Search

IntroductionMany consequences of cerebrovascular disease are identifiable by magnetic resonance imaging (MRI), but variation in methods limits multicenter studies and pooling of data. The European Union Joint Program on Neurodegenerative Diseases (EU JPND) funded the HARmoNizing Brain Imaging MEthodS for VaScular Contributions to Neurodegeneration (HARNESS) initiative, with a focus on cerebral small vessel disease.MethodsSurveys, teleconferences, and an in-person workshop were used to identify gaps in knowledge and to develop tools for harmonizing imaging and analysis.ResultsA framework for neuroimaging biomarker development was developed based on validating repeatability and reproducibility, biological principles, and feasibility of implementation. The status of current MRI biomarkers was reviewed. A website was created at www.harness-neuroimaging.org with acquisition protocols, a software database, rating scales and case report forms, and a deidentified MRI repository.ConclusionsThe HARNESS initiative provides resources to reduce variability in measurement in MRI studies of cerebral small vessel disease.

Background: Maternal alcohol consumption during pregnancy can have widespread and long-lasting effects on children's cognition, behaviour, brain function and structure. The pregenual anterior cingulate cortex (ACC) and the anterior midcingulate cortex (MCC) mediate emotional and cognitive behaviours that are affected by prenatal alcohol exposure. However, the neurobehavioural development of the pregenual ACC and anterior MCC has not been examined in people with prenatal alcohol exposure. Methods: We recruited 30 children and adolescents with prenatal alcohol exposure and 50 age- and gender-matched unexposed controls. We acquired structural MRI data sets on a 3 T scanner. We manually delineated 2 areas of the rostral cingulate cortex--the pregenual ACC and the anterior MCC--and compared them between groups. We measured behavioural and emotional problems using the Behaviour Assessment System for Children, 2nd Edition, Parent Rating Scale, and then explored their associations with rostral cingulate cortex volumes. Results: Intracranial-normalized volumes of the right pregenual ACC and the right total rostral cingulate cortex were significantly smaller in individuals with prenatal alcohol exposure than in unexposed controls. The volume of the right anterior MCC had a significant positive association with scores on the Internalizing Problems scale in individuals with prenatal alcohol exposure. Limitations: This study was cross-sectional, and detailed information about the timing and amount of exposure was not always available. Conclusion: Prenatal alcohol exposure is associated with lower volumes in the right pregenual ACC. This finding may underlie some of the emotional and behavioural problems experienced by individuals with prenatal alcohol exposure., Introduction The first well-known reports of the dystrophic and teratogenic effects of alcohol were published in the late 1960s (1) and early 1970s. (2,3) Since then, a growing body of [...]

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

ntroduction: The rate of neurodegeneration in multiple sclerosis (MS) is an important biomarker for disease progression but can be challenging to quantify. The brain age gap, which quantifies the difference between a patient's chronological and their estimated biological brain age, might be a valuable biomarker of neurodegeneration in patients with MS. Thus, the aim of this study was to investigate the value of an image-based prediction of the brain age gap using a deep learning model and compare brain age gap values between healthy individuals and patients with MS. Methods: A multi-center dataset consisting of 5,294 T1-weighted magnetic resonance images of the brain from healthy individuals aged between 19 and 89 years was used to train a convolutional neural network (CNN) for biological brain age prediction. The trained model was then used to calculate the brain age gap in 195 patients with relapsing remitting MS (20--60 years). Additionally, saliency maps were generated for healthy subjects and patients with MS to identify brain regions that were deemed important for the brain age prediction task by the CNN Results: Overall, the application of the CNN revealed accelerated brain aging with a larger brain age gap for patients with MS with a mean of 6.98 ± 7.18 years in comparison to healthy test set subjects (0.23 ± 4.64 years). The brain age gap for MS patients was weakly to moderately correlated with age at disease onset (ρ = 0.299, p < 0.0001), EDSS score (ρ = 0.206, p = 0.004), disease duration (ρ = 0.162, p = 0.024), lesion volume (ρ = 0.630, p < 0.0001), and brain parenchymal fraction (ρ = 0.718, p < 0.0001). The saliency maps indicated significant differences in the lateral ventricle (p < 0.0001), insula (p < 0.0001), third ventricle (p < 0.0001), and fourth ventricle (p = 0.0001) in the right hemisphere. In the left hemisphere, the inferior lateral ventricle (p < 0.0001) and the third ventricle (p < 0.0001) showed significant differences. Furthermore, the Dice similarity coefficient showed the highest overlap of salient regions between the MS patients and the oldest healthy subjects, indicating that neurodegeneration is accelerated in this patient cohort. Discussion: In conclusion, the results of this study show that the brain age gap is a valuable surrogate biomarker to measure disease progression in patients with multiple sclerosis [ABSTRACT FROM AUTHOR]

During adolescence, cannabis experimentation is common, and its association with interindividual variations in brain maturation well studied. Cellular and molecular underpinnings of these system-level relationships are, however, unclear. We thus conducted a three-step study. First, we exposed adolescent male mice to Δ-9-tetrahydrocannabinol (THC) or a synthetic cannabinoid WIN 55,212-2 (WIN) and assessed differentially expressed genes (DEGs), spine numbers, and dendritic complexity in their frontal cortex. Second, in human (male) adolescents, we examined group differences in cortical thickness in 34 brain regions, using magnetic resonance imaging, between those who experimented with cannabis before age 16 (n = 140) and those who did not (n = 327). Finally, we correlated spatially these group differences with gene expression of human homologs of mouse-identified DEGs. The spatial expression of 13 THC-related human homologs of DEGs correlated with cannabis-related variations in cortical thickness, and virtual histology revealed coexpression patterns of these 13 genes with cell-specific markers of astrocytes, microglia, and a type of pyramidal cells enriched in dendrite-regulating genes. Similarly, the spatial expression of 18 WIN-related human homologs of DEGs correlated with group differences in cortical thickness and showed coexpression patterns with the same three cell types. Gene ontology analysis indicated that 37 THC-related human homologs are enriched in neuron projection development, while 33 WIN-related homologs are enriched in processes associated with learning and memory. In mice, we observed spine loss and lower dendritic complexity in pyramidal cells of THC-exposed animals (vs controls). Experimentation with cannabis during adolescence may influence cortical thickness by impacting glutamatergic synapses and dendritic arborization. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS) are risk factors for Alzheimer's disease (AD) but can also manifest secondary to AD pathology. Mild behavioral impairment (MBI) refers to later‐life emergent and persistent NPS that may mark early‐stage AD. To distinguish MBI from NPS that are transient or which represent psychiatric conditions (non‐MBI NPS), we investigated the effect of applying MBI criteria on NPS associations with AD structural imaging biomarkers and incident cognitive decline. Data for participants (n = 1273) with normal cognition (NC) or mild cognitive impairment (MCI) in the National Alzheimer's Coordinating Center Uniform Data Set were analyzed. NPS status (MBI, non‐MBI NPS) was derived from the Neuropsychiatric Inventory Questionnaire and psychiatric history. Normalized measures of bilateral hippocampal (HPC) and entorhinal cortex (EC) volume, and AD meta‐region of interest (ROI) mean cortical thickness were acquired from T1‐weighted magnetic resonance imaging scans. Multivariable linear and Cox regressions examined NPS associations with imaging biomarkers and incident cognitive decline, respectively. MBI was associated with lower volume and cortical thickness in all ROIs in both NC and MCI, except for EC volume in NC. Non‐MBI NPS were only associated with lower HPC volume in NC. Although both of the NPS groups showed higher hazards for MCI/dementia than No NPS, MBI participants showed more rapid decline. Although both types of NPS were linked to HPC atrophy, only NPS that emerged and persisted in later‐life, consistent with MBI criteria, were related to AD neurodegenerative patterns beyond the HPC. Moreover, MBI predicted faster progression to dementia than non‐MBI NPS. [ABSTRACT FROM AUTHOR]

Background and aimsPrenatal exposure to maternal cigarette smoking (PEMCS) is associated with a higher probability of substance use in adolescence. We explore if externalizing behavior mediates this relationship, while controlling for a number of potential covariates of this mediation process.MethodsWe used data obtained in two geographically distinct community samples of adolescents. The first (cross-sectional) sample consisted of 996 adolescents (12-18 years of age) recruited from the Saguenay Youth Study (SYS) in Canada (47% with PEMCS). The second (longitudinal) sample consisted of 1141 adolescents (49% with PEMCS) from the Northern Finland Birth Cohort (NFBC1986). In both samples, externalizing behavior and substance use were assessed during adolescence. In the NFBC1986 cohort, externalizing behavior was also assessed in childhood.ResultsIn both populations, PEMCS is associated with a higher likelihood of adolescent drug experimentation. In the NFBC1986 cohort, exposed (versus non-exposed) adolescents experiment with an extra 1.27 [B = 0.24, 95% confidence intervals (CI) = 0.15, 0.33 P

Background: Previous reports have suggested that patients with cerebral amyloid angiopathy (CAA) may harbor smaller white matter, basal ganglia, and cerebellar volumes compared to age-matched healthy controls (HC) or patients with Alzheimer's disease (AD). We investigated whether CAA is associated with subcortical atrophy. Methods: The study was based on the multi-site Functional Assessment of Vascular Reactivity cohort and included 78 probable CAA (diagnosed according to the Boston criteria v2.0), 33 AD, and 70 HC. Cerebral and cerebellar volumes were extracted from brain 3D T1-weighted MRI using FreeSurfer (v6.0). Subcortical volumes, including total white matter, thalamus, basal ganglia, and cerebellum were reported as proportion (%) of estimated total intracranial volume. White matter integrity was quantified by the peak width of skeletonized mean diffusivity. Results: Participants in the CAA group were older (74.0 ± 7.0, female 44%) than the AD (69.7 ± 7.5, female 42%) and HC (68.8 ± 7.8, female 69%) groups. CAA participants had the highest white matter hyperintensity volume and worse white matter integrity of the three groups. After adjusting for age, sex, and study site, CAA participants had smaller putamen volumes (mean differences, -0.024% of intracranial volume; 95% confidence intervals, -0.041% to -0.006%; p = 0.005) than the HCs but not AD participants (-0.003%; -0.024 to 0.018%; p = 0.94). Other subcortical volumes including subcortical white matter, thalamus, caudate, globus pallidus, cerebellar cortex or cerebellar white matter were comparable between all three groups. Conclusion: In contrast to prior studies, we did not find substantial atrophy of subcortical volumes in CAA compared to AD or HCs, except for the putamen. Differences between studies may reflect heterogeneity in CAA presenting syndromes or severity. [ABSTRACT FROM AUTHOR]

Background: The role of tumor-associated macrophages (TAMs) in glioblastoma (GBM) disease progression has received increasing attention. Recent advances have shown that TAMs can be re-programmed to exert a pro-inflammatory, anti-tumor effect to control GBMs. However, imaging methods capable of differentiating tumor progression from immunotherapy treatment effects have been lacking, making timely assessment of treatment response difficult. We showed that tracking monocytes using iron oxide nanoparticle (USPIO) with MRI can be a sensitive imaging method to detect therapy response directed at the innate immune system. Methods: We implanted syngeneic mouse glioma stem cells into C57/BL6 mice and treated the animals with either niacin (a stimulator of innate immunity) or vehicle. Animals were imaged using an anatomical MRI sequence, R2* mapping, and quantitative susceptibility mapping (QSM) before and after USPIO injection. Results: Compared to vehicles, niacin-treated animals showed significantly higher susceptibility and R2*, representing USPIO and monocyte infiltration into the tumor. We observed a significant reduction in tumor size in the niacin-treated group 7 days later. We validated our MRI results with flow cytometry and immunofluoresence, which showed that niacin decreased pro-inflammatory Ly6C high monocytes in the blood but increased CD16/32 pro-inflammatory macrophages within the tumor, consistent with migration of these pro-inflammatory innate immune cells from the blood to the tumor. Conclusion: MRI with USPIO injection can detect therapeutic responses of innate immune stimulating agents before changes in tumor size have occurred, providing a potential complementary imaging technique to monitor cancer immunotherapies. Manuscript highlight: We show that iron oxide nanoparticles (USPIOs) can be used to label innate immune cells and detect the trafficking of pro-inflammatory monocytes into the glioblastoma. This preceded changes in tumor size, making it a more sensitive imaging technique. [ABSTRACT FROM AUTHOR]