Structural brain abnormalities in 12 persons with aniridia.
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ABSTRACT:
SUBMITTER: Grant MK
PROVIDER: S-EPMC5615777 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To report the clinical and genetic study of patients with autosomal dominant aniridia.We studied ten patients with aniridia from three families of Egyptian origin. All patients underwent full ophthalmologic, general and neurological examination, and blood drawing. Cerebral magnetic resonance imaging was performed in the index case of each family. Genomic DNA was prepared from venous leukocytes, and direct sequencing of all the exons and intron-exon junctions of the Paired Box gene 6 (PAX6) was performed after PCR amplification. Phenotype description, including ophthalmic and cerebral anomalies, mutation detection in PAX6 and phenotype-genotype correlation was acquired.Common features observed in the three families included absence of iris tissue, corneal pannus with different degrees of severity, and foveal hypoplasia with severely reduced visual acuity. In Families 2 and 3, additional findings, such as lens dislocation, lens opacities or polar cataract, and glaucoma, were observed. We identified two novel (c.170-174delTGGGC [p.L57fs17] and c.475delC [p.R159fs47]) and one known (c.718C>T [p.R240X]) PAX6 mutations in the affected members of the three families. Systemic and neurological examination was normal in all ten affected patients. Cerebral magnetic resonance imaging showed absence of the pineal gland in all three index patients. Severe hypoplasia of the brain anterior commissure was associated with the p.L57fs17 mutation, absence of the posterior commissure with p.R159fs47, and optic chiasma atrophy and almost complete agenesis of the corpus callosum with p.R240X.We identified two novel PAX6 mutations in families with severe aniridia. In addition to common phenotype of aniridia and despite normal neurological examination, absence of the pineal gland and interhemispheric brain anomalies were observed in all three index patients. The heterogeneity of PAX6 mutations and brain anomalies are highlighted. This report emphasizes the association between aniridia and brain anomalies with or without functional impact, such as neurodevelopment delay or auditory dysfunction.
| S-EPMC2765237 | biostudies-literature
Project description:Type 2 diabetes mellitus has been linked to structural brain abnormalities, but evidence of the association among prediabetes and structural brain abnormalities has not been systematically evaluated. Comprehensive searching strategies and relevant studies were systematically retrieved from PubMed, Embase, Medline and web of science. Twelve articles were included overall. Stratified analyses and regression analyses were performed. A total of 104 468 individuals were included. The risk of infarct was associated with continuous glycosylated haemoglobin (HbA1c ) [adjusted odds ratio (OR) 1.19 (95% confidence interval [CI]: 1.05-1.34)], or prediabetes [adjusted OR 1.13 (95% CI: 1.00-1.27)]. The corresponding ORs associated with white matter hyperintensities were 1.08 (95%CI: 1.04-1.13) for prediabetes, and 1.10 (95%CI: 1.08-1.12) for HbA1c . The association was significant between the decreased risk of brain volume with continuous HbA1c (the combined OR 0.92, 95% CI: 0.87-0.98). Grey matter volume and white matter volume were inversely associated with prediabetes [weighted mean deviation (WMD), -9.65 (95%CI: -15.25 to -4.04) vs WMD, -9.25 (95%CI: -15.03 to -3.47)]. There were no significant association among cerebral microbleeds, hippocampal volume, continuous total brain volume, and prediabetes. Our findings demonstrated that (a) both prediabetes and continuous HbA1c were significantly associated with increasing risk of infarct or white matter hyperintensities; (b) continuous HbA1c was associated with a decreased risk of brain volume; (c) prediabetes was inversely associated with grey matter volume and white matter volume. To confirm these findings, further studies on early diabetes onset and structural brain abnormalities are needed.
| S-EPMC7685098 | biostudies-literature
Project description:ImportanceStructural brain abnormalities are prominent in psychotic disorders, including schizophrenia. However, it is unclear when aberrations emerge in the disease process and if such deficits are present in association with less severe psychosis spectrum (PS) symptoms in youth.ObjectiveTo investigate the presence of structural brain abnormalities in youth with PS symptoms.Design, setting, and participantsThe Philadelphia Neurodevelopmental Cohort is a prospectively accrued, community-based sample of 9498 youth who received a structured psychiatric evaluation. A subsample of 1601 individuals underwent neuroimaging, including structural magnetic resonance imaging, at an academic and children's hospital health care network between November 1, 2009, and November 30, 2011.Main outcomes and measuresMeasures of brain volume derived from T1-weighted structural neuroimaging at 3 T. Analyses were conducted at global, regional, and voxelwise levels. Regional volumes were estimated with an advanced multiatlas regional segmentation procedure, and voxelwise volumetric analyses were conducted as well. Nonlinear developmental patterns were examined using penalized splines within a general additive model. Psychosis spectrum (PS) symptom severity was summarized using factor analysis and evaluated dimensionally.ResultsFollowing exclusions due to comorbidity and image quality assurance, the final sample included 791 participants aged youth 8 to 22 years. Fifty percent (n = 393) were female. After structured interviews, 391 participants were identified as having PS features (PS group) and 400 participants were identified as typically developing comparison individuals without significant psychopathology (TD group). Compared with the TD group, the PS group had diminished whole-brain gray matter volume (P = 1.8 × 10-10) and expanded white matter volume (P = 2.8 × 10-11). Voxelwise analyses revealed significantly lower gray matter volume in the medial temporal lobe (maximum z score = 5.2 and cluster size of 1225 for the right and maximum z score = 4.5 and cluster size of 310 for the left) as well as in frontal, temporal, and parietal cortex. Volumetric reduction in the medial temporal lobe was correlated with PS symptom severity.Conclusions and relevanceStructural brain abnormalities that have been commonly reported in adults with psychosis are present early in life in youth with PS symptoms and are not due to medication effects. Future longitudinal studies could use the presence of such abnormalities in conjunction with clinical presentation, cognitive profile, and genomics to predict risk and aid in stratification to guide early interventions.
| S-EPMC5048443 | biostudies-literature
Project description:BackgroundPallister-Killian syndrome (PKS) is a rare multisystem developmental syndrome usually caused by mosaic tetrasomy of chromosome 12p that is known to be associated with neurological defects.MethodsWe describe two patients with PKS, one of whom has bilateral perisylvian polymicrogyria (PMG), the other with macrocephaly, enlarged lateral ventricles and hypogenesis of the corpus callosum. We have also summarized the current literature describing brain abnormalities in PKS.ResultsWe reviewed available cases with intracranial scans (n = 93) and found a strong association between PKS and structural brain abnormalities (77.41%; 72/93). Notably, ventricular abnormalities (45.83%; 33/72), abnormalities of the corpus callosum (25.00%; 18/72) and cerebral atrophy (29.17%; 21/72) were the most frequently reported, while macrocephaly (12.5%; 9/72) and PMG (4.17%; 3/72) were less frequent. To further understand how 12p genes might be relevant to brain development, we identified 63 genes which are enriched in the nervous system. These genes display distinct temporal as well as region-specific expression in the brain, suggesting specific roles in neurodevelopment and disease. Finally, we utilized these data to define minimal critical regions on 12p and their constituent genes associated with atrophy, abnormalities of the corpus callosum, and macrocephaly in PKS.ConclusionOur study reinforces the association between brain abnormalities and PKS, and documents a diverse neurogenetic basis for structural brain abnormalities and impaired function in children diagnosed with this rare disorder.
| S-EPMC5823685 | biostudies-literature
Project description:Our aim is to investigate the association of cerebral deep medullary veins (DMVs) with white matter microstructural integrity and regional brain atrophy in MRI. In a community-based cohort of 979 participants (mean age 55.4 years), DMVs were identified on susceptibility-weighted imaging. Brain structural measurements including gray matter and hippocampus volumes, as well as diffusion tensor metrics, were evaluated. The mean (SD)number of DMVs was 19.0 (1.7). A fewer number of DMVs was related to lower fractional anisotropy and higher mean diffusivity in multiple voxels on the white matter skeleton (threshold-free cluster enhancement corrected p < 0.05, adjusted for age and sex). Also, fewer DMVs were significantly related to a lower gray matter fraction and a hippocampal fraction (0.10 and 0.11 per DMV, respectively; SE, 0.03 for both; p < 0.001 for both). A significant correlation between DMVs' reduction and cortical atrophy was observed in the bilateral occipital lobes, temporal lobes, hippocampus, and frontal lobes (p < 0.001, adjusted for age, sex, and total intracranial volume). Our results provided evidence that cerebral small venules disease play a role in brain parenchymal lesions and neurodegenerative processes.
| S-EPMC9125483 | biostudies-literature
Project description:PAX6 encodes a highly conserved transcription factor necessary for normal development of the eyes and central nervous system. Heterozygous loss-of-function mutations in PAX6 cause the disorder aniridia in humans and the Small eye trait in mice. Aniridia is a congenital and progressive disorder known for ocular phenotypes; however, recently, consequences of PAX6 haploinsufficiency in the brains of aniridia patients have been identified. These findings span structural and functional abnormalities, including deficits in cognitive and sensory processing. Furthermore, some of these abnormalities are accelerated as aniridia patients age. Although some functional abnormalities may be explained by structural changes, variability of results remain, and the effects of PAX6 heterozygous loss-of-function mutations on neuroanatomy, particularly with regard to aging, have yet to be resolved. Our study used high-resolution magnetic resonance imaging (MRI) and histology to investigate structural consequences of such mutations in the adult brain of our aniridia mouse model, Small eye Neuherberg allele (Pax6SeyNeu/+), at two adult age groups. Using both MRI and histology enables a direct comparison with human studies, while providing higher resolution for detection of more subtle changes. We show volumetric changes in major brain regions of the the Pax6SeyNeu/+ mouse compared to wild-type including genotype- and age-related olfactory bulb differences, age-related cerebellum differences, and genotype-related eye differences. We also show alterations in thickness of major interhemispheric commissures, particularly those anteriorly located within the brain including the optic chiasm, corpus callosum, and anterior commissure. Together, these genotype and age related changes to brain volumes and structures suggest a global decrease in adult brain structural plasticity in our Pax6SeyNeu/+ mice.
| S-EPMC10712278 | biostudies-literature
Project description:Mutations in the EPM2A and EPM2B genes, encoding laforin and malin proteins respectively, are responsible for Lafora disease, a fatal form of progressive myoclonus epilepsy with autosomal recessive inheritance. Neuroimaging studies of patients with Lafora disease have shown different degrees of brain atrophy, decreased glucose brain uptake and alterations on different brain metabolites mainly in the frontal cortex, basal ganglia and cerebellum. Mice deficient for laforin and malin present many features similar to those observed in patients, including cognitive, motor, histological and epileptic hallmarks. We describe the neuroimaging features found in two mouse models of Lafora disease. We found altered volumetric values in the cerebral cortex, hippocampus, basal ganglia and cerebellum using magnetic resonance imaging (MRI). Positron emission tomography (PET) of the cerebral cortex, hippocampus and cerebellum of Epm2a-/- mice revealed abnormal glucose uptake, although no alterations in Epm2b-/- mice were observed. Magnetic resonance spectroscopy (MRS) revealed significant changes in the concentration of several brain metabolites, including N-acetylaspartate (NAA), in agreement with previously described findings in patients. These data may provide new insights into disease mechanisms that may be of value for developing new biomarkers for diagnosis, prevention and treatment of Lafora disease using animal models.
| S-EPMC7589150 | biostudies-literature
Project description:BackgroundPrevious voxel-based morphometric (VBM) and functional magnetic resonance imaging (fMRI) studies have shown changes in brain structure and function in cocaine addiction (CD) patients compared to healthy controls (HC). However, the results of these studies are poorly reproducible, and it is unclear whether there are common and specific neuroimaging changes. This meta-analysis study aimed to identify structural, functional, and multimodal abnormalities in CD patients.MethodsThe PubMed database was searched for VBM and task-state fMRI studies performed in CD patients between January 1, 2010, and December 31, 2021, using the SEED-BASE d MAP software package to perform two independent meta-groups of functional neural activation and gray matter volume, respectively. Analysis, followed by multimodal analysis to uncover structural, functional, and multimodal abnormalities between CD and HC.ResultsThe meta-analysis included 14 CD fMRI studies (400 CD patients and 387 HCs) and 11 CD VBM studies (368 CD patients and 387 controls). Structurally, VBM analysis revealed significantly lower gray matter volumes in the right superior temporal gyrus, right insula, and right retrocentral gyrus than in the HC. On the other hand, the right inferior parietal gyrus increased in gray matter (GM) volume in CD patients. Functionally, fMRI analysis revealed activation in the right temporal pole, right insula, and right parahippocampal gyrus. In the right inferior parietal gyrus, the left inferior parietal gyrus, the left middle occipital gyrus, and the right middle frontal gyrus, the degree of activation was lower.ConclusionThis meta-analysis showed that CD patients had significant brain GM and neural changes compared with normal controls. Furthermore, multi-domain assessments capture different aspects of neuronal alterations in CD, which may help develop effective interventions for specific functions.
| S-EPMC9263080 | biostudies-literature
Project description:AIMS:Urgency urinary incontinence (UUI) is a major problem for seniors. The underlying mechanisms of disease and therapy are unknown. We sought structural brain abnormalities that might underlie the functional differences previously observed by functional Magnetic Resonance Imaging in UUI patients versus controls, or among UUI responders versus non-responders to therapy-and thereby reveal potential disease mechanisms and therapeutic targets. METHODS:Secondary study of a trial of biofeedback-assisted pelvic floor muscle training (BFB) in 60 women (>60 yrs) with UUI, plus 11 age-matched continent controls. Brain structural abnormalities were investigated using: (1) white-matter hyperintensities (WMH); (2) diffusion tensor imaging (DTI) to reveal white-matter pathways with impaired integrity; and (3) voxel-based morphometry (VBM) to show regions of atrophy or hypertrophy. RESULTS:WMH burden was greater in UUI patients than controls (globally and in superior longitudinal fasciculus and cingulum), suggesting a possible causal connection. WMH burden was unexpectedly greater in responders than non-responders to BFB, and appeared to increase in non-responders but not in responders. DTI revealed even worse integrity of the cingulum than was apparent by WMH. VBM showed parahippocampal atrophy in UUI. CONCLUSIONS:Many women with UUI have white-matter damage that interferes with pathways critical to bladder control; they can be taught by techniques like BFB to exert stronger control over the bladder. For others, in whom abnormalities of key brain areas are less marked, UUI's cause may reside elsewhere, and therapy targeting these brain centers may be less effective than therapy targeting the bladder or other brain centers.
| S-EPMC6473817 | biostudies-literature
Project description:ObjectiveTo determine the association between brain MRI abnormalities and incident epilepsy in older adults.MethodsMen and women (ages 45-64 years) from the Atherosclerosis Risk in Communities study were followed up from 1987 to 2018 with brain MRI performed between 2011 and 2013. We identified cases of incident late-onset epilepsy (LOE) with onset of seizures occurring after the acquisition of brain MRI. We evaluated the relative pattern of cortical thickness, subcortical volume, and white matter integrity among participants with incident LOE after MRI in comparison with participants without seizures. We examined the association between MRI abnormalities and incident LOE using Cox proportional hazards regression. Models were adjusted for demographics, hypertension, diabetes, smoking, stroke, and dementia status.ResultsAmong 1251 participants with brain MRI data, 27 (2.2%) developed LOE after MRI over a median of 6.4 years (25-75 percentile 5.8-6.9) of follow-up. Participants with incident LOE after MRI had higher levels of cortical thinning and white matter microstructural abnormalities before seizure onset compared to those without seizures. In longitudinal analyses, greater number of abnormalities was associated with incident LOE after controlling for demographic factors, risk factors for cardiovascular disease, stroke, and dementia (gray matter: hazard ratio [HR]: 2.3, 95% confidence interval [CI]: 1.0-4.9; white matter diffusivity: HR: 3.0, 95% CI: 1.2-7.3).InterpretationThis study demonstrates considerable gray and white matter pathology among individuals with LOE, which is present prior to the onset of seizures and provides important insights into the role of neurodegeneration, both of gray and white matter, and the risk of LOE.
| S-EPMC10863905 | biostudies-literature