the frontal-temporal/parietal brain volume component. These results are in part confirming our hypotheses and offer a first insight into the underlying mechanisms linking dietary composition, frontal-parietal brain volume, and behavioral disinhibition in the general adult population.

Download Full-text

Association of polygenic risk for major psychiatric illness with subcortical volumes and white matter integrity in UK Biobank

10.1101/080283 ◽

2016 ◽

Cited By ~ 1

Author(s):

LM Reus ◽

X Shen ◽

J Gibson ◽

E Wigmore ◽

L Ligthart ◽

...

Keyword(s):

White Matter ◽

Psychiatric Disorders ◽

Brain Regions ◽

Uk Biobank ◽

Imaging Data ◽

Brain Volumes ◽

Polygenic Risk ◽

Subcortical Brain ◽

The Impact ◽

Subcortical Volumes

AbstractMajor depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BP) are common, disabling and heritable psychiatric diseases with a complex overlapping polygenic architecture. Individuals with these disorders, as well as their unaffected relatives, show widespread structural differences in corticostriatal and limbic networks. Structural variation in many of these brain regions is also heritable and polygenic but whether their genetic architecture overlaps with major psychiatric disorders is unknown. We sought to address this issue by examining the impact of polygenic risk of MDD, SCZ, and BP on subcortical brain volumes and white matter (WM) microstructure in a large single sample of neuroimaging data; the UK Biobank Imaging study. The first release of UK Biobank imaging data compromised participants with overlapping genetic data and subcortical volumes (N = 978) and WM measures (N = 816). Our, findings however, indicated no statistically significant associations between either subcortical volumes or WM microstructure, and polygenic risk for MDD, SCZ or BP. In the current study, we found little or no evidence for genetic overlap between major psychiatric disorders and structural brain measures. These findings suggest that subcortical brain volumes and WM microstructure may not be closely linked to the genetic mechanisms of major psychiatric disorders.

Download Full-text

Concordance of Genetic Variation that Increases Risk for Tourette Syndrome and that Influences its Underlying Neurocircuitry

10.1101/366294 ◽

2018 ◽

Cited By ~ 2

Author(s):

Mary Mufford ◽

Josh Cheung ◽

Neda Jahanshad ◽

Celia van der Merwe ◽

Linda Ding ◽

...

Keyword(s):

Tourette Syndrome ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Brain Regions ◽

Genetic Variations ◽

Summary Statistics ◽

Brain Volumes ◽

Subcortical Brain ◽

Genome Wide ◽

A Genome

ABSTRACTBACKGROUNDThere have been considerable recent advances in understanding the genetic architecture of Tourette Syndrome (TS) as well as its underlying neurocircuitry. However, the mechanisms by which genetic variations that increase risk for TS - and its main symptom dimensions - influence relevant brain regions are poorly understood. Here we undertook a genome-wide investigation of the overlap between TS genetic risk and genetic influences on the volume of specific subcortical brain structures that have been implicated in TS.METHODSWe obtained summary statistics for the most recent TS genome-wide association study (GWAS) from the TS Psychiatric Genomics Consortium Working Group (4,644 cases and 8,695 controls) and GWAS of subcortical volumes from the ENIGMA consortium (30,717 individuals). We also undertook analyses using GWAS summary statistics of key symptom factors in TS, namely social disinhibition and symmetry behaviour. SNP Effect Concordance Analysis (SECA) was used to examine genetic pleiotropy - the same SNP affecting two traits - and concordance - the agreement in SNP effect directions across these two traits. In addition, a conditional false discovery rate (FDR) analysis was performed, conditioning the TS risk variants on each of the seven subcortical and the intracranial brain volume GWAS. Linkage Disequilibrium Score Regression (LDSR) was used as validation of SECA.RESULTSSECA revealed significant pleiotropy between TS and putaminal (p=2×10−4) and caudal (p=4×10−4) volumes, independent of direction of effect, and significant concordance between TS and lower thalamic volume (p=1×10−3). LDSR lent additional support for the association between TS and thalamic volume (p=5.85×10−2). Furthermore, SECA revealed significant evidence of concordance between the social disinhibition symptom dimension and lower thalamic volume (p=1×10−3), as well as concordance between symmetry behaviour and greater putaminal volume (p=7×10−4). Conditional FDR analysis further revealed novel variants significantly associated with TS (p<8×10−7) when conditioning on intracranial (rs2708146, q=0.046; and rs72853320, q=0.035 and hippocampal (rs1922786, q=0.001 volumes respectively.CONCLUSIONThese data indicate concordance for genetic variations involved in disorder risk and subcortical brain volumes in TS. Further work with larger samples is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.

Download Full-text

Investigating the causal nature of the relationship of subcortical brain volume with smoking and alcohol use

The British Journal of Psychiatry ◽

10.1192/bjp.2021.81 ◽

2021 ◽

pp. 1-9

Author(s):

Emma Logtenberg ◽

Martin F. Overbeek ◽

Joëlle A. Pasman ◽

Abdel Abdellaoui ◽

Maartje Luijten ◽

...

Keyword(s):

Alcohol Use ◽

Genetic Variants ◽

Brain Volume ◽

Hippocampal Volume ◽

Causal Effects ◽

Mendelian Randomisation ◽

Brain Volumes ◽

Subcortical Brain ◽

Causal Nature ◽

Relationship Of

Background Structural variation in subcortical brain regions has been linked to substance use, including the most commonly used substances nicotine and alcohol. Pre-existing differences in subcortical brain volume may affect smoking and alcohol use, but there is also evidence that smoking and alcohol use can lead to structural changes. Aims We assess the causal nature of the complex relationship of subcortical brain volume with smoking and alcohol use, using bi-directional Mendelian randomisation. Method Mendelian randomisation uses genetic variants predictive of a certain ‘exposure’ as instrumental variables to test causal effects on an ‘outcome’. Because of random assortment at meiosis, genetic variants should not be associated with confounders, allowing less biased causal inference. We used summary-level data of genome-wide association studies of subcortical brain volumes (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus; n = 50 290) and smoking and alcohol use (smoking initiation, n = 848 460; cigarettes per day, n = 216 590; smoking cessation, n = 378 249; alcoholic drinks per week, n = 630 154; alcohol dependence, n = 46 568). The main analysis, inverse-variance weighted regression, was verified by a wide range of sensitivity methods. Results There was strong evidence that liability to alcohol dependence decreased amygdala and hippocampal volume, and smoking more cigarettes per day decreased hippocampal volume. From subcortical brain volumes to substance use, there was no or weak evidence for causal effects. Conclusions Our findings suggest that heavy alcohol use and smoking can causally reduce subcortical brain volume. This adds to accumulating evidence that alcohol and smoking affect the brain, and likely mental health, warranting more recognition in public health efforts.

Download Full-text

Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease

10.1101/2021.04.08.439100 ◽

2021 ◽

Author(s):

Jo Beldring Henningsen ◽

Rana Soylu Kucharz ◽

Maria Bjorkqvist ◽

Asa Petersen

Keyword(s):

Mouse Model ◽

Transgenic Mouse ◽

Huntington Disease ◽

Selective Vulnerability ◽

Brain Regions ◽

Cag Repeat ◽

Therapeutic Interventions ◽

Mutant Huntingtin ◽

Neuronal Populations ◽

Underlying Mechanisms

Huntington disease (HD) is a fatal neurodegenerative movement disorder caused by an expanded CAG repeat in the huntingtin gene (HTT). The mutant huntingtin protein is ubiquitously expressed, but only certain brain regions are affected. The hypothalamus has emerged as an important area of pathology with selective loss of neurons expressing the neuropeptides orexin (hypocretin), oxytocin and vasopressin in human postmortem HD tissue. Hypothalamic changes in HD may have implications for early disease manifestations affecting the regulation of sleep, emotions and metabolism. The underlying mechanisms of selective vulnerability of certain neurons in HD are not fully understood, but excitotoxicity has been proposed to play a role. Further understanding of mechanisms rendering neurons sensitive to mutant huntingtin may reveal novel targets for therapeutic interventions. In the present study, we wanted to examine whether transgenic HD mice display altered sensitivity to excitotoxicity in the hypothalamus. We first assessed effects of hypothalamic injections of the excitotoxin quinolinic acid (QA) into wild-type (WT) mice. We show that neuronal populations expressing melanin-concentrating hormone (MCH) and cocaine and amphetamine-regulated transcript (CART) display a dose-dependent sensitivity to QA. In contrast, neuronal populations expressing orexin, oxytocin, vasopressin as well as tyrosine hydroxylase in the A13 area are resistant to QA-induced toxicity. We demonstrate that the R6/2 transgenic mouse model expressing a short fragment of mutant HTT displays hypothalamic neuropathology with discrete loss of the neuronal populations expressing orexin, MCH, CART, and orexin at 12 weeks of age. The BACHD mouse model expressing full-length mutant HTT does not display any hypothalamic neuropathology at 2 months of age. There was no effect of hypothalamic injections of QA on the neuronal populations expressing orexin, MCH, CART or oxytocin in neither HD mouse model. In conclusion, we find no support for a role of excitotoxicity in the loss of hypothalamic neuronal populations in HD.

Download Full-text