Reduced Brain Volume Research Articles

Brain MRI in infants exposed to the Zika virus, with one-year follow-up: expanding the phenotype.

To analyze longitudinal changes between two brain magnetic resonance imaging (MRI) exams performed one year apart in symptomatic infants with congenital Zika syndrome (CZS) and normocephalic infants exposed to the Zika virus (ZIKV) prenatally. This was a prospective observational study. Infants born to women who tested positive for ZIKV on reverse transcription-quantitative polymerase chain reaction during pregnancy were classified into two groups: symptomatic infants with CZS and asymptomatic infants. All of the infants underwent brain MRI at presentation and after one year of follow-up. All MRI scans were evaluated independently by a pediatric radiologist and a pediatric neuroradiologist, and the infants underwent clinical monitoring by a pediatric neurologist. The sample included 36 infants exposed to ZIKV perinatally. Therefore, a total of 72 MRI scans were evaluated. Among the 36 infants included a diagnosis of CZS was made in 25 (69.4%), of whom 18 presented with a combination of classic findings (including reduced brain volume, subcortical calcifications, brainstem hypoplasia, malformations of the corpus callosum, malformations of cortical development, and ventriculomegaly), as well as atypical findings such as hyperintense foci in the white matter on T2-weighted sequences. Of those same 25 infants, seven presented with mild lesions. Of the 11 normocephalic patients, five (13.9%) had atypical findings such as hyperintense foci in the white matter on T2-weighted sequences and no other manifestations of CZS, although there was mild neurological involvement. Six (16.6%) of the 36 patients had completely normal MRI scans with no neurological changes. No disease progression was observed during follow-up. In infants exposed to ZIKV perinatally, the frequency of classic and atypical findings on brain MRI seems to be associated with the neurological status. Brain MRI is an important diagnostic tool in the evaluation and monitoring of patients with congenital infection, because intracranial changes other than microcephaly can occur.

Non-alcoholic fatty liver disease causally affects the brain cortical structure: a Mendelian randomization study.

Reduced brain volume, impaired cognition, and possibly a range of psychoneurological disorders have been reported in patients with non-alcoholic fatty liver disease (NAFLD); however, no underlying cause has been specified. Here, Mendelian randomization (MR) was employed to determine the causative NAFLD effects on cortical structure. We used pooled-level data from FinnGen's published genome-wide association study (GWAS) of NAFLD (1908 cases and 340,591 healthy controls), as well as published GWAS with NAFLD activity score (NAS) and fibrosis stage-associated SNPs as genetic tools, in addition to the Enigma Consortium data from 51,665 patients, were used to assess genetic susceptibility in relation to changes with cortical thickness (TH) and surface area (SA). A main estimate was made by means of inverse variance weighted (IVW), while heterogeneity and pleiotropy were detected using MR-Egger, weighted median, and MR Pleiotropy RESidual Sum and Outlier to perform a two-sample MR analysis. At the global level, NAFLD reduced SA (beta = -586.72 mm2, se = 217.73, p = 0.007) and several changes in the cortical structure of the cerebral gyrus were found, with no detectable pleiotropy. NAFLD causally affects cortical structures, which supports the presence of an intricate liver-brain axis.

Chronic Hyponatremia and Brain Structure and Function Before and After Treatment

Rationale & ObjectiveHyponatremia is the most common electrolyte disorder and is associated with significant morbidity and mortality. This study investigated neurocognitive impairment, brain volume, and alterations in MRI-based measures of cerebral function in patients before and after treatment for hyponatremia. Study DesignProspective cohort study. Setting & ParticipantsPatients with presumed chronic hyponatremia without signs of hypo- or hypervolemia treated in the Emergency Department of a German tertiary care hospital. ExposureHyponatremia ([Na+] <125 mmol/L) before and after treatment leading to [Na+] >130 mmol/L. OutcomesStandardized neuropsychological testing (Mini-Mental-State examination [MMSE], DemTect, Trail-Making Test [TMT] A/B, Beck’s Depression Inventory, Timed Up and Go) and resting-state MRI were performed prior to and following treatment of hyponatremia to assess volumes of total brain, white and gray matter, as well as neuronal activity and its synchronization. Analytical ApproachChanges in outcomes after treatment for hyponatremia assessed using bootstrapped confidence intervals and Cohen’s d. Associations between parameters were assessed using correlation analyses. ResultsDuring a 3.7-year period, 26 patients were enrolled. Complete data were available for 21 patients. Mean [Na+] was 118.4 mmol/L before treatment and 135.5 mmol/L following treatment. Most measures of cognition improved significantly. Comparison of MRI studies showed a decrease in brain tissue volumes, neuronal activity, and synchronization across all gray matter after normalization of [Na+]. Volume effects were particularly prominent in the hippocampus. During hyponatremia, synchronization of neuronal activity was negatively correlated with [Na+] (r=-.836, [-.979, -.446]) and cognitive function (MMSE: r=-.523, [-.805, -.069]; DemTect: r=-.744, [-.951, -.385] and TMT-A: r=.692, [.255, .922]). LimitationsSmall sample size, insufficient quality of several MRI scans due to motion artifact. ConclusionsResolution of hyponatremia was associated with improved cognition and reductions in brain volumes and neuronal activity. Impaired cognition during hyponatremia is closely linked to increased neuronal activity rather than to tissue volumes. Furthermore, the hippocampus appears to be particularly susceptible to hyponatremia, exhibiting pronounced changes in tissue volume.

Association of mild and complex multimorbidity with structural brain changes in older adults: A population-based study.

We quantified the association of mild (ie, involving one or two body systems) and complex (ie, involving ≥3 systems) multimorbidity with structural brain changes in older adults. We included 390 dementia-free participants aged 60+ from the Swedish National Study on Aging and Care in Kungsholmen who underwent brain magnetic resonance imaging at baseline and after 3 and/or 6 years. Using linear mixed models, we estimated the association between multimorbidity and changes in total brain tissue, ventricular, hippocampal, and white matter hyperintensities volumes. Compared to non-multimorbid participants, those with complex multimorbidity showed the steepest reduction in total brain (β*time -0.03, 95% CI -0.05, -0.01) and hippocampal (β*time -0.05, 95% CI -0.08, -0.03) volumes, the greatest ventricular enlargement (β*time 0.03, 95% CI 0.01, 0.05), and the fastest white matter hyperintensities accumulation (β*time 0.04, 95% CI 0.01, 0.07). Multimorbidity, particularly when involving multiple body systems, is associated with accelerated structural brain changes, involving both neurodegeneration and vascular pathology. Multimorbidity accelerates structural brain changes in cognitively intact older adults These brain changes encompass both neurodegeneration and cerebrovascular pathology The complexity of multimorbidity is associated with the rate of brain changes' progression.

Neuroinflammation, blood-brain barrier dysfunction, hippocampal atrophy and delayed neurodevelopment: Contributions for a rat model of congenital Zika syndrome

The congenital Zika syndrome (CZS) has been characterized as a set of several brain changes, such as reduced brain volume and subcortical calcifications, in addition to cognitive deficits. Microcephaly is one of the possible complications found in newborns exposed to Zika virus (ZIKV) during pregnancy, although it is an impacting clinical sign. This study aimed to investigate the consequences of a model of congenital ZIKV infection by evaluating the histopathology, blood-brain barrier, and neuroinflammation in pup rats 24 h after birth, and neurodevelopment of the offspring. Pregnant rats were inoculated subcutaneously with ZIKV-BR at the dose 1 × 107 plaque-forming unit (PFU mL-1) of ZIKV isolated in Brazil (ZIKV-BR) on gestational day 18 (G18). A set of pups, 24 h after birth, was euthanized. The brain was collected and later evaluated for the histopathology of brain structures through histological analysis. Additionally, analyses of the blood-brain barrier were conducted using western blotting, and neuroinflammation was assessed using ELISA. Another set of animals was evaluated on postnatal days 3, 6, 9, and 12 for neurodevelopment by observing the developmental milestones. Our results revealed hippocampal atrophy in ZIKV animals, in addition to changes in the blood-brain barrier structure and pro-inflammatory cytokines expression increase. Regarding neurodevelopment, a delay in important reflexes during the neonatal period in ZIKV animals was observed. These findings advance the understanding of the pathophysiology of CZS and contribute to enhancing the rat model of CZS.

A brief review of the neuroimaging modalities in schizophrenia and their scope

Abstract Schizophrenia is a serious mental disorder characterized by diverse symptoms, including hallucinations, delusions, and disorders in thinking, behavior and cognition. Its etiology is multifactorial involving genetic, environmental, developmental, and neurobiological factors. Neuroimaging studies have significantly contributed to understanding the underlying neural abnormalities associated with this disorder. Reduced brain volume was observed in frontal and temporal lobes in most studies using structural imaging techniques. Hypofrontality was observed in functional studies. Neuroimaging also aids in differentiating structural lesions causing symptoms mimicking schizophrenia. However, challenges persist due to variables such as age, gender, comorbidities, therapy history, substance use, and coexisting psychiatric conditions, which are often insufficiently controlled for, in the literature. This review article comprehensively consolidates the diagnostic and prognostic potential of various neuroimaging techniques in schizophrenia.

Masticatory Function, Sex, and Risk of Dementia Among Older Adults: A Population-Based Cohort Study.

A decline in masticatory function may indicate brain dysfunction related to dementia, but the relationship between masticatory function and dementia risk remains unclear. This study aimed to investigate whether masticatory function is associated with the risk of cognitive decline and dementia. Data were obtained from the nationwide prospective cohort study of randomly sampled community-dwelling Koreans aged ≥ 60 years. The 5,064 non-demented participants, whose number of chewing cycles per bite was assessed by clinical interview, were followed for 8 years with biennial assessments of cognitive performance and clinical diagnoses of all-cause dementia and Alzheimer's disease (AD). Structural brain magnetic resonance imaging was collected from a subset of cohort participants and their spouses for imaging analyses. Males who chewed ≥ 30 cycles/bite had faster decline in global cognition and memory function and were at higher risk for incident all-cause dementia (hazard ratio [HR], 2.91; 95% confidence interval [CI], 1.18-7.18) and AD (HR, 3.22; 95% CI, 1.14-9.11) compared to males with less than 10 cycles/bite. Additionally, increased chewing cycles in males were associated with reduced brain volume, particularly in regions involved in compensatory cognitive control of mastication. There was no significant association between chewing cycles and the risk of dementia or brain volume in females. Older men who frequently chew their meals could be considered a notable population at risk for dementia who should be carefully assessed for their cognitive trajectories.

Cerebral Small Vessel Disease Is Associated With Smaller Brain Volumes in Adults With Type 1 Diabetes.

Introduction: Type 1 diabetes has been linked to brain volume reductions as well as to cerebral small vessel disease (cSVD). This study concerns the relationship between normalized brain volumes (volume fractions) and cSVD, which has not been examined previously. Methods: We subjected brain magnetic resonance imaging studies of 187 adults of both sexes with Type 1 diabetes and 30 matched controls to volumetry and neuroradiological interpretation. Results: Participants with Type 1 diabetes had smaller thalami compared to controls without diabetes (p = 0.034). In subgroup analysis of the Type 1 diabetes group, having any sign of cSVD was associated with smaller cortical (p = 0.031) and deep gray matter volume fractions (p = 0.029), but a larger white matter volume fraction (p = 0.048). After correcting for age, the smaller putamen volume remained significant. Conclusions: We found smaller thalamus volume fractions in individuals with Type 1 diabetes as compared to those without diabetes, as well as reductions in brain volume fractions related to signs of cSVD in individuals with Type 1 diabetes.

Cerebral perfusion differences are linked to executive function performance in very preterm-born children and adolescents

Children and adolescents born very preterm are at risk of cognitive impairment, particularly affecting executive functions. To date, the neural correlates of these cognitive differences are not yet fully understood, although converging evidence points to a pattern of structural and functional brain alterations, including reduced brain volumes, altered connectivity, and altered brain activation patterns. In very preterm neonates, alterations in brain perfusion have also been reported, but the extent to which these perfusion alterations persist into later childhood is not yet known. This study evaluated global and regional brain perfusion, measured with arterial spin labelling (ASL) MRI, in 26 very preterm children and adolescents and 34 term-born peers. Perfusion was compared between groups and relative to executive function (EF) scores, derived from an extensive EF battery assessing working memory, cognitive flexibility, and planning. Very preterm children and adolescents showed regions of altered perfusion, some of which were also related to EF scores. Most of these regions were located in the right hemisphere and included regions like the thalamus and hippocampus, which are known to play a role in executive functioning and can be affected by prematurity. In addition, perfusion decreased with age during adolescence and showed a significant interaction between birth status and sex, such that very preterm girls showed lower perfusion than term-born girls, but this trend was not seen in boys. Taken together, our results indicate a regionally altered perfusion in very preterm children and adolescents, with age and sex related changes during adolescence.

The Effects of Moderate and High Intensity Aerobic Exercise on Lipid and Lipoprotein Metabolism and Brain Volume in Cognitively Normal Older Australians: Data from the IPAC Study

AbstractBackgroundA common misconception about ageing is that a decline in brain health is solely observed in those who have dementia. In fact, decreases in cognitive function and reductions in brain volume are commonly observed in adults over the age of 65. Brain changes in older adulthood have been shown to be decreased in individuals who are more physically active, with alterations in lipid and lipoprotein metabolism emerging as a potential mechanism, however this is still not well understood. In light of this, our study aims to investigate the effects of moderate and high intensity aerobic exercise on lipid and lipoprotein metabolism to assess the efficacy of exercise in reducing brain atrophy in cognitively normal older adults.MethodSamples were collected from the Intense Physical Activity and Cognition (IPAC) study, during which a six‐month randomised controlled trial was performed to observe the impact of aerobic exercise on brain volume measurements in cognitively normal older adults (n = 99, aged 60‐80). Blood samples and neuroimaging measures were collected at baseline and following the completion of the intervention (6 months). Baseline and post‐intervention plasma samples were collected and analysed using 1H‐NMR spectroscopy to quantify 112 lipoproteins, followed by a comprehensive in‐house mass spectrometry (MS) lipids screen targeting &gt;1200 individual lipid species.ResultPreliminary analyses suggest that lipid and lipoprotein metabolism is altered by aerobic exercise and that these alterations are associated with changes in brain volume. Further analyses will increase the sample size, and also evaluate other factors (i.e. sex, APOE status) as potential moderators of the link between aerobic exercise and the metabolism of lipids and lipoproteins.ConclusionTo our knowledge, this study is the first to establish the relationship between exercise and lipids and lipoprotein metabolism, and their association to brain volume in cognitively normal older adults. The significance of our findings will be evaluated further using an external validation cohort. The discovery of novel lipids or metabolic pathways will create avenues for future research into new therapeutic targets for future healthy ageing interventions.

Impaired ability to smile in Alzheimer’s disease is associated with reduced brain volume of nucleus accumbens and pallidum, revealed by artificial intelligence

AbstractBackgroundPatients tend to lose the ability to smile during the clinical course of dementia. However, details of such impairment remain obscure presumably due to difficulty of quantifying facial expression. Feature extraction is now automated as a result of recent developments in artificial intelligence (AI). The authors applied a model to quantify impaired smile expression in patients with Alzheimer disease (AD). The relationship between the expression of a smile and subcortical volumes was also investigated.MethodThis study included 280 and 190 participants with AD and with normal cognition (NC), respectively. The faces of the participants were photographed as they smiled or maintained a neutral expression. Subcortical brain volume was assessed in 210 and 90 of those with AD and NC, respectively, using MRI and the FSL‐FIRST algorithm. Datasets of the photographs were prepared with combinations of smiling and neutral expression in NC and AD, smiling in AD and NC, and neutral expression in AD and NC, then binary discrimination proceeded using the VGG‐Face convolutional neural network (CNN).ResultThe accuracy of discriminating a smile from a neutral expression was of 92.3% in NC, and 61.2% in AD, indicating that a considerable proportion of patients with AD have difficulties forming a natural smile. 48.5% of smile AD were classified as negative in NC dataset. The smile/neutral‐NC scores for AD were robustly associated with the volume of the bilateral nucleus accumbens (right, r = 0.51, p = 2.59 × 10−15; left, r = 0.493, p = 2.89 × 10−14) and the bilateral pallidum (right, r = 0.266, p = 0.0000981; left, r = 0.256, p = 0.000174). The accuracy of discriminating between AD and NC was 95.2% with smile and 90.1% with a neutral expression, respectively (p = 0.0045). The neutral‐AD/NC score inversely correlated with the results of the MMSE (p = 1.62 × 10−7), but not with smile/neutral‐NC or smile‐AD/NC scores.ConclusionThe ability to form smile was impaired in AD and associated with nucleus accumbens and pallidum shrinkage. Such impairment enhanced the accuracy of facial discrimination between AD and NC, whereas a neutral expression was associated with cognitive function.

Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with cognitive dysfunction as its major clinical symptom. However, there is no disease-modifying small molecular medicine to effectively slow down progression of the disease. Here, we show an optimized asparagine endopeptidase (AEP, also known as δ-secretase) inhibitor, #11 A, that displays an orderly in vivo pharmacokinetics/pharmacodynamics (PK/PD) relationship and robustly attenuates AD pathologies in a sporadic AD mouse model. #11 A is brain permeable with great oral bioavailability. It blocks AEP cleavage of APP and Tau dose-dependently, and significantly decreases Aβ40 and Aβ42 and p-Tau levels in APP/PS1 and Tau P301S mice after oral administration. Notably, #11 A strongly inhibits AEP and prevents mouse APP and Tau fragmentation by AEP, leading to reduction of mouse Aβ42 (mAβ42), mAβ40 and mouse p-Tau181 levels in Thy1-ApoE4/C/EBPβ transgenic mice in a dose-dependent manner. Repeated oral administration of #11 A substantially decreases mAβ aggregation as validated by Aβ PET assay, Tau pathology, neurodegeneration and brain volume reduction, resulting in alleviation of cognitive impairment. Therefore, our results support that #11 A is a disease-modifying preclinical candidate for pharmacologically treating AD.

Cigarette smoking and structural brain deficits in patients with atrial fibrillation

Abstract Background Brain lesions are common in patients with atrial fibrillation (AF). Whether cigarette smoking is associated with an increased risk of brain lesions and reduced brain volume in patients with AF is currently unknown. Purpose In this analysis, we aimed to investigate the association of cigarette smoking habits with cerebral small vessel disease and overall brain volume. Methods For this cross-sectional analysis, we included AF patients from a multicentre cohort study. Smoking habits were defined by smoking status categories (never, former, current), duration (tertiles of years), cigarettes per day (CPD as obtained at baseline), packyears (PKY, tertiles) and time since smoking cessation (≤5 years, 6-10 years, 11-15 and ≥16 years). A standardized brain magnetic resonance imaging was done to assess the prevalence of small vessel disease white matter lesions (WML, graded according to the Fazekas scale) and small non-cortical infarcts (SNCI). Additionally, MRI was used to quantify the volumes of WML and SNCI; as well as to measure grey matter (GM) and white matter (WM) brain volumes. Multivariable adjusted logistic and linear regression analyses were applied. Results 1746 patients were enrolled (mean age 72.6 years, 27.5% females). 131 (7.5%) were current smokers, 846 (48.5%) former and 769 (44%) never smokers. Patients with a longer smoking duration, higher amount of CPD and PKY had reduced GM brain volume (p for linear trend 0.05, 0.005 and 0.02, respectively). Patient with higher CPD also had a reduced WM brain volume (p for linear trend 0.04). Compared to patients with a smoking duration in the lowest tertile (≤18 years), patients who had smoked for 19-34 years (second tertile) and more than 35 years (third tertile) had a higher risk for WML Fazekas ≥2 with an OR (95% CI) of 1.85 (1.29; 2.66, p=0.001) and 1.46 (1.01; 2.09, p=0.04) (Figure 1). Additionally, increasing smoking duration tertiles exhibited larger WML volumes, with a significant linear trend (p=0.05). AF patients who quit smoking ≥16 years ago had a lower odds for SNCI (OR 0.47 (0.24; 0.94, p= 0.03), less WML volume (β: -0.451 (-0.8; -0.11, p=0.01), and a higher WM brain volume (β: 16.9 (0.3; 33.6, p= 0.05) compared to patients who quit 5 years prior to the study enrolment (Figure 2). We found no significant difference in any structural brain deficit between current and former smokers compared to never smokers. Conclusion In a large AF population, we found that smoking duration and amount were associated with the loss of brain volumes. Smoking duration and time since smoking cessation were associated with small vessel disease.

Complement component 4A protein levels are negatively related to frontal volumes in patients with schizophrenia spectrum disorders.

Excessive C4A-gene expression may result in increased microglia-mediated synaptic pruning. As C4A overexpression is observed in schizophrenia spectrum disorders (SSD), this mechanism may account for the altered brain morphology (i.e. reduced volume and cortical thickness) and cognitive symptoms that characterize SSD. Therefore, this study investigates the association of C4A serum protein levels with brain morphology and cognition, and in particular whether this association differs between recent-onset SSD (n=69) and HC (n=40). Serum C4A protein levels were compared between groups. Main outcomes included total gray matter volume, mean cortical thickness and cognitive performance. Regression analysis on these outcomes included C4A level, group (SSD vs. HC), and C4A*Group interactions. All statistical tests were corrected for age, sex, BMI, and antipsychotic medication dose. Follow-up analyses were performed on separate brain regions and scores on cognitive sub-tasks. The group difference in C4A levels was not statistically significant (p=0.86). The main outcomes did not show a significant interaction effect (p>0.13) or a C4A main effect (p>0.27). Follow-up analyses revealed significant interaction effects for the left medial orbitofrontal and left frontal pole volumes (p<0.001): C4A was negatively related to these volumes in SSD, but positively in HC. This study demonstrated that C4A was negatively related to - specifically - frontal brain volumes in SSD, but this relation was inverse for HC. The results support the hypothesis of complement-mediated brain volume reduction in SSD. The results also suggest that C4A has a differential association with brain morphology in SSD compared to HC.

30 Hippocampal Internal Architecture Subfield Volumes Associated with Systematic Inflammatory Biomarkers in Multiple Sclerosis

Objective:Multiple Sclerosis (MS) affects up to 500,000 adults in the United States, with cognitive impairment present in 45%-65% of people. Studies showed hippocampal atrophy in MS, but the underlying mechanisms remain unknown. Inflammation has been proposed to play a significant role, and associations between systemic inflammatory biomarkers and hippocampal atrophy have been shown in other neurological conditions. However, research exploring serum biomarker and volumetric associations in MS are lacking. Given that conventional imaging methods lack resolution for hippocampal internal architecture (HIA), new protocols were developed. We used the High-Resolution Multiple Image Co-Registration and Averaging (HR-MICRA) method to visualize the HIA subfields. We investigated the relationship between subfield volumes generated from HR-MICRA scans and systemic serum biomarkers in MS.Participants and Methods:Patients with MS were recruited (N= 34, mean age= 54.6, 35.3% Black) underwent Magnetic Resonance Imaging (MRI), and serum biomarkers were obtained, specifically chosen for their potential role in MS. Inflammatory biomarkers included; granulocyte colony stimulating factor (G-CSF), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor- a (TNF- a), and growth factors; vascular endothelial growth factor (VEGF); insulin-like growth factor-1 (IGF-1), and brain derived growth factor (BDNF). Imaging was performed in a Siemens Prisma 3T scanner with a 64-channel head coil using the HR-MICRA method. Hippocampal subfields were calculated using the Automated Segmentation of Hippocampal Subfields (ASHS) package. We used the Magdeburg Young Adult 7T Atlas for sub-hippocampal structures and Penn Temporal Lobe Epilepsy T1-MRI Whole Hippocampus ASHS Atlas for general hippocampal structure and segmentation. Pearson's product-moment analyses provided correlations between biomarkers and hippocampal subfield volumes for each cerebral hemisphere. A statistical significance level of p &lt; 0.05 was used for all analyses.Results:Correlations emerged between left hemisphere Cornu Ammonis (CA) 2 and G-CSF (r = -.384; p = .025); IL-10 (r = -.342; p = .048); VEGF (r = -.371; p= .031); and CA3 with IL-10 (r = -.488, p = .003); G-CSF (r = -.386; p= .024); VEGF (r = -.352; p= .041). Dentate gyrus correlated with MMP-9 (r =.416; p=.014); IL-10 (r = -.365; p =.034). BDNF was correlated with right hemisphere CA1 (r = -.417, p = .014), CA2 (r = -.497; p= .003) and CA3 (r = -.451; p=.007).Conclusions:In our sample of persons with MS, left hemisphere hippocampal subfield volumes were negatively correlated with inflammatory biomarkers, supporting previous reports linking inflammation to reduced brain volumes in other neurological conditions. In the right hemisphere, we found negative correlations between HIA and BDNF, suggesting a neuroprotective function for BDNF in this neurodegenerative disease. These findings in a representative sample of patients with MS highlight the need for further research exploring the relationship between HIA and systemic serum biomarkers in MS.

Cohort study finds prenatal SSRI exposure linked to reduced brain volume

A population‐based cohort study has found that prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants was associated with reduced brain volume in children aged 7 to 15. The study did not examine whether any of the observed changes in the brain predisposed these young people to any impairments.

Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target.

Schizophrenia is one of the most serious psychiatric disorders and is characterized by reductions in both brain volume and spine density in the frontal cortex. RhoA belongs to the RAS homolog (Rho) family and plays critical roles in neuronal development and structural plasticity via Rho-kinase. RhoA activity is regulated by GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Several variants in GAPs and GEFs associated with RhoA have been reported to be significantly associated with schizophrenia. Moreover, several mouse models carrying schizophrenia-associated gene variants involved in RhoA/Rho-kinase signaling have been developed. In this review, we summarize clinical evidence showing that variants in genes regulating RhoA activity are associated with schizophrenia. In the last half of the review, we discuss preclinical evidence indicating that RhoA/Rho-kinase is a potential therapeutic target of schizophrenia. In particular, Rho-kinase inhibitors exhibit anti-psychotic-like effects not only in Arhgap10 S490P/NHEJ mice, but also in pharmacologic models of schizophrenia (methamphetamine- and MK-801-treated mice). Accordingly, we propose that Rho-kinase inhibitors may have antipsychotic effects and reduce cognitive deficits in schizophrenia despite the presence or absence of genetic variants in small GTPase signaling pathways.

KIBRA single nucleotide polymorphism is associated with hippocampal subfield volumes and cognition across development.

The hippocampus (Hc) consists of cytoarchitectonically and functionally distinct subfields: dentate gyrus (DG), cornu ammonis (CA1-3), and subiculum. In adults, a single nucleotide polymorphism (rs17070145, C→ T) in KIBRA, a gene encoding the eponymous (KIdney-BRAin) protein, is associated with variability in Hc subfield volumes and episodic memory. T-allele carriers have larger DG and CA volumes and better episodic memory compared to C-homozygotes. Little is known, however, about KIBRA's role in the development of the brain and cognition. In a sample of children, adolescents, and young adults (N = 176, ages 5- 25years), we replicated the adult association between KIBRA T-allele and larger DG and CA volumes but observed no relationship between KIBRA rs17070145 polymorphism and episodic memory. We noted, however, that a general cognitive performance index (IQ) differed across the allelic groups, with the lowest scores among T-homozygotes and the highest among C-homozygotes. Thus, in this developmental sample, KIBRA appears to have opposing effects on regional brain volume and cognition. These influences of KIBRA SNP may stem from associations between developmental reduction in brain volume and gains in cognitive performance-a hypothesis to be tested in longitudinal studies.

Combined Oxidative Phosphorylation Deficiency Type-13 with Perinatal Presentation: A Case Report.

Polynucleotide phosphorylase is involved in RNA processing in mitochondria. Biallelic variants in PNPT1 cause mitochondrial RNA import protein deficiency and heterogeneous clinical manifestations. The patiest was the first child of remote consanguineous parents, born at 35 weeks by caesarean section due to fetal growth restriction. Apgar index was 9/10/10. Birth weight, length and head circumference were at 3rd, <3rd and 10th percentiles, respectively. In the first hours of life, respiratory distress, hypoglycaemia and seizures ensued. She started invasive mechanic ventilation, phenobarbital and was transferred to ICU. Physical examination showed minor facial dysmorphisms, brief eye-opening, hypotonia and hyporeflexia. Electroencephalogram showed immature pattern and multifocal paroxysmal activity. MRI at D8 of life showed severe reduced brain volume. Normal aminoacid screen was also observed. Expanded newborn screening was negative. Mitochondrial organic aciduria was seen. WES showed a homozygotic likely pathogenic variant in the PNPT1 gene. MRI at 6-months showed brain atrophy, thin corpus callosum, reduced brainstem volume. Bilateral and symmetrical lesions in globi pallidi, compatible with Leigh síndrome were observed. Currently, at 14 months, no neurodevelopment progress, dystonia, visual deficit, sensorineural deafness, hypertrophic cardiomyopathy and microcephaly are observed. The early and severe Leigh-like presentation of our patient expands the phenotype spectrum of this disease. As far as we know, this is the first reported case of PNPT1 mutation with onset in the perinatal period. Moreover, hypertrophic cardiomyopathy has not yet been described in association with mutation of the PNPT1 gene. WES was the key for early diagnosis in this patient. It should be done in all children with severe clinical presentation of unknown origin.

Associations of hypertensive disorders of pregnancy with cognition, dementia, and brain structure: a Mendelian randomization study.

Observational studies have found associations between hypertensive disorders of pregnancy and an increased risk of cognitive dysfunction and reduced brain volume. However, the results of observational studies may have been influenced by confounding factors. This study applied two-sample Mendelian randomization (MR) to explore the causal associations of hypertensive disorders of pregnancy with cognition, dementia, and brain structure. Summary data on hypertensive disorders of pregnancy and their main subtypes, cognition, dementia, and brain structure were obtained from recent European genome-wide association studies. We computed the inverse-variance weighted, MR-Egger, and weighted median MR estimates. Cochran's Q statistics and the MR-Egger intercept test were used to quantify the heterogeneity and horizontal pleiotropy of the instrumental variables. Genetically predicted preeclampsia or eclampsia was inversely associated with gray matter volume [beta = -0.072; 95% confidence interval (CI) = -0.131 to -0.014; P = 1.53 × 10 -2 ]; possibly with brain volume (beta = -0.064; 95% CI = -0.117 to -0.012; P = 1.68 × 10 -2 ). However, the association of hypertensive pregnancy disorders or gestational hypertension with brain structure was not significant. We did not find any significant association between hypertensive disorders of pregnancy, gestational hypertension, or preeclampsia or eclampsia and cognition and dementia-related outcomes. This study provided genetic evidence supporting an association between preeclampsia or eclampsia and reduced brain volume. This supports the view of PE as a risk factor for gray matter volume reduction.