Hypoparathyroidism: changes in brain structure, cognitive impairment, and reduced quality of life.

Hypoparathyroidism (HypoPT) is a disease with no/or inadequate production/secretion of parathyroid hormone (PTH) from the parathyroid glands. Low levels of PTH result in hypocalcemia, which is often treated with calcium supplementation and active vitamin-D analogs. However, increasing evidence suggests that HypoPT has a profound impact on several organ systems. Quality of life (QOL) is reduced in patients with HypoPT, partly due to symptoms related to the central nervous system-including subjective feelings of confusion, a reduced ability to focus and think clearly(i.e., "brain fog"). However, the extent to which these complex symptoms relate to quantifiable changes in patients' cognitive performance as determined by neuropsychological tests remains unclear. The brains of HypoPT patients may reveal tissue calcifications, but the extent to which long-term brain exposure to low PTH levels and/or changing calcium levels affects brain structure is unknown. In a cross-sectional study, we investigated PTH levels, QOL, cognitive impairment, and brain structure in well-treated post-surgical and non-surgical hypoparathyroid patients compared with healthy controls. QOL was quantified by the SF36v2, WHO-5 wellbeing Index, and two disease-specific questionnaires-the HPQ28 and Hypoparathyroidism Symptom Diary. Cognitive functions were tested using comprehensive neuropsychological. Brain structure was quantified by morphological analyses of MRI images. We found reduced QOL and cognitive functioning in terms of processing speed, executive functions, visual memory, and auditory memory in HypoPT. Furthermore, HypoPT revealed a reduced volume of the hippocampus-and the size of the thalamus in postsurgical patients was associated with the disease duration. Importantly, patients reporting severe brain fog had a smaller hippocampus than those with less brainfog. HypoPT is associated with quantifiable cognitive deficits and changes in brain structure that align with patient symptoms. Our exploratory study warrants further studies of the neurobiological impact of PTH and of the impact of PTH replacements therapy on patients' cognitive functioning.

Hypoparathyroidism (HypoPT) is a disease with insufficient or no production of Parathyroid hormone (PTH) from the parathyroid glands resulting in low plasma levels of PTH and calcium. One of the reported symptoms and complications of HypoPT is low quality of life (QOL) and mild impaired cognitive function, often described as "brain fog". We have compared patients with HypoPT and healthy controls in regard to QOL, cognitive function, and brain structure. We have used QOL questionnaires, neuropsychological tests, and Magnetic resonance imaging (MRI). We found a reduced QOL and cognitive function in patients with HypoPT. Furthermore, MRI showed a difference in brain structure, with a reduced volume of the hippocampus area, especially in those reporting severe symptoms of "brain fog". Disease duration was found to be associated with the size of the thalamus. Our study suggests that there might be an association between HypoPT patients' symptoms of cognitive deficits and changes in brain structure.

Effects of power training in older patients with multiple sclerosis on neurodegeneration, neuromuscular function, and physical function. A study protocol for the "power training in older multiple sclerosis patients (PoTOMS) randomized control trial.

Introduction: Approximately one-third of all persons with multiple sclerosis (pwMS) are older, i.e., having an age ≥60 years. Whilst ageing and MS separately elicit deteriorating effects on brain morphology, neuromuscular function, and physical function, the combination of ageing and MS may pose a particular challenge. To counteract such detrimental changes, power training (i.e., a type of resistance exercise focusing on moderate-to-high loading at maximal intended movement velocity) presents itself as a viable and highly effective solution. Power training is known to positively impact physical function, neuromuscular function, as well as brain morphology. Existing evidence is promising but limited to young and middle-aged pwMS, with the effects of power training remaining to be elucidated in older pwMS. Methods: The presented 'Power Training in Older MS patients (PoTOMS)' trial is a national, multi-center, parallel-group, randomized controlled trial. The trial compares 24 weeks of usual care(n = 30) to 24 weeks of usual care and power training (n = 30). The primary outcome is whole brain atrophy rate. The secondary outcomes include changes in brain micro and macro structures, neuromuscular function, physical function, cognitive function, bone health, and patient-reported outcomes. Ethics and dissemination: The presented study is approved by The Regional Ethics Committee (reference number 1-10-72-222-20) and registered at the Danish Data Protection Agency (reference number 2016-051-000001). All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences independent of the results. The www.clinicaltrials.gov identifier is NCT04762342.

Amyloid-ß aggregates activate peripheral monocytes in mild cognitive impairment.

The peripheral immune system is important in neurodegenerative diseases, both in protecting and inflaming the brain, but the underlying mechanisms remain elusive. Alzheimer's Disease is commonly preceded by a prodromal period. Here, we report the presence of large Aß aggregates in plasma from patients with mild cognitive impairment (n = 38). The aggregates are associated with low level Alzheimer's Disease-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes. We characterize complement receptor 4 as a strong binder of amyloids and show Aß aggregates are preferentially phagocytosed and stimulate lysosomal activity through this receptor in stem cell-derived microglia. KIM127 integrin activation in monocytes promotes size selective phagocytosis of Aß. Hydrodynamic calculations suggest Aß aggregates associate with vessel walls of the cortical capillaries. In turn, we hypothesize aggregates may provide an adhesion substrate for recruiting CD18-rich monocytes into the cortex. Our results support a role for complement receptor 4 in regulating amyloid homeostasis.

Performance on complex memory tests is associated with ß-amyloid in individuals at risk of developing Alzheimer's disease.

The pathophysiological development of Alzheimer's disease (AD) begins in the brain years before the onset of clinical symptoms. The accumulation of beta-amyloid (Aß) is thought to be the first cortical pathology to occur. Carrying one apolipoprotein E (APOE) ε4 allele increases the risk of developing AD at least 2-3 times and is associated with earlier Aß accumulation. Although it is difficult to identify Aß-related cognitive impairment in early AD with standard cognitive tests, more sensitive memory tests may be able to do this. We sought to examine associations between Aß and performance on three tests within three subdomains of memory, verbal, visual, and associative memory, to elucidate which of these tests were sensitive to Aß-related cognitive impairment in at-risk subjects. 55 APOE ε4 carriers underwent MRI, 11 C-Pittsburgh Compound B (PiB) PET, and cognitive testing. A composite cortical PiB SUVR cut-off score of 1.5 was used to categorise subjects as either APOE ε4 Aß+ or APOE ε4 Aß-. Correlations were carried out using cortical surface analysis. In the whole APOE ε4 group, we found significant correlations between Aß load and performance on verbal, visual, and associative memory tests in widespread cortical areas, the strongest association being with performance on associative memory tests. In the APOE ε4 Aß+ group, we found significant correlations between Aß load and performance of verbal and associative, but not visual, memory in localised cortical areas. Performance on verbal and associative memory tests provides sensitive markers of early Aß-related cognitive impairment in at-risk subjects.

Capillary dysfunction in healthy elderly APOE ε4 carriers with raised brain Aß deposition.

INTRODUCTION: Capillary dysfunction, characterized by disturbances in capillary blood flow distribution, might be an overlooked factor in the development of Alzheimer's disease (AD). This study investigated microvascular blood flow in preclinical and prodromal AD individuals. METHODS: Using dynamic susceptibility contrast magnetic resonance imaging and positron emission tomography, we examined alterations in microvascular circulation and levels of Aß deposition in two independent cohorts of APOE ε4 carriers. RESULTS: Capillary dysfunction was elevated in both prodromal and preclinical AD individuals compared to age-matched controls. Additionally, the prodromal group exhibited higher levels of capillary dysfunction compared to the preclinical group. DISCUSSION: These findings suggest that capillary dysfunction can be detected at the preclinical stage of AD and indicates a worsening of capillary dysfunction throughout the AD continuum. Understanding the interaction between capillary dysfunction and Aß could provide insights into the relationship between cardiovascular risk factors and the development of AD. HIGHLIGHTS: Alzheimer's disease (AD) is associated with disturbances in microvascular circulation. Capillary dysfunction can be detected in preclinical AD. As cognitive symptoms progress in prodromal AD, capillary dysfunction worsens. Capillary dysfunction may impede the clearance of beta-amyloid (Aß). Capillary dysfunction might contribute to the development of AD.

Dynamic Amyloid and Metabolic Signatures of Delayed Recall Performance within the Clinical Spectrum of Alzheimer's Disease.

Associations between pathophysiological events and cognitive measures provide insights regarding brain networks affected during the clinical progression of Alzheimer's disease (AD). In this study, we assessed patients' scores in two delayed episodic memory tests, and investigated their associations with regional amyloid deposition and brain metabolism across the clinical spectrum of AD. We assessed the clinical, neuropsychological, structural, and positron emission tomography (PET) baseline measures of participants from the Alzheimer's Disease Neuroimaging Initiative. Subjects were classified as cognitively normal (CN), or with early (EMCI) or late (LMCI) mild cognitive impairment, or AD dementia. The memory outcome measures of interest were logical memory 30 min delayed recall (LM30) and Rey Auditory Verbal Learning Test 30 min delayed recall (RAVLT30). Voxel-based [18F]florbetapir and [18F]FDG uptake-ratio maps were constructed and correlations between PET images and cognitive scores were calculated. We found that EMCI individuals had LM30 scores negatively correlated with [18F]florbetapir uptake on the right parieto-occipital region. LMCI individuals had LM30 scores positively associated with left lateral temporal lobe [18F]FDG uptake, and RAVLT30 scores positively associated with [18F]FDG uptake in the left parietal lobe and in the right enthorhinal cortex. Additionally, LMCI individuals had LM30 scores negatively correlated with [18F]florbetapir uptake in the right frontal lobe. For the AD group, [18F]FDG uptake was positively correlated with LM30 in the left temporal lobe and with RAVLT30 in the right frontal lobe, and [18F]florbetapir uptake was negatively correlated with LM30 scores in the right parietal and left frontal lobes. The results show that the association between regional brain metabolism and the severity of episodic memory deficits is dependent on the clinical disease stage, suggesting a dynamic relationship between verbal episodic memory deficits, AD pathophysiology, and clinical disease stages.

Capillary dysfunction correlates with cortical amyloid load in early Alzheimer's disease.

Alterations in cerebral perfusion is increasingly considered to play a crucial role in Alzheimer's disease (AD) and together with accumulated amyloid-ß, deficiencies in the brain microvascular circulation may result in local hypoxia. Here, we studied alterations in cerebral circulation and the correlation between amyloid-ß load and cerebral perfusion in prodromal AD (pAD). Using dynamic susceptibility contrast MRI and PET, we evaluated cerebral perfusion and amyloid-ß levels in 19 individuals with mild cognitive impairment (MCI) and high amyloid-ß load (pAD-MCI), 13 MCI individuals without AD pathology and 21 healthy controls. The pAD-MCI group showed significantly lower microvascular blood flow and significantly higher heterogeneity of microvascular blood transit times (p < 0.01) compared with the other 2 groups. Additionally, in the pAD-MCI group raised amyloid-ß levels correlated with decreased microvascular blood flow and increased heterogeneity of microvascular blood flow in frontal and temporal areas (p < 0.01). These results indicate a close connection between levels of amyloid-ß deposition and brain microvascular perfusion in pAD. A vicious cycle may be established where amyloid-ß load and deficiencies in brain perfusion may reinforce each other.

Altered Cerebral Microstructure in Adults With Atrial Septal Defect and Ventricular Septal Defect Repaired in Childhood.

Background Delayed brain development, brain injury, and neurodevelopmental disabilities are commonly observed in infants operated for complex congenital heart defect. Our previous findings of poorer neurodevelopmental outcomes in individuals operated for simple congenital heart defects calls for further etiological clarification. Hence, we examined the microstructural tissue composition in cerebral cortex and subcortical structures in comparison to healthy controls and whether differences were associated with neurodevelopmental outcomes. Methods and Results Adults (n=62) who underwent surgical closure of an atrial septal defect (n=33) or a ventricular septal defect (n=29) in childhood and a group of healthy, matched controls (n=38) were enrolled. Brain diffusional kurtosis imaging and neuropsychological assessment were performed. Cortical and subcortical tissue microstructure were assessed using mean kurtosis tensor and mean diffusivity and compared between groups and tested for associations with neuropsychological outcomes. Alterations in microstructural tissue composition were found in the parietal, temporal, and occipital lobes in the congenital heart defects, with distinct mean kurtosis tensor cluster-specific changes in the right visual cortex (pericalcarine gyrus, P=0.002; occipital part of fusiform and lingual gyri, P=0.019). Altered microstructural tissue composition in the subcortical structures was uncovered in atrial septal defects but not in ventricular septal defects. Associations were found between altered cerebral microstructure and social recognition and executive function. Conclusions Children operated for simple congenital heart defects demonstrated altered microstructural tissue composition in the cerebral cortex and subcortical structures during adulthood when compared with healthy peers. Alterations in cerebral microstructural tissue composition were associated with poorer neuropsychological performance. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871881.

Investigating the potential disease-modifying and neuroprotective efficacy of exercise therapy early in the disease course of multiple sclerosis: The Early Multiple Sclerosis Exercise Study (EMSES).

BACKGROUND: Potential supplemental disease-modifying and neuroprotective treatment strategies are warranted in multiple sclerosis (MS). Exercise is a promising non-pharmacological approach, and an uninvestigated 'window of opportunity' exists early in the disease course. OBJECTIVE: To investigate the effect of early exercise on relapse rate, global brain atrophy and secondary magnetic resonance imaging (MRI) outcomes. METHODS: This randomized controlled trial (n = 84, disease duration <2 years) included 48 weeks of supervised aerobic exercise or control condition. Population-based control data (Danish MS Registry) was included (n = 850, disease duration <2 years). Relapse rates were obtained from medical records, and patients underwent structural and diffusion-kurtosis MRI at baseline, 24 and 48 weeks. RESULTS: No between-group differences were observed for primary outcomes, relapse rate (incidence-rate-ratio exercise relative to control: (0.49 (0.15; 1.66), p = 0.25) and global brain atrophy rate (-0.04 (-0.48; 0.40)%, p = 0.87), or secondary measures of lesion load. Aerobic fitness increased in favour of the exercise group. Microstructural integrity was higher in four of eight a priori defined motor-related tracts and nuclei in the exercise group compared with the control (thalamus, corticospinal tract, globus pallidus, cingulate gyrus) at 48 weeks. CONCLUSION: Early supervised aerobic exercise did not reduce relapse rate or global brain atrophy, but does positively affect the microstructural integrity of important motor-related tracts and nuclei.

Capillary function progressively deteriorates in prodromal Alzheimer's disease: A longitudinal MRI perfusion study.

Cardiovascular risk factors are associated with the development of Alzheimer's disease (AD), and increasing evidence suggests that cerebral microvascular dysfunction plays a vital role in the disease progression. Using magnetic resonance imaging, we investigated the two-year changes of the cerebral microvascular blood flow in 11 mild cognitively impaired (MCI) patients with prodromal AD compared to 12 MCI patients without evidence of AD and 10 cognitively intact age-matched controls. The pAD-MCI patients displayed widespread deterioration in microvascular cerebral perfusion associated with capillary dysfunction. No such changes were observed in the other two groups, suggesting that the dysfunction in capillary perfusion is linked to the AD pathophysiology. The observed capillary dysfunction may limit local oxygenation in AD leading to downstream ß-amyloid aggregation, tau hyperphosphorylation, neuroinflammation and neuronal dysfunction. The findings are in agreement with the capillary dysfunction hypothesis of AD, suggesting that increasing heterogeneity of capillary blood flow is a primary pathological event in AD.

Clinical, Neurophysiological, and MRI Markers of Fampridine Responsiveness in Multiple Sclerosis-An Explorative Study.

Objective: Persons with multiple sclerosis (PwMS), already established as responders or non-responders to Fampridine treatment, were compared in terms of disability measures, physical and cognitive performance tests, neurophysiology, and magnetic resonance imaging (MRI) outcomes in a 1-year explorative longitudinal study. Materials and Methods: Data from a 1-year longitudinal study were analyzed. Examinations consisted of the timed 25-foot walk test (T25FW), six spot step test (SSST), nine-hole peg test (9-HPT), five times sit-to-stand test (5-STS), symbol digit modalities test (SDMT), transcranial magnetic stimulation (TMS) elicited motor evoked potentials (MEP) examining central motor conduction times (CMCT), peripheral motor conduction times (PMCT) and their amplitudes, electroneuronography (ENG) of the lower extremities, and brain structural MRI measures. Results: Forty-one responders and eight non-responders to Fampridine treatment were examined. There were no intergroup differences except for the PMCT, where non-responders had prolonged conduction times compared to responders to Fampridine. Six spot step test was associated with CMCT throughout the study. After 1 year, CMCT was further prolonged and cortical MEP amplitudes decreased in both groups, while PMCT and ENG did not change. Throughout the study, CMCT was associated with the expanded disability status scale (EDSS) and 12-item multiple sclerosis walking scale (MSWS-12), while SDMT was associated with number of T2-weighted lesions, lesion load, and lesion load normalized to brain volume. Conclusions: Peripheral motor conduction time is prolonged in non-responders to Fampridine when compared to responders. Transcranial magnetic stimulation-elicited MEPs and SDMT can be used as markers of disability progression and lesion activity visualized by MRI, respectively. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03401307.

Cerebral hemodynamics and capillary dysfunction in late-onset major depressive disorder.

In major depressive disorder (MDD), perfusion changes in cortico-limbic pathways are interpreted as altered neuronal activity, but they could also signify changes in neurovascular coupling due to altered capillary function. To examine capillary function in late-onset MDD, 22 patients and 22 age- and gender-matched controls underwent perfusion MRI. We measured normalized cerebral blood flow (nCBF), cerebral blood volume (nCBV), and relative transit-time heterogeneity (RTH). Resulting brain oxygenation was estimated in terms of oxygen tension and normalized metabolic rate of oxygen (nCMRO2). Patients revealed signs of capillary dysfunction (elevated RTH) in the anterior prefrontal cortex and ventral anterior cingulate cortex bilaterally and in the left insulate cortex compared to controls, bilateral hypometabolism (parallel reductions of nCBV, nCBF, and CMRO2) but preserved capillary function in the subthalamic nucleus and globus pallidus bilaterally, and hyperactivity with preserved capillary function (increased nCBF) in the cerebellum and brainstem. Our data support that perfusion changes in deep nuclei and cerebellum reflect abnormally low and high activity, respectively, in MDD patients, but suggest that microvascular pathology affects neurovascular coupling in ventral circuits. We speculate that microvascular pathology is important for our understanding of etiology of late-onset MDD as well as infererences about resulting brain activity changes.

A Critical Systematic Review of Current Evidence on the Effects of Physical Exercise on Whole/Regional Grey Matter Brain Volume in Populations at Risk of Neurodegeneration.

BACKGROUND: Despite the intriguing potential of physical exercise being able to preserve or even restore brain volume (grey matter volume in particular)-a tissue essential for both cognitive and physical function-no reviews have so far synthesized the existing knowledge from randomized controlled trials investigating exercise-induced changes of the brain's grey matter volume in populations at risk of neurodegeneration. Our objective was to critically review the existing evidence regarding this topic. METHODS: A systematic search was carried out in MEDLINE and EMBASE databases primo April 2020, to identify randomized controlled trials evaluating the effects of aerobic training, resistance training or concurrent training on brain grey volume changes (by MRI) in adult clinical or healthy elderly populations. RESULTS: A total of 20 articles (from 19 RCTs) evaluating 3-12 months of aerobic, resistance, or concurrent training were identified and included, involving a total of 1662 participants (populations: healthy older adults, older adults with mild cognitive impairment or Alzheimer's disease, adults with schizophrenia or multiple sclerosis or major depression). While few studies indicated a positive effect-although modest-of physical exercise on certain regions of brain grey matter volume, the majority of study findings were neutral (i.e., no effects/small effect sizes) and quite divergent across populations. Meta-analyses showed that different exercise modalities failed to elicit any substantial effects on whole brain grey volume and hippocampus volume, although with rather large confidence interval width (i.e., variability). CONCLUSION: Altogether, the current evidence on the effects of physical exercise on whole/regional grey matter brain volume appear sparse and inconclusive, and does not support that physical exercise is as potent as previously proposed when it comes to affecting brain grey matter volume.

Cortical diffusion kurtosis imaging and thalamic volume are associated with cognitive and walking performance in relapsing-remitting multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), pronounced neurodegeneration manifests itself as cerebral gray matter (GM) atrophy, which is associated with cognitive and physical impairments. Microstructural changes in GM estimated by diffusion kurtosis imaging (DKI) may reveal neurodegeneration that is undetectable by conventional structural MRI and thus serve as a more sensitive marker of disease progression. OBJECTIVE: The primary objective was to investigate the relationships between morphological and diffusional properties in cerebral GM and physical and cognitive performance in relapsing-remitting MS (RRMS) patients. A secondary objective was to investigate the relationship between GM microstructure and white matter (WM) injury, estimated by the volume of WM lesions. METHODS: Sixty-seven RRMS patients performed the brief repeatable battery of neuropsychological tests (BRB-N), the 6-minute walk test (6MWT), the six spot step test (SSST), and underwent MRI scans using structural and DKI protocols. GM volumetrics and DKI measurements were analyzed in the cortex and deep GM structures using a general linear model with demographics, physical- and cognitive performance as covariates. RESULTS: Mean diffusivity (MD) in the cortex was associated with the SSST, 6MWT, information processing, global cognitive performance, and volume of WM lesions. In addition, thalamic volume was associated with SSST (r2 = 0.21, 6MWT (r2 = 0.18), information processing (r2 = 0.21), and WM lesion volume (r2 = 0.60). CONCLUSION: Cortical diffusion and thalamic volume are associated with walking and cognitive performance in RRMS patients and are highly affected by the presence of WM lesions.

Impaired cerebral microcirculation in isolated REM sleep behaviour disorder.

During the prodromal period of Parkinson's disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, behaviour, and memory functions, these nuclei also innervate parenchymal arterioles and capillaries throughout the cortex, possibly to ensure that oxygen supplies are adjusted according to the needs of neural activity. The aim of this study was to examine whether patients with isolated REM sleep behaviour disorder, a parasomnia considered to be a prodromal phenotype of α-synucleinopathies, reveal microvascular flow disturbances consistent with disrupted central blood flow control. We applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow in the cortex of 20 polysomnographic-confirmed patients with isolated REM sleep behaviour disorder (17 males, age range: 54-77 years) and 25 healthy matched controls (25 males, age range: 58-76 years). Patients and controls were cognitively tested by Montreal Cognitive Assessment and Mini Mental State Examination. Results revealed profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. In patients, the microvascular flow disturbances were seen in cortical areas associated with language comprehension, visual processing and recognition and were associated with impaired cognitive performance. We conclude that cortical blood flow abnormalities, possibly related to impaired neurogenic control, are present in patients with isolated REM sleep behaviour disorder and associated with cognitive dysfunction. We hypothesize that pharmacological restoration of perivascular neurotransmitter levels could help maintain cognitive function in patients with this prodromal phenotype of parkinsonism.

Abnormal Left-Hemispheric Sulcal Patterns in Adults With Simple Congenital Heart Defects Repaired in Childhood.

Background Children operated on for a simple congenital heart defect (CHD) are at risk of neurodevelopmental abnormalities. Abnormal cortical development and folding have been observed in fetuses with CHD. We examined whether sulcal folding patterns in adults operated on for simple CHD in childhood differ from those of healthy controls, and whether such differences are associated with neuropsychological outcomes. Methods and Results Patients (mean age, 24.5 years) who underwent childhood surgery for isolated atrial septal defect (ASD; n=33) or ventricular septal defect (VSD; n=30) and healthy controls (n=37) were enrolled. Sulcal pattern similarity to healthy controls was determined using magnetic resonance imaging and looking at features of sulcal folds, their intersulcal relationships, and sulcal graph topology. The sulcal pattern similarity values were tested for associations with comprehensive neuropsychological scores. Patients with both ASD and VSD had decreased sulcal pattern similarity in the left hemisphere compared with controls. The differences were found in the left temporal lobe in the ASD group and in the whole left hemisphere in the VSD group (P=0.033 and P=0.039, respectively). The extent of abnormal left hemispheric sulcal pattern similarity was associated with worse neuropsychological scores (intelligence, executive function, and visuospatial abilities) in the VSD group, and special educational support in the ASD group. Conclusions Adults who underwent surgery for simple CHD in childhood display altered left hemisphere sulcal folding patterns, commensurate with neuropsychological scores for patients with VSD and special educational support for ASD. This may indicate that simple CHD affects early brain development. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871881.

Dairy-Derived Emulsifiers in Infant Formula Show Marginal Effects on the Plasma Lipid Profile and Brain Structure in Preterm Piglets Relative to Soy Lecithin.

Breastfed infants have higher intestinal lipid absorption and neurodevelopmental outcomes compared to formula-fed infants, which may relate to a different surface layer structure of fat globules in infant formula. This study investigated if dairy-derived emulsifiers increased lipid absorption and neurodevelopment relative to soy lecithin in newborn preterm piglets. Piglets received a formula diet containing soy lecithin (SL) or whey protein concentrate enriched in extracellular vesicles (WPC-A-EV) or phospholipids (WPC-PL) for 19 days. Both WPC-A-EV and WPC-PL emulsions, but not the intact diets, increased in vitro lipolysis compared to SL. The main differences of plasma lipidomics analysis were increased levels of some sphingolipids, and lipid molecules with odd-chain (17:1, 19:1, 19:3) as well as mono- and polyunsaturated fatty acyl chains (16:1, 20:1, 20:3) in the WPC-A-EV and WPC-PL groups and increased 18:2 fatty acyls in the SL group. Indirect monitoring of intestinal triacylglycerol absorption showed no differences between groups. Diffusor tensor imaging measurements of mean diffusivity in the hippocampus were lower for WPC-A-EV and WPC-PL groups compared to SL indicating improved hippocampal maturation. No differences in hippocampal lipid composition or short-term memory were observed between groups. In conclusion, emulsification of fat globules in infant formula with dairy-derived emulsifiers altered the plasma lipid profile and hippocampal tissue diffusivity but had limited effects on other absorptive and learning abilities relative to SL in preterm piglets.

Study protocol: randomised controlled trial evaluating exercise therapy as a supplemental treatment strategy in early multiple sclerosis: the Early Multiple Sclerosis Exercise Study (EMSES).

INTRODUCTION: In the relapsing remitting type of multiple sclerosis (MS) reducing relapses and neurodegeneration is crucial in halting the long-term impact of the disease. Medical disease-modifying treatments have proven effective, especially when introduced early in the disease course. However, patients still experience disease activity and disability progression, and therefore, supplemental early treatment strategies are warranted. Exercise appear to be one of the most promising supplemental treatment strategies, but a somewhat overlooked 'window of opportunity' exist early in the disease course. The objective of this study is to investigate exercise as a supplementary treatment strategy early in the disease course of MS. METHODS AND ANALYSIS: The presented Early Multiple Sclerosis Exercise Study is a 48-week (plus 1-year follow-up) national multicentre single-blinded parallel group randomised controlled trial comparing two groups receiving usual care plus supervised high-intense exercise or plus health education (active control). Additionally, data will be compared with a population-based control group receiving usual care only obtained from the Danish MS Registry. The primary outcomes are annual relapse rate and MRI derived global brain atrophy. The secondary outcomes are disability progression, physical and cognitive function, MS-related symptoms, and exploratory MRI outcomes. All analyses will be performed as intention to treat. ETHICS AND DISSEMINATION: The study is approved by The Central Denmark Region Committees on Health Research Ethics (1-10-72-388-17) and registered at the Danish Data Protection Agency (2016-051-000001 (706)). All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences. TRIAL REGISTRATION NUMBER: NCT03322761.

Microstructural changes in the brain after long-term post-concussion symptoms: A randomized trial.

A recent randomized controlled trial in young patients with long-term post-concussion symptoms showed that a novel behavioral intervention "Get going After concussIoN" is superior to enhanced usual care in terms of symptom reduction. It is unknown whether these interventional effects are associated with microstructural brain changes. The aim of this study was to examine whether diffusion-weighted MRI indices, which are sensitive to the interactions between cellular structures and water molecules' Brownian motion, respond differently to the interventions of the above-mentioned trial and whether such differences correlate with the improvement of post-concussion symptoms. Twenty-three patients from the intervention group (mean age 22.8, 18 females) and 19 patients from the control group (enhanced usual care) (mean age 23.9, 14 females) were enrolled. The primary outcome measure was the mean kurtosis tensor, which is sensitive to the microscopic complexity of brain tissue. The mean kurtosis tensor was significantly increased in the intervention group (p = 0.003) in the corpus callosum but not in the thalamus (p = 0.78) and the hippocampus (p = 0.34). An increase in mean kurtosis tensor in the corpus callosum tended to be associated with a reduction in symptoms, but this association did not reach significance (p = 0.059). Changes in diffusion tensor imaging metrics did not differ between intervention groups and were not associated with symptoms. The current study found different diffusion-weighted MRI responses from the microscopic cellular structures of the corpus callosum between patients receiving a novel behavioral intervention and patients receiving enhanced usual care. Correlations with improvement of post-concussion symptoms were not evident.

Efficacy of High-Intensity Aerobic Exercise on Brain MRI Measures in Multiple Sclerosis.

OBJECTIVE: To determine whether 24 weeks of high-intensity progressive aerobic exercise (PAE) affects brain MRI measures in people with multiple sclerosis (MS). METHODS: We conducted a randomized, controlled, phase 2 trial (with a crossover follow-up) including an exercise group (supervised PAE followed by self-guided physical activity) and a waitlist group (habitual lifestyle followed by supervised PAE). Mildly to severely impaired patients with MS aged 18-65 years were randomized (1:1). The primary outcome was percentage brain volume change (PBVC) after 24 weeks, analyzed using the intention-to-treat principle. RESULTS: Eighty-six participants were recruited. PBVC did not change over the intervention period (mean between-group change +0.12%, 95% confidence interval [CI] -0.27 to 0.51, p = 0.55). In contrast, cardiorespiratory fitness (+3.5 mL O2/min/kg, 2.0 to 5.1, p < 0.01) and annualized relapse rate (0.00, 0.00-0.07 vs +0.45, 0.28 to 0.61, p < 0.01) improved in the exercise group. CONCLUSION: These findings do not support a neuroprotective effect of PAE in terms of total brain atrophy in people with MS and it did not lead to a statistically significant difference in gray matter parenchymal fraction. PAE led to improvements in cardiorespiratory fitness and a lower relapse rate. While these exploratory findings cautiously support PAE as a potential adjunct disease-modifying treatment in MS, further investigations are warranted. CLINICALTRIALSGOV IDENTIFIER: NCT02661555. CLASSIFICATION OF EVIDENCE: This study provides Level I evidence that 24 weeks of high-intensity PAE did not elicit disease-modifying effects in PBVC in people with MS. Exploratory analyses showed that PAE may reduce relapse rate.