Both brain size and biological sex contribute to variation in white matter microstructure in middle-aged healthy adults

Whether head size and/or biological sex influence proxies of white matter (WM) microstructure such as fractional anisotropy (FA) and mean diffusivity (MD) remains controversial. Diffusion tensor imaging (DTI) indices are also associated with age, but there are large discrepancies in the spatial distribution and timeline of age-related differences reported. The aim of this study was to evaluate the associations between intracranial volume (ICV), sex, and age and DTI indices from WM in a population-based study of healthy individuals (n = 812) aged 50–66 in the Nord-Trøndelag health survey. Semiautomated tractography and tract-based spatial statistics (TBSS) analyses were performed on the entire sample and in an ICV-matched sample of men and women. The tractography results showed a similar positive association between ICV and FA in all major WM tracts in men and women. Associations between ICV and MD, radial diffusivity and axial diffusivity were also found, but to a lesser extent than FA. The TBSS results showed that both men and women had areas of higher and lower FA when controlling for age, but after controlling for age and ICV only women had areas with higher FA. The ICV matched analysis also demonstrated that only women had areas of higher FA. Age was negatively associated with FA across the entire WM skeleton in the TBSS analysis, independent of both sex and ICV. Combined, these findings demonstrated that both ICV and sex contributed to variation in DTI indices and emphasized the importance of considering ICV as a covariate in DTI analysis

Neuropsychological parameters indexing executive processes are associated with independent components of ERPs

AbstractLesion studies have indicated that at least the three executive processes can be differentiated in the frontal lobe: Energization, monitoring and task setting. Event related potentials (ERPs) in Go/NoGo tasks have been widely used in studying executive processes. In this study, ERPs were obtained from EEG recorded during performance of a cued Go/NoGo task. The Contingent Negative Variation (CNV) and P3NoGo waves were decomposed into four independent components (ICs), by applying Independent Component Analysis (ICA) to a collection of ERPs from 193 healthy individuals. The components were named IC CNVearly, IC CNVlate, IC P3NoGoearly and IC P3NoGolate according to the conditions and time interval in which they occurred. A sub-group of 28 individuals was also assessed with neuropsychological tests. The test parameters were selected on the basis of studies demonstrating their sensitivity to executive processes as defined in the ROtman-Baycrest Battery for Investigating Attention (ROBBIA) model. The test scores were categorized into the domain scores of energization, monitoring and task setting and correlated with the amplitudes of the individual ICs from the sub-group of 28 individuals. The energization domain correlated with the IC CNVlate and IC P3NoGoearly. The monitoring domain correlated with the IC P3NoGolate, while the task setting domain correlated with the IC CNVlate. The IC CNVearly was not correlated with any of the neuropsychological domain scores. The correlations between the domains and ICs remained largely unchanged when controlling for full-scale IQ. This is the first study to demonstrate that executive processes, as indexed by neuropsychological test parameters, are associated with particular event-related potentials in a cued Go/NoGo paradigm

Moderate Traumatic Brain Injury:Clinical Characteristics and a Prognostic Model of 12-Month Outcome

BACKGROUND: Patients with moderate traumatic brain injury (TBI) often are studied together with patients with severe TBI, even though the expected outcome of the former is better. Therefore, we aimed to describe patient characteristics and 12-month outcomes, and to develop a prognostic model based on admission data, specifically for patients with moderate TBI. METHODS: Patients with Glasgow Coma Scale scores of 9-13 and age ≥16 years were prospectively enrolled in 2 level I trauma centers in Europe. Glasgow Outcome Scale Extended (GOSE) score was assessed at 12 months. A prognostic model predicting moderate disability or worse (GOSE score ≤6), as opposed to a good recovery, was fitted by penalized regression. Model performance was evaluated by area under the curve of the receiver operating characteristics curves. RESULTS: Of the 395 enrolled patients, 81% had intracranial lesions on head computed tomography, and 71% were admitted to an intensive care unit. At 12 months, 44% were moderately disabled or worse (GOSE score ≤6), whereas 8% were severely disabled and 6% died (GOSE score ≤4). Older age, lower Glasgow Coma Scale score, no day-of-injury alcohol intoxication, presence of a subdural hematoma, occurrence of hypoxia and/or hypotension, and preinjury disability were significant predictors of GOSE score ≤6 (area under the curve = 0.80). CONCLUSIONS: Patients with moderate TBI exhibit characteristics of significant brain injury. Although few patients died or experienced severe disability, 44% did not experience good recovery, indicating that follow-up is needed. The model is a first step in development of prognostic models for moderate TBI that are valid across centers

Retirement age and disability status as pathways to later-life cognitive impairment: Evidence from the Norwegian HUNT Study linked with Norwegian population registers

Background Research shows that retirement age is associated with later-life cognition but has not sufficiently distinguished between retirement pathways. We examined how retirement age was associated with later-life dementia and mild cognitive impairment (MCI) for people who retired via the disability pathway (received a disability pension prior to old-age pension eligibility) and those who retired via the standard pathway. Methods The study sample comprised 7210 participants from the Norwegian Trøndelag Health Study (HUNT4 70+, 2017–2019) who had worked for at least one year in 1967–2019, worked until age 55+, and retired before HUNT4. Dementia and MCI were clinically assessed in HUNT4 70+ when participants were aged 69–85 years. Historical data on participants' retirement age and pathway were retrieved from population registers. We used multinomial regression to assess the dementia/MCI risk for women and men retiring via the disability pathway, or early (<67 years), on-time (age 67, old-age pension eligibility) or late (age 68+) via the standard pathway. Results In our study sample, 9.5% had dementia, 35.3% had MCI, and 28.1% retired via the disability pathway. The disability retirement group had an elevated risk of dementia compared to the on-time standard retirement group (relative risk ratio [RRR]: 1.64, 95% CI 1.14–2.37 for women, 1.70, 95% CI 1.17–2.48 for men). MCI risk was lower among men who retired late versus on-time (RRR, 0.76, 95% CI 0.61–0.95). Conclusion Disability retirees should be monitored more closely, and preventive policies should be considered to minimize the dementia risk observed among this group of retirees.publishedVersio

Family history of Alzheimer's disease alters cognition and is modified by medical and genetic factors

In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer's disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18-85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E epsilon 4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.Mueller Family Charitable Trust; Arizona Department of Health Services; National Institutes of Health [R01-AG041232, R01-AG049465-05]; Flinn FoundationOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Conservation of Distinct Genetically-Mediated Human Cortical Pattern

The many subcomponents of the human cortex are known to follow an anatomical pattern and functional relationship that appears to be highly conserved between individuals. This suggests that this pattern and the relationship among cortical regions are important for cortical function and likely shaped by genetic factors, although the degree to which genetic factors contribute to this pattern is unknown. We assessed the genetic relationships among 12 cortical surface areas using brain images and genotype information on 2,364 unrelated individuals, brain images on 466 twin pairs, and transcriptome data on 6 postmortem brains in order to determine whether a consistent and biologically meaningful pattern could be identified from these very different data sets. We find that the patterns revealed by each data set are highly consistent (p<10−3), and are biologically meaningful on several fronts. For example, close genetic relationships are seen in cortical regions within the same lobes and, the frontal lobe, a region showing great evolutionary expansion and functional complexity, has the most distant genetic relationship with other lobes. The frontal lobe also exhibits the most distinct expression pattern relative to the other regions, implicating a number of genes with known functions mediating immune and related processes. Our analyses reflect one of the first attempts to provide an assessment of the biological consistency of a genetic phenomenon involving the brain that leverages very different types of data, and therefore is not just statistical replication which purposefully use very similar data sets.publishedVersio

Tricarboxylic Acid Cycle Activity Measured by 13C Magnetic Resonance Spectroscopy in Rats Subjected to the Kaolin Model of Obstructed Hydrocephalus

Evaluating early changes in cerebral metabolism in hydrocephalus can help in the decision making and the timing of surgical intervention. This study was aimed at examining the tricarboxylic acid (TCA) cycle rate and 13C label incorporation into neurotransmitter amino acids and other compounds 2 weeks after rats were subjected to kaolin-induced progressive hydrocephalus. In vivo and ex vivo magnetic resonance spectroscopy (MRS), combined with the infusion of [1,6-13C]glucose, was used to monitor the time courses of 13C label incorporation into the different carbon positions of glutamate in the forebrains of rats with hydrocephalus as well as in those of controls. Metabolic rates were determined by fitting the measured data into a one-compartment metabolic model. The TCA cycle rate was 1.3 ± 0.2 μmoles/gram/minute in the controls and 0.8 ± 0.4 μmoles/gram/minute in the acute hydrocephalus group, the exchange rate between α-ketoglutarate and glutamate was 4.1 ± 2.5 μmoles/gram/minute in the controls and 2.7 ± 2.6 μmoles/gram/minute in the hydrocephalus group calculated from in vivo MRS. There were no statistically significant differences between these rates. Hydrocephalus caused a decrease in the amounts of glutamate, alanine and taurine. In addition, the concentration of the neuronal marker N-acetyl aspartate was decreased. 13C Labelling of most amino acids derived from [1,6-13C]glucose was unchanged 2 weeks after hydrocephalus induction. The only indication of astrocyte impairment was the decreased 13C enrichment in glutamine C-2. This study shows that hydrocephalus causes subtle but significant alterations in neuronal metabolism already early in the course of the disease. These sub-lethal changes, however, if maintained and if ongoing might explain the delayed and programmed neuronal damage as seen in chronic hydrocephalus

Brain death and postmortem organ donation : report of a questionnaire from the CENTER-TBI study

Rahul Raj tutkimusryhmän jäsenenäBackgroundWe aimed to investigate the extent of the agreement on practices around brain death and postmortem organ donation.MethodsInvestigators from 67 Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study centers completed several questionnaires (response rate: 99%).ResultsRegarding practices around brain death, we found agreement on the clinical evaluation (prerequisites and neurological assessment) for brain death determination (BDD) in 100% of the centers. However, ancillary tests were required for BDD in 64% of the centers. BDD for nondonor patients was deemed mandatory in 18% of the centers before withdrawing life-sustaining measures (LSM). Also, practices around postmortem organ donation varied. Organ donation after circulatory arrest was forbidden in 45% of the centers. When withdrawal of LSM was contemplated, in 67% of centers the patients with a ventricular drain in situ had this removed, either sometimes or all of the time.ConclusionsThis study showed both agreement and some regional differences regarding practices around brain death and postmortem organ donation. We hope our results help quantify and understand potential differences, and provide impetus for current dialogs toward further harmonization of practices around brain death and postmortem organ donation.Peer reviewe

The genetic organization of longitudinal subcortical volumetric change is stable throughout the lifespan.

Development and aging of the cerebral cortex show similar topographic organization and are governed by the same genes. It is unclear whether the same is true for subcortical regions, which follow fundamentally different ontogenetic and phylogenetic principles. We tested the hypothesis that genetically governed neurodevelopmental processes can be traced throughout life by assessing to which degree brain regions that develop together continue to change together through life. Analyzing over 6000 longitudinal MRIs of the brain, we used graph theory to identify five clusters of coordinated development, indexed as patterns of correlated volumetric change in brain structures. The clusters tended to follow placement along the cranial axis in embryonic brain development, suggesting continuity from prenatal stages, and correlated with cognition. Across independent longitudinal datasets, we demonstrated that developmental clusters were conserved through life. Twin-based genetic correlations revealed distinct sets of genes governing change in each cluster. Single-nucleotide polymorphisms-based analyses of 38,127 cross-sectional MRIs showed a similar pattern of genetic volume-volume correlations. In conclusion, coordination of subcortical change adheres to fundamental principles of lifespan continuity and genetic organization

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P &lt; 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes