Increase In Brain Volume Research Articles

Molecular signatures of cortical expansion in the human foetal brain

The third trimester of human gestation is characterised by rapid increases in brain volume and cortical surface area. Recent studies have revealed a remarkable molecular diversity across the prenatal cortex but little is known about how this diversity translates into the differential rates of cortical expansion observed during gestation. We present a digital resource, μBrain, to facilitate knowledge translation between molecular and anatomical descriptions of the prenatal brain. Using μBrain, we evaluate the molecular signatures of preferentially-expanded cortical regions, quantified in utero using magnetic resonance imaging. Our findings demonstrate a spatial coupling between areal differences in the timing of neurogenesis and rates of neocortical expansion during gestation. We identify genes, upregulated from mid-gestation, that are highly expressed in rapidly expanding neocortex and implicated in genetic disorders with cognitive sequelae. The μBrain atlas provides a tool to comprehensively map early brain development across domains, model systems and resolution scales.

Effects of a 6-month aerobic exercise intervention on brain morphology in women with breast cancer receiving aromatase inhibitor therapy: a sub-study of the EPICC trial.

Physical exercise may increase brain volume and cortical thickness in late adulthood. However, few studies have examined the possibility for exercise to influence brain morphology in women treated for breast cancer. We conducted a nested sub-study within a randomized clinical trial to examine whether 6 months of moderate-intensity aerobic exercise in postmenopausal women with early-stage breast cancer influences brain morphology. We included twenty-eight postmenopausal women newly diagnosed with Stage 0-IIIa breast cancer (M age = 62.96 ± 5.40) who were randomized to either 45-60 min of supervised aerobic exercise 3 days/week (n = 16) or usual care (n = 12). Before beginning aromatase inhibitor aromatase inhibitor therapy, and the exercise intervention, and again at 6-month follow-up, volumetric and cortical thickness measures were derived from magnetic resonance imaging scans. There were no significant intervention effects on brain volume and cortical thickness. However, greater average exercise intensity (%) during the intervention was associated with greater post-intervention cortical volume, mean cortical thickness, precentral gyrus thickness, and superior parietal thickness (all p < 0.05). Finally, total supervised exercise time was associated with higher precentral gyrus thickness after the intervention (p = 0.042, R 2 = 0.263). The exercise intervention did not significantly affect brain volumes and cortical thickness compared to the control group. However, positive associations were found between exercise intensity and brain morphology changes after the 6-month intervention, indicating that exercise may reduce the vulnerability of the brain to the deleterious effects of breast cancer and its treatment.

The influence of birthweight, socioeconomic status, and adult health on brain volumes during aging.

Introduction Greater late-life brain volumes are associated with resilience against dementia. We examined relationships between birthweight, life-long socioeconomic status and health with late-life brain volumes. We hypothesised that early-life factors directly affect late-life brain volumes. Methods Adults aged 59-67y underwent MRI and brain volumes were measured. Birthweight and lifelong health, and socioeconomic status were quantified and the principle components of each extracted. Relationships were examined using regression and structural equation analysis. Results Birthweight (β=0.095, p=0.017) and childhood socioeconomic status (β=0.091, p=0.033, n=280) were directly associated with brain volume. Childhood socioeconomic status was further associated with grey matter volume (β=0.04, p=0.047). Adult health was linked to increased brain volume (β=0.15, p=0.003). Conclusion Birthweight and childhood socioeconomic status are associated with whole and regional brain volume through direct mechanisms. Optimal fetal development, reduced childhood poverty and good adult health could reduce brain atrophy and delay dementia onset in late-life.

Increased brain volume in the early phase of aneurysmal subarachnoid hemorrhage leads to delayed cerebral ischemia.

To investigate the correlation between the swelling rate of brain volume within the first 48 h after aneurysmal subarachnoid hemorrhage and the subsequent development of delayed cerebral ischemia. A retrospective analysis was conducted on patients with spontaneous aneurysmal subarachnoid hemorrhage admitted to the Neurosurgery Intensive Care Unit of the First Affiliated Hospital of Chongqing Medical University between January 2020 and January 2023. The clinical data, treatment outcomes, and imaging data were analyzed. Brain volume was evaluated using 3D-Slicer software at two time points post-hemorrhage: within the first 24 h and between 24 and 48 h. The swelling rate of brain volume was defined as the ratio of the absolute difference between two measurements to the smaller of values. Patients were categorized into two groups based on established diagnostic criteria of delayed cerebral ischemia. Univariate and multivariate logistic regression analyses were performed to identify factors influencing delayed cerebral ischemia. A total of 140 patients were enrolled in this study. 46 patients experienced delayed cerebral ischemia after bleeding. The swelling rate of brain volume was larger in the DCI group (10.66 ± 8.45) compared to the non-DCI group (3.59 ± 2.62), which showed a statistically significant difference. Additionally, advanced age, smoking history, history of hypertension, loss of consciousness, poor Hunt-Hess grade, high mFisher score, brain volume within 24 h, and IVH were also statistically different between the two groups. Multivariate logistic regression analysis revealed that the swelling rate of brain volume was an independent risk factor for DCI with adjusting the advanced age, smoking history, history of hypertension, poor Hunt-Hess grade, high mFisher score, brain volume within 24 h, and IVH. Brain volume significantly increased in patients with aneurysmal subarachnoid hemorrhage during the early phase (within 48 h post-onset). The larger swelling rate of brain volume is an independent risk factor for the development of delayed cerebral ischemia, and it may hold significant predictive value for the incidence of delayed cerebral ischemia.

How domestication, feralization and experience-dependent plasticity affect brain size variation in Sus scrofa

Among domestic species, pigs experienced the greatest brain size reduction, but the extent and factors of this reduction remain unclear. Here, we used the brain endocast volume collected from 92 adult skulls of wild, captive, feral and domestic Sus scrofa to explore the effects of domestication, feralization and captivity over the brain size variation of this species. We found a constant brain volume increase over 24 months, while body growth slowed down from month 20. We observed an 18% brain size reduction between wild boars and pigs, disagreeing with the 30%–40% reduction previously mentioned. We did not find significant sexual differences in brain volume, refuting the theory of the attenuation of male secondary sexual characteristics through the selection for reduced male aggression. Feralization in Australia led to brain size reduction—probably as an adaptation to food scarcity and drought, refuting the reversal to wild ancestral brain size. Finally, free-born wild boars raised in captivity showed a slight increase in brain size, potentially due to a constant and high-quality food supply as well as new allospecific interactions. These results support the need to further explore the influence of diet, environment and experience on brain size evolution during animal domestication.

Application of diceCT to Study the Development of the Zika Virus-Infected Mouse Brain.

Zika virus (ZIKV) impacts the developing brain. Here, a technique was applied to define, in 3D, developmental changes in the brains of ZIKV-infected mice. Postnatal day 1 mice were uninfected or ZIKV-infected, then analysed by iodine staining and micro-CT scanning (diffusible iodine contrast-enhanced micro-CT; diceCT) at 3-, 6-, and 10-days post-infection (dpi). Multiple brain regions were visualised using diceCT: the olfactory bulb, cerebrum, hippocampus, midbrain, interbrain, and cerebellum, along with the lens and retina of the eye. Brain regions were computationally segmented and quantitated, with increased brain volumes and developmental time in uninfected mice. Conversely, in ZIKV-infected mice, no quantitative differences were seen at 3 or 6 dpi when there were no clinical signs, but qualitatively, diverse visual defects were identified at 6-10 dpi. By 10 dpi, ZIKV-infected mice had significantly lower body weight and reduced volume of brain regions compared to 10 dpi-uninfected or 6 dpi ZIKV-infected mice. Nissl and immunofluorescent Iba1 staining on post-diceCT tissue were successful, but RNA extraction was not. Thus, diceCT shows utility for detecting both 3D qualitative and quantitative changes in the developing brain of ZIKV-infected mice, with the benefit, post-diceCT, of retaining the ability to apply traditional histology and immunofluorescent analysis to tissue.

Arsenic impairs Drosophila neural stem cell mitotic progression and sleep behavior in a tauopathy model.

Despite established exposure limits, arsenic remains the most significant environmental risk factor detrimental to human health and is associated with carcinogenesis and neurotoxicity. Arsenic compromises neurodevelopment, and it is associated with peripheral neuropathy in adults. Exposure to heavy metals, such as arsenic, may also increase the risk of neurodegenerative disorders. Nevertheless, the molecular mechanisms underlying arsenic-induced neurotoxicity remain poorly understood. Elucidating how arsenic contributes to neurotoxicity may mitigate some of the risks associated with chronic sublethal exposure and inform future interventions. In this study, we examine the effects of arsenic exposure on Drosophila larval neurodevelopment and adult neurologic function. Consistent with prior work, we identify significant developmental delays and heightened mortality in response to arsenic. Within the developing larval brain, we identify a dose-dependent increase in brain volume. This aberrant brain growth is coupled with impaired mitotic progression of the neural stem cells (NSCs), progenitors of the neurons and glia of the central nervous system. Live imaging of cycling NSCs reveals significant delays in cell cycle progression upon arsenic treatment, leading to genomic instability. In adults, chronic arsenic exposure reduces neurologic function, such as locomotion. Finally, we show arsenic selectively impairs circadian rhythms in a humanized tauopathy model. These findings inform mechanisms of arsenic neurotoxicity and reveal sex-specific and genetic vulnerabilities to sublethal exposure.

Magnetic resonance imaging pattern recognition of metabolic and neurodegenerative encephalopathies in dogs and cats.

Metabolic/neurodegenerative encephalopathies encompass a wide list of conditions that share similar clinical and magnetic resonance imaging (MRI) characteristics, challenging the diagnostic process and resulting in numerous tests performed in order to reach a definitive diagnosis. The aims of this multicentric, retrospective and descriptive study are: (I) to describe the MRI features of dogs and cats with metabolic/neurodegenerative encephalopathies; (II) to attempt an MRI recognition pattern classifying these conditions according to the involvement of grey matter, white matter or both; and (III) to correlate the MRI findings with previous literature. A total of 100 cases were recruited, comprising 81 dogs and 19 cats. These included hepatic encephalopathy (20 dogs and three cats), myelinolysis (five dogs), intoxications (seven dogs and one cat), thiamine deficiency (two dogs and seven cats), hypertensive encephalopathy (three dogs and two cats), neuronal ceroid lipofuscinosis (11 dogs and one cat), gangliosidosis (three dogs and two cats), fucosidosis (one dog), L-2-hydroxyglutaric aciduria (13 dogs and one cat), Lafora disease (11 dogs), spongiform leukoencephalomyelopathy (one dog) and cerebellar cortical degeneration (four dogs and two cats). None of the hepatic encephalopathies showed the previously described T1-weighted hyperintensity of the lentiform nuclei. Instead, there was involvement of the cerebellar nuclei (8/23), which is a feature not previously described. Dogs with myelinolysis showed novel involvement of a specific white matter structure, the superior longitudinal fasciculus (5/5). Thiamine deficiency affected numerous deep grey nuclei with novel involvement of the oculomotor nuclei (3/9), thalamic nuclei, subthalamus and cerebellar nuclei (1/9). Cats with hypertensive encephalopathy had a more extensive distribution of the white matter changes when compared to dogs, extending from the parietal and occipital lobes into the frontal lobes with associated mass effect and increased brain volume. Lysosomal storage disease showed white matter involvement only, with neuronal ceroid lipofuscinosis characterised by severe brain atrophy when compared to gangliosidosis and fucosidosis. All patients with L-2-hydroxyglutaric aciduria had a characteristic T2-weighted hyperintense swelling of the cerebral and cerebellar cortical grey matter, resulting in increased brain volume. Lafora disease cases showed either normal brain morphology (5/11) or mild brain atrophy (6/11). Dogs with cerebellar cortical degeneration had more marked cerebellar atrophy when compared to cats. This study shows the important role of MRI in distinguishing different metabolic/neurodegenerative encephalopathies according to specific imaging characteristics.

Ultrahigh field diffusion magnetic resonance imaging uncovers intriguing microstructural changes in the adult zebrafish brain caused by Toll-like receptor 2 genomic deletion.

Toll-like receptor 2 (TLR2) belongs to the TLR protein family that plays an important role in the immune and inflammation response system. While TLR2 is predominantly expressed in immune cells, its expression has also been detected in the brain, specifically in microglia and astrocytes. Recent studies indicate that genomic deletion of TLR2 can result in impaired neurobehavioural function. It is currently not clear if the genomic deletion of TLR2 leads to any alterations in the microstructural features of the brain. In the current study, we noninvasively assess microstructural changes in the brain of TLR2-deficient (tlr2-/-) zebrafish using state-of-the art magnetic resonance imaging (MRI) methods at ultrahigh magnetic field strength (17.6 T). A significant increase in cortical thickness and an overall trend towards increased brain volumes were observed in young tlr2-/- zebrafish. An elevated T2 relaxation time and significantly reduced apparent diffusion coefficient (ADC) unveil brain-wide microstructural alterations, potentially indicative of cytotoxic oedema and astrogliosis in the tlr2-/- zebrafish. Multicomponent analysis of the ADC diffusivity signal by the phasor approach shows an increase in the slow ADC component associated with restricted diffusion. Diffusion tensor imaging and diffusion kurtosis imaging analysis revealed diminished diffusivity and enhanced kurtosis in various white matter tracks in tlr2-/- compared with control zebrafish, identifying the microstructural underpinnings associated with compromised white matter integrity and axonal degeneration. Taken together, our findings demonstrate that the genomic deletion of TLR2 results in severe alterations to the microstructural features of the zebrafish brain. This study also highlights the potential of ultrahigh field diffusion MRI techniques in discerning exceptionally fine microstructural details within the small zebrafish brain, offering potential for investigating microstructural changes in zebrafish models of various brain diseases.

Increases in regional brain volume across two native South American male populations

Industrialized environments, despite benefits such as higher levels of formal education and lower rates of infections, can also have pernicious impacts upon brain atrophy. Partly for this reason, comparing age-related brain volume trajectories between industrialized and non-industrialized populations can help to suggest lifestyle correlates of brain health. The Tsimane, indigenous to the Bolivian Amazon, derive their subsistence from foraging and horticulture and are physically active. The Moseten, a mixed-ethnicity farming population, are physically active but less than the Tsimane. Within both populations (N = 1024; age range = 46–83), we calculated regional brain volumes from computed tomography and compared their cross-sectional trends with age to those of UK Biobank (UKBB) participants (N = 19,973; same age range). Surprisingly among Tsimane and Moseten (T/M) males, some parietal and occipital structures mediating visuospatial abilities exhibit small but significant increases in regional volume with age. UKBB males exhibit a steeper negative trend of regional volume with age in frontal and temporal structures compared to T/M males. However, T/M females exhibit significantly steeper rates of brain volume decrease with age compared to UKBB females, particularly for some cerebro-cortical structures (e.g., left subparietal cortex). Across the three populations, observed trends exhibit no interhemispheric asymmetry. In conclusion, the age-related rate of regional brain volume change may differ by lifestyle and sex. The lack of brain volume reduction with age is not known to exist in other human population, highlighting the putative role of lifestyle in constraining regional brain atrophy and promoting elements of non-industrialized lifestyle like higher physical activity.

Relation of connectome topology to brain volume across 103 mammalian species.

The brain connectome is an embedded network of anatomically interconnected brain regions, and the study of its topological organization in mammals has become of paramount importance due to its role in scaffolding brain function and behavior. Unlike many other observable networks, brain connections incur material and energetic cost, and their length and density are volumetrically constrained by the skull. Thus, an open question is how differences in brain volume impact connectome topology. We address this issue using the MaMI database, a diverse set of mammalian connectomes reconstructed from 201 animals, covering 103 species and 12 taxonomy orders, whose brain size varies over more than 4 orders of magnitude. Our analyses focus on relationships between volume and modular organization. After having identified modules through a multiresolution approach, we observed how connectivity features relate to the modular structure and how these relations vary across brain volume. We found that as the brain volume increases, modules become more spatially compact and dense, comprising more costly connections. Furthermore, we investigated how spatial embedding shapes network communication, finding that as brain volume increases, nodes' distance progressively impacts communication efficiency. We identified modes of variation in network communication policies, as smaller and bigger brains show higher efficiency in routing- and diffusion-based signaling, respectively. Finally, bridging network modularity and communication, we found that in larger brains, modular structure imposes stronger constraints on network signaling. Altogether, our results show that brain volume is systematically related to mammalian connectome topology and that spatial embedding imposes tighter restrictions on larger brains.

Abstract 37: The Brain Care Score and Neuroimaging Markers in Asymptomatic Individuals in the UK Biobank

The 21-point Brain Care Score (BCS) is a novel tool designed to motivate individuals and care providers to take action to reduce the risk of stroke and dementia by motivating lifestyle changes (Fig 1). In this study we aimed to assess if the BCS is also associated with brain changes on MRI in people who have not yet developed dementia or stroke. Methods: This study was conducted within the MRI substudy of the longitudinal cohort study UK Biobank. The assessed MRI neuroimaging markers included: brain volume, white matter hyperintensities (WMH) volume, fractional anisotropy (FA) and mean diffusivity (MD). FA/MD metrics were calculated as the average across 48 discrete brain regions. We used multivariable linear regression to test for association between the BCS computed using baseline data (2006-2010) and neuroimaging markers, measured both during first (2014+) and repeat (2019+) MRI assessments. Results: There were 34,772 study participants with MRIs and available BCS data (mean age 55, 53% female). Every five-point increase in the BCS was associated with an 11% increase in brain volume (Beta 0.11, SE 0.01), a 26% reduction in WMH volume (Beta -0.26, SE 0.01), a 13% increase in average FA (Beta 0.13, SE 0.02), and a 9% decrease in average MD (Beta -0.09, SE 0.01). There were 3,778 study participants with first and repeat MRI (mean age 53, 53% female). Comparing the first and repeat imaging assessments, every five-point increase in baseline BCS was associated with a slower growth in WMH volume (Beta -0.08, SE 0.03) and a slower reduction in average FA (Beta 0.11, SE 0.03). Discussion: Among middle-aged adults without dementia or stroke, a higher BCS is strongly associated with better neuroimaging brain health profiles and slower rates of brain health decline. Given that the neuroimaging markers evaluated in our study are recognized risk factors that precede stroke and dementia by many years, our results support the BCS is a promising tool for early intervention to prevent these conditions.

Exercise-Related Physical Activity Relates to Brain Volumes in 10,125 Individuals.

The potential neuroprotective effects of regular physical activity on brain structure are unclear, despite links between activity and reduced dementia risk. To investigate the relationships between regular moderate to vigorous physical activity and quantified brain volumes on magnetic resonance neuroimaging. A total of 10,125 healthy participants underwent whole-body MRI scans, with brain sequences including isotropic MP-RAGE. Three deep learning models analyzed axial, sagittal, and coronal views from the scans. Moderate to vigorous physical activity, defined by activities increasing respiration and pulse rate for at least 10 continuous minutes, was modeled with brain volumes via partial correlations. Analyses adjusted for age, sex, and total intracranial volume, and a 5% Benjamini-Hochberg False Discovery Rate addressed multiple comparisons. Participant average age was 52.98±13.04 years (range 18-97) and 52.3% were biologically male. Of these, 7,606 (75.1%) reported engaging in moderate or vigorous physical activity approximately 4.05±3.43 days per week. Those with vigorous activity were slightly younger (p < 0.00001), and fewer women compared to men engaged in such activities (p = 3.76e-15). Adjusting for age, sex, body mass index, and multiple comparisons, increased days of moderate to vigorous activity correlated with larger normalized brain volumes in multiple regions including: total gray matter (Partial R = 0.05, p = 1.22e-7), white matter (Partial R = 0.06, p = 9.34e-11), hippocampus (Partial R = 0.05, p = 5.96e-7), and frontal, parietal, and occipital lobes (Partial R = 0.04, p≤1.06e-5). Exercise-related physical activity is associated with increased brain volumes, indicating potential neuroprotective effects.

MRI-Based Brain Volume Scoring in Cerebral Malaria Is Externally Valid and Applicable to Lower-Resolution Images.

Children with cerebral malaria have an elevated risk of mortality and neurologic morbidity. Both mortality and morbidity are associated with initially increased brain volume on MR imaging, as graded by the Brain Volume Score, a subjective ordinal rating scale created specifically for brain MRIs in children with cerebral malaria. For the Brain Volume Score to be more widely clinically useful, we aimed to determine its independent reproducibility and whether it can be applicable to lower-resolution MRIs. To assess the independent reproducibility of the Brain Volume Score, radiologists not associated with the initial study were trained to score MRIs from a new cohort of patients with cerebral malaria. These scores were then compared with survival and neurologic outcomes. To assess the applicability to lower-resolution MRI, we assigned Brain Volume Scores to brain MRIs degraded to simulate a very-low-field (64 mT) portable scanner and compared these with the original scores assigned to the original nondegraded MRIs. Brain Volume Scores on the new cohort of patients with cerebral malaria were highly associated with outcomes (OR for mortality = 16, P < .001). Scoring of the simulated degraded images remained consistent with the Brain Volume Scores assigned to the original higher-quality (0.35 T) images (intraclass coefficients > 0.86). Our findings demonstrate that the Brain Volume Score is externally valid in reproducibly predicting outcomes and can be reliably assigned to lower-resolution images.

Thyroid hormone dysfunction in MOGAD and other demyelinating diseases

BackgroundThyroid hormones play a critical role in both neuronal and glial cell functions. Multiple sclerosis (MS) has increased co-occurrence with autoimmune thyroid diseases, and recent studies have suggested a potential link between neuromyelitis optica spectrum disorder (NMOSD) and thyroid hormones. However, no previous studies have examined the relationship between thyroid hormones and myelin oligodendrocyte glycoprotein-associated demyelination (MOGAD). MethodsWe investigated the role of thyroid hormones in central nervous system (CNS) autoimmune demyelinating diseases in 26 MOGAD patients, 52 NMOSD patients, 167 patients with MS, and 16 patients with other noninflammatory neurological disorders. Thyroid hormone levels and clinical data (Expanded Disability Status Scale [EDSS]) were analyzed. Volumetric brain information was determined in brain magnetic resonance imaging (MRI) using the MDbrain platform. ResultsMOGAD patients had significantly higher levels of free triiodothyronine (FT3) compared to NMOSD patients. No correlation was found between FT3 levels and disease severity or brain volume. Thyroid-stimulating hormone (TSH) levels did not differ significantly between the groups, but in NMOSD patients, higher TSH levels were associated with lower disability scores and increased brain volume. No significant differences in free thyroxine (FT4) levels were observed between the different groups, however, FT4 levels were significantly higher in relapsing versus monophasic MOGAD patients and increased FT4 levels were associated with a higher EDSS and lower brain volume in NMOSD patients. ConclusionOur findings highlight the potential involvement of thyroid hormones specifically in MOGAD patients and other demyelinating CNS disorders. Understanding the role of thyroid hormones in relapsing vs monophasic MOGAD patients and in comparison to other demyelinating disorder could lead to the development of therapeutic interventions. Further studies are needed to explore the precise mechanisms and potential interventions targeting the thyroid axis as a treatment strategy.

Cross-sectional associations between sedentary time with cognitive engagement and brain volume among community-dwelling vulnerable older adults.

Vulnerable older adults tend to decrease physical activity (PA) and increase sedentary time (ST). Previous research on the associations between ST and brain volume have yielded inconsistent findings, without considering the impact of cognitive engagement (CE) on cognitive function. We aimed to examine the association between ST with CE and brain volume. A structural magnetic resonance imaging survey was conducted among community-dwelling vulnerable older adults. Brain volumetric measurements were obtained using 3T magnetic resonance imaging and pre-processed using FreeSurfer. ST with low or high CE was assessed using a 12-item questionnaire. PA was assessed by the frequency of light and moderate levels of physical exercise according to the Japanese version of the Cardiovascular Health Study criteria. Participants were categorized into a low PA group and a moderate-to-high PA group. Among 91 participants (83.1 ± 5.2 years old, 61.5% female), 26 were low PA. The overall sample and moderate-to-high PA group did not show significant positive associations with brain volume for ST with high CE. In the low PA group, isotemporal substitution models showed that replacing ST with low CE by ST with high CE was significantly associated with increased brain volume in some areas, including the rostral and caudal anterior cingulate (β = 0.486-0.618, all P < 0.05, adjusted R2 = 0.344-0.663). Our findings suggest that replacing ST with low CE by ST with high CE is positively associated with brain volume in vulnerable older adults with low PA. Geriatr Gerontol Int 2024; 24: 82-89.

Moderate to Vigorous Physical Activity Protects Deep Learning Derived Brain Volumes in 9637 Individuals

AbstractBackgroundRegular physical activity has been linked to a reduced risk of dementia, while loss of brain volume as measured by MRI is a marker of neurodegeneration. However, it remains unclear whether engaging in moderate or vigorous physical activity has any positive impact on brain structure and potential neuroprotective effects.MethodA total of 9637 healthy participants were scanned across four 1.5T MRI machines with a whole‐body MR imaging protocol. Brain sequences included isotropic MP‐RAGE. An ensemble of three Deep learning models corresponding to each axial, sagittal, and coronal views with FastSurfer architecture was trained on 134 participants aged 27‐66 segmented 96 brain regions. Partial correlations modeled moderate to vigorous physical activity, defined as sports, fitness and recreational activities that increased respiration and pulse rate for at least 10 continuous minutes, with brain volumes. Analyses controlled for age, sex, and total intracranial volume. Benjamini‐Hochberg False Discovery Rate of 5% accounted for multiple comparisons.ResultAverage age was 52.98 ± 13.06 years ranging from 11‐97 years with 52.5% biologically male. Overall, 7215 individuals (74.8%) reported moderate or vigorous physical activity on average 4.03 ± 3.48 days per week. Persons with vigorous activity were slightly older (mean age 54.3 versus 52.5 years) for non‐vigorous physical activity (p &lt; .00001) and 54.8% men versus 45.2% women undertook moderate to vigorous physical activity compared to 45.4% men and 54.6% women. Fewer women engaged in moderate to vigorous physical activity compared to men (p = 9.92e‐16). Accounting for age, sex, and intracranial volume co‐variates and multiple comparisons, moderate to vigorous physical activity predicted larger volumes in multiple regions including: total gray matter volume (Partial R = 0.09, p = 2.59e‐18), total white matter volume (Partial R = 0.09, p = 4.21e‐19), hippocampus (Partial R = .098, p = 1.4e‐21), frontal cortex (Partial R = 0.08, p = 1.06e‐15), parietal lobes (Partial R = 0.055, p = 9.01e‐8), occipital lobe (Partial R = 0.071, p = 5.27e‐12). Whole brain volumes of gray matter and white matter were also larger with an increasing number of days engaged in moderate to vigorous physical activity (Partial R = 0.105, p = 6.31e‐25).ConclusionEngagement in moderate to vigorous physical activity was found to be associated with increased brain volumes, a metric of neural health.

Moderate to Vigorous Physical Activity Protects Deep Learning Derived Brain Volumes in 9637 Individuals

AbstractBackgroundRegular physical activity has been linked to a reduced risk of dementia, while loss of brain volume as measured by MRI is a marker of neurodegeneration. However, it remains unclear whether engaging in moderate or vigorous physical activity has any positive impact on brain structure and potential neuroprotective effects.MethodA total of 9637 healthy participants were scanned across four 1.5T MRI machines with a whole‐body MR imaging protocol. Brain sequences included isotropic MP‐RAGE. An ensemble of three Deep learning models corresponding to each axial, sagittal, and coronal views with FastSurfer architecture was trained on 134 participants aged 27‐66 segmented 96 brain regions. Partial correlations modeled moderate to vigorous physical activity, defined as sports, fitness and recreational activities that increased respiration and pulse rate for at least 10 continuous minutes, with brain volumes. Analyses controlled for age, sex, and total intracranial volume. Benjamini‐Hochberg False Discovery Rate of 5% accounted for multiple comparisons.ResultAverage age was 52.98 ± 13.06 years ranging from 11‐97 years with 52.5% biologically male. Overall, 7215 individuals (74.8%) reported moderate or vigorous physical activity on average 4.03 ± 3.48 days per week. Persons with vigorous activity were slightly older (mean age 54.3 versus 52.5 years) for non‐vigorous physical activity (p &lt; .00001) and 54.8% men versus 45.2% women undertook moderate to vigorous physical activity compared to 45.4% men and 54.6% women. Fewer women engaged in moderate to vigorous physical activity compared to men (p = 9.92e‐16). Accounting for age, sex, and intracranial volume co‐variates and multiple comparisons, moderate to vigorous physical activity predicted larger volumes in multiple regions including: total gray matter volume (Partial R = 0.09, p = 2.59e‐18), total white matter volume (Partial R = 0.09, p = 4.21e‐19), hippocampus (Partial R = .098, p = 1.4e‐21), frontal cortex (Partial R = 0.08, p = 1.06e‐15), parietal lobes (Partial R = 0.055, p = 9.01e‐8), occipital lobe (Partial R = 0.071, p = 5.27e‐12). Whole brain volumes of gray matter and white matter were also larger with an increasing number of days engaged in moderate to vigorous physical activity (Partial R = 0.105, p = 6.31e‐25).ConclusionEngagement in moderate to vigorous physical activity was found to be associated with increased brain volumes, a metric of neural health.

Antisense oligonucleotide-mediated disruption of HTT caspase-6 cleavage site ameliorates the phenotype of YAC128 Huntington disease mice

In Huntington disease, cellular toxicity is particularly caused by toxic protein fragments generated from the mutant huntingtin (HTT) protein. By modifying the HTT protein, we aim to reduce proteolytic cleavage and ameliorate the consequences of mutant HTT without lowering total HTT levels. To that end, we use an antisense oligonucleotide (AON) that targets HTT pre-mRNA and induces partial skipping of exon 12, which contains the critical caspase-6 cleavage site. Here, we show that AON-treatment can partially restore the phenotype of YAC128 mice, a mouse model expressing the full-length human HTT gene including 128 CAG-repeats. Wild-type and YAC128 mice were treated intracerebroventricularly with AON12.1, scrambled AON or vehicle starting at 6 months of age and followed up to 12 months of age, when MRI was performed and mice were sacrificed. AON12.1 treatment induced around 40% exon skip and protein modification. The phenotype on body weight and activity, but not rotarod, was restored by AON treatment. Genes differentially expressed in YAC128 striatum changed toward wild-type levels and striatal volume was preserved upon AON12.1 treatment. However, scrambled AON also showed a restorative effect on gene expression and appeared to generally increase brain volume.

Brain volume increase after discontinuing natalizumab therapy: Evidence for reversible pseudoatrophy

BackgroundThe phenomenon of pseudoatropy after initiation of anti-inflammatory therapy is believed to be reversible, but a rebound in brain volume following cessation of highly-effective therapy has not been reported. ObjectivesTo evaluate brain volume change in a treatment interruption study (RESTORE) in which relapsing-remitting multiple sclerosis (RRMS) patients were randomized to switch from natalizumab to placebo, from natalizumab to once-monthly intravenous methylprednisolone (IVMP), or to remain on natalizumab. MethodsT2 lesion volume (T2LV), baseline normalized brain volumes, and follow-up percent brain volume changes (PBVC) were calculated. Approximate T2 relaxation-time (pT2) was calculated within the brain mask and the T2 lesions to estimate changes in water content. Linear mixed effects models were used to detect differences in T2LV, pT2 in whole brain, pT2 in T2-weighted lesions, and PBVC among the placebo, natalizumab, and IVMP groups. We also estimated contributions of T2LV and pT2 (in whole brain and T2 lesions) to PBVC. ResultsT2LV increased in the placebo group (by 0.66 ml/year, p<0.0001) and IVMP (+1.98 ml/year, p = 0.05) groups relative to the natalizumab group. The rates of PBVC were significantly different: −0.239%/year with continued natalizumab and +0.126 %/year after switch to placebo (p = 0.03), while the IVMP group showed brain volume loss (−0.74 %/ year, p = 0.08). pT2 was not statistically different between the groups (p ≥ 0.29) and did not have significant effects on PBVC (p ≥ 0.25). ConclusionThe increase in the brain volume in patients witching from natalizumab to placebo is consistent with reversal of so-called pseudoatrophy after starting natalizumab.