Ganglia Volumes Research Articles

Iron deficiency and internalizing symptom severity in unmedicated adolescents: a pilot study.

Iron plays a key role in a broad set of metabolic processes. Iron deficiency is the most common nutritional deficiency in the world, but its neuropsychiatric implications in adolescents have not been examined. Twelve- to 17-year-old unmedicated females with major depressive or anxiety disorders or with no psychopathology underwent a comprehensive psychiatric assessment for this pilot study. A T1-weighted magnetic resonance imaging scan was obtained, segmented using Freesurfer. Serum ferritin concentration (sF) was measured. Correlational analyses examined the association between body iron stores, psychiatric symptom severity, and basal ganglia volumes, accounting for confounding variables. Forty females were enrolled, 73% having a major depressive and/or anxiety disorder, 35% with sF < 15 ng/mL, and 50% with sF < 20 ng/mL. Serum ferritin was inversely correlated with both anxiety and depressive symptom severity (r = -0.34, p < 0.04 and r = -0.30, p < 0.06, respectively). Participants with sF < 15 ng/mL exhibited more severe depressive and anxiety symptoms as did those with sF < 20 ng/mL. Moreover, after adjusting for age and total intracranial volume, sF was inversely associated with left caudate (Spearman's r = -0.46, p < 0.04), left putamen (r = -0.58, p < 0.005), and right putamen (r = -0.53, p < 0.01) volume. Brain iron may become depleted at a sF concentration higher than the established threshold to diagnose iron deficiency (i.e. 15 ng/mL), potentially disrupting brain maturation and contributing to the emergence of internalizing disorders in adolescents.

Perivascular space volumes relate to arterial stiffness and cognition

AbstractBackgroundEnlarged perivascular spaces (PVS) are a marker of small vessel disease (SVD). PVS in the basal ganglia are associated with hypertensive damage to arteries and arterioles; however, prior work relating arterial stiffness to changes in PVS have been inconclusive. Additionally, clinical consequences of PVS are poorly understood, possibly due to reliance on manual rating systems that lack precision. This study used an automated process to measure basal ganglia PVS count and volume and cross‐sectionally assess their associations with central arterial stiffness and cognition.MethodVanderbilt Memory and Aging Project participants free of clinical stroke and dementia (n=327, 73±7 years, 41% female) completed T1‐weighted brain MRI to measure PVS burden, neuropsychological assessment, and cardiac MR to quantify pulse wave velocity (PWV) in the thoracic aorta, a marker of central arterial stiffness. PVS volume and count were quantified using an automated approach. Basal ganglia volume and count measures were log‐transformed. Linear regression models related PWV separately to PVS volume and count adjusting for demographic and health variables, apolipoprotein E‐e4 status, and intracranial volume. Models were repeated separately relating PVS volume and count to neuropsychological performance with identical covariates.ResultHigher PWV related to greater basal ganglia PVS volume (b=7.0e‐5, p=0.04) and count (b=0.02, p=0.03). When excluding outliers, PVS volume results were attenuated (p=0.17) but count results persisted (p=0.03). Higher PVS volume was associated with worse sequencing (b=1560, p=0.002), digit symbol (b=‐979, p=0.003), executive function (b=‐82.3, p&lt;0.001), and visuospatial performances (b=‐193, p=0.02). Cognitive results were comparable for models using PVS count as the predictor.ConclusionCentral arterial stiffness is associated with greater PVS burden in the basal ganglia. Findings support the hypothesis that increased aortic stiffness and resulting changes in hemodynamics essential for maintaining perfusion pressure may result in PVS damage. Greater PVS burden is associated with worse cognitive performance, primarily on tests of executive function and information processing, aligning with our prior findings relying on a manual PVS rating system. PVS may account for damage to frontal subcortical networks which integrate the basal ganglia and play an important role in executive function and information processing. Funding: F31‐AG066358, T32‐AG058524, Alzheimer’s Association IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082

Atypical development of Broca's area in a large family with inherited stuttering.

Developmental stuttering is a condition of speech dysfluency, characterized by pauses, blocks, prolongations and sound or syllable repetitions. It affects around 1% of the population, with potential detrimental effects on mental health and long-term employment. Accumulating evidence points to a genetic aetiology, yet gene-brain associations remain poorly understood due to a lack of MRI studies in affected families. Here we report the first neuroimaging study of developmental stuttering in a family with autosomal dominant inheritance of persistent stuttering. We studied a four-generation family, 16 family members were included in genotyping analysis. T1-weighted and diffusion-weighted MRI scans were conducted on seven family members (six male; aged 9-63 years) with two age and sex matched controls without stuttering (n = 14). Using Freesurfer, we analysed cortical morphology (cortical thickness, surface area and local gyrification index) and basal ganglia volumes. White matter integrity in key speech and language tracts (i.e. frontal aslant tract and arcuate fasciculus) was also analysed using MRtrix and probabilistic tractography. We identified a significant age by group interaction effect for cortical thickness in the left hemisphere pars opercularis (Broca's area). In affected family members this region failed to follow the typical trajectory of age-related thinning observed in controls. Surface area analysis revealed the middle frontal gyrus region was reduced bilaterally in the family (all cortical morphometry significance levels set at a vertex-wise threshold of P < 0.01, corrected for multiple comparisons). Both the left and right globus pallidus were larger in the family than in the control group (left P = 0.017; right P = 0.037), and a larger right globus pallidus was associated with more severe stuttering (rho = 0.86, P = 0.01). No white matter differences were identified. Genotyping identified novel loci on chromosomes 1 and 4 that map with the stuttering phenotype. Our findings denote disruption within the cortico-basal ganglia-thalamo-cortical network. The lack of typical development of these structures reflects the anatomical basis of the abnormal inhibitory control network between Broca's area and the striatum underpinning stuttering in these individuals. This is the first evidence of a neural phenotype in a family with an autosomal dominantly inherited stuttering.

Antipsychotic treatment effects and structural MRI brain changes in schizophrenia.

Progressive brain structural MRI changes are described in schizophrenia and have been ascribed to both illness progression and antipsychotic treatment. We investigated treatment effects, in terms of total cumulative antipsychotic dose, efficacy and tolerability, on brain structural changes over the first 24 months of treatment in schizophrenia. A prospective, 24-month, single-site cohort study in 99 minimally treated patients with first-episode schizophrenia, schizophreniform and schizoaffective disorder, and 98 matched healthy controls. We treated the patients according to a fixed protocol with flupenthixol decanoate, a long-acting injectable antipsychotic. We assessed psychopathology, cognition, extrapyramidal symptoms and BMI, and acquired MRI scans at months 0, 12 and 24. We selected global cortical thickness, white matter volume and basal ganglia volume as the regions of interest. The only significant group × time interaction was for basal ganglia volumes. However, patients, but not controls, displayed cortical thickness reductions and increases in white matter and basal ganglia volumes. Cortical thickness reductions were unrelated to treatment. White matter volume increases were associated with lower cumulative antipsychotic dose, greater improvements in psychopathology and cognition, and more extrapyramidal symptoms. Basal ganglia volume increases were associated with greater improvements in psychopathology, greater increases in BMI and more extrapyramidal symptoms. We provide evidence for plasticity in white matter and basal ganglia associated with antipsychotic treatment in schizophrenia, most likely linked to the dopamine blocking actions of these agents. Cortical changes may be more closely related to the neurodevelopmental, non-dopaminergic aspects of the illness.

A volumetric magnetic resonance imaging study in migraine

BackgroundAlthough migraine phenotype has been widely described, the explanation of migraine pathophysiology still has a gap that might be partly bridged by neuroimaging investigations. The aim of the study is to assess volumetric brain changes in migraineurs compared with controls, and in episodic migraine in comparison to chronic type. Structural brain changes in migraineurs (with and without aura) were assessed by an automated segmentation method (Free Surfer). T1-weighted MRIs of 25 migraineurs (14 diagnosed as episodic type and 11 diagnosed as chronic migraine) and 25 headache-free controls were evaluated and processed.ResultsMigraine patients had significant reduction of the volume of total brain, grey matter, brain stem, cerebellum, basal ganglia, thalamus, hippocampus and amygdala in comparison to control subjects. Patients with chronic migraine had significant reduction in volume of total brain, grey matter, cerebellum and frontal lobe thickness in comparison to those with episodic migraine.ConclusionMigraineurs showed volumetric brain changes mainly in areas related to central processing of pain and in areas specific for migraine (such as brain stem) when compared to healthy controls. Chronic migraineurs showed significant reduction in grey matter, in areas involved in processing of pain, cognition and multisensory integration versus patients with episodic migraine, which adds insight into the pathophysiology of migraine as a progressive disorder that may have long-term impacts on the brain as regards structure and function.

Basal ganglia shape features differentiate schizoaffective disorder from schizophrenia

There is growing evidence that schizophrenia and schizoaffective disorder represent closely related syndromes that vary in severity along a neurobiological continuum. In the present study, volume and shape of the basal ganglia was examined in people with schizophrenia and schizoaffective disorder relative to healthy controls and hypothesized that unique neuroanatomical differences would be observed in each patient group. Magnetic resonance 1.5T images were obtained from schizophrenia (n = 47), schizoaffective disorder (n = 15), and from healthy control (n = 42) participants, matched for age, gender, parental socioeconomic status, and race. The caudate, putamen, and globus pallidus were characterized using high-dimensional brain mapping procedures (Csernansky et al., 2004b). Results revealed significant shape deformations between schizophrenia and schizoaffective disorder that also differed from control subjects. Relative to schizophrenia, schizoaffective subjects showed exaggerated inward deformations indicative of localized volume loss in subregions of the caudate, putamen, and globus pallidus (all p < 0.001). These shape features correlated with mental flexibility and negative symptoms in schizophrenia (all p < 0.05), but not schizoaffective disorder. To the extent that differences in important basal ganglia substructures reflect biological heterogeneity among these two psychotic illnesses, this data could prove useful in improving diagnostic precision, as well as informing the affective component of mental illness.

Changes of Dorsal Root Ganglion Volume in Dogs with Clinical Signs of Degenerative Myelopathy Detected by Water-Excitation Magnetic Resonance Imaging.

Simple SummaryCanine degenerative myelopathy (DM) is a chronic, progressive, and fatal neurodegenerative disease. Although degenerative changes in dogs with DM are observed not only in the spinal cord white matter but also the dorsal root ganglion (DRG) neurons, these changes are undetectable on conventional magnetic resonance imaging (MRI). Therefore, we investigated the ability of water-excitation MRI to visualize the DRG in dogs, and whether volumetry of DRG has a premortem diagnostic value for DM. Using water-excitation MRI, DRG could be depicted in all dogs. To normalize the volumes of DRG, body surface area was the most suitable denominator. The normalized DRG volume in dogs with DM was significantly lower than those in control dogs and dogs with intervertebral disc herniation. The results of this study revealed that widespread atrophy of DRG was likely to occur in DM. Moreover, volume reductions of DRG were observed in dogs with DM in both the early disease stage and late disease stage. Our research suggests that the DRG volume obtained by the water-excitation technique could be used as a clinical biomarker for DM.Canine degenerative myelopathy (DM) is a progressive and fatal neurodegenerative disease. However, a definitive diagnosis of DM can only be achieved by postmortem histopathological examination of the spinal cord. The purpose of this study was to investigate whether the volumetry of DRG using the ability of water-excitation magnetic resonance imaging (MRI) to visualize the DRG in dogs has premortem diagnostic value for DM. Eight dogs with DM, twenty-four dogs with intervertebral disc herniation (IVDH), and eight control dogs were scanned using a 3.0-tesla MRI system, and water-excitation images were obtained to visualize and measure the volume of DRG, normalized by body surface area. The normalized mean DRG volume between each spinal cord segment and mean volume of all DRG between T8 and L2 in the DM group was significantly lower than that in the control and the IVDH groups (P = 0.011, P = 0.002, respectively). There were no correlations within the normalized mean DRG volume between DM stage 1 and stage 4 (rs = 0.312, P = 0.128, respectively). In conclusion, DRG volumetry by the water-excitation MRI provides a non-invasive and quantitative assessment of neurodegeneration in DRG and may have diagnostic potential for DM.

Decreased Basal Ganglia Volume in Cerebral Amyloid Angiopathy.

Background and PurposeCerebral amyloid angiopathy (CAA) is a common pathology of the leptomeningeal and cortical small vessels associated with hemorrhagic and non-hemorrhagic brain injury. Given previous evidence for CAA-related loss of cortical thickness and white matter volume, we hypothesized that CAA might also cause tissue loss in the basal ganglia. MethodsWe compared basal ganglia volumes expressed as a percentage of total intracranial volume (pBGV) of non-demented patients with sporadic and hereditary CAA to age-matched healthy control (HC) and Alzheimer’s disease (AD) cohorts. ResultsPatients with sporadic CAA had lower pBGV (n=80, 1.16%±0.14%) compared to HC (n=80, 1.30%±0.13%, P<0.0001) and AD patients (n=80, 1.23%±0.11%, P=0.001). Similarly, patients with hereditary CAA demonstrated lower pBGV (n=25, 1.26%±0.17%) compared to their matched HC (n=25, 1.36%±0.15%, P=0.036). Using a measurement of normalized basal ganglia width developed for analysis of clinical-grade magnetic resonance images, we found smaller basal ganglia width in patients with CAA-related lobar intracerebral hemorrhage (ICH; n=93, 12.35±1.47) compared to age-matched patients with hypertension-related deep ICH (n=93, 13.46±1.51, P<0.0001) or HC (n=93, 15.45±1.22, P<0.0001). Within the sporadic CAA research cohort, decreased basal ganglia volume was independently correlated with greater cortical gray matter atrophy (r=0.45, P<0.0001), increased basal ganglia fractional anisotropy (r=–0.36, P=0.001), and worse performance on language processing (r=0.35, P=0.003), but not with cognitive tests of executive function or processing speed. ConclusionsThese findings suggest an independent effect of CAA on basal ganglia tissue loss, indicating a novel mechanism for CAA-related brain injury and neurologic dysfunction.

Orthoptic assessment of vision in patients with complex disability: the importance of understanding the patient’s communication methods

ABSTRACT Care for children with acquired brain injury requires a multi-disciplinary team (MDT) to maximize rehabilitation. These children frequently present to the orthoptic clinic with complex difficulties impacting visual functions and eye movements. We report on one case which led to a reevaluation of our current assessment methods, clinical care pathways and the contents of clinic correspondence. We present a case report of a 14-year-old girl who suffered a cardiac arrest due to underlying Wolff–Parkinson–White syndrome; MRI revealed hypoxic brain injury with extensive white matter and basal ganglia volume loss. On presentation, it was evident there was a significant impact on visual function. Conventional optotype acuity testing was not possible. Her inability to maintain fixation made observational responses unreliable. Observations revealed no steady fixation, exotropia and roving eye movements. Although she was reported to be unable to speak, progress with communication was reported and she was able to give repeatable, reliable responses to indicate “yes” or “no.” These cues were used and a response of 1.70 cycles per degree was obtained under binocular conditions. This communication method was also utilized to assess visual fields by confrontation. However, the clinic letter written by the ophthalmologist based on the orthoptic assessment simply provided the acuity score with no interpretation of the information or how it was obtained. This case highlighted the importance of understanding a child’s communication methods so that assessment can be appropriately adapted. The referral letter was lacking in detail regarding the patient’s abilities but equally the ophthalmology letter provided limited detail impacting on the MDT practitioner’s ability to understand and apply the information. This case has highlighted the importance of good communication: professionals need to acknowledge and work with an individual’s communication methods so that assessment can be completed. Professionals also need to improve communication of relevant findings to others involved in the patient’s care.

A longitudinal study of the association between basal ganglia volumes and psychomotor symptoms in subjects with late life depression undergoing ECT

Psychomotor dysfunction (PMD) is a core element and key contributor to disability in late life depression (LLD), which responds well to electroconvulsive therapy (ECT). The neurobiology of PMD and its response to ECT are not well understood. We hypothesized that PMD in LLD is associated with lower striatal volume, and that striatal volume increase following ECT explains PMD improvement. We analyzed data from a two-center prospective cohort study of 110 LLD subjects (>55 years) receiving ECT. Brain MRI and assessment of mood, cognition, and PMD was performed 1 week before, 1 week after, and 6 months after ECT. Volumetry of the caudate nucleus, putamen, globus pallidus, and nucleus accumbens was derived from automatically segmented brain MRIs using Freesurfer®. Linear multiple regression analyses were used to study associations between basal ganglia volume and PMD. Brain MRI was available for 66 patients 1 week post ECT and in 22 patients also six months post ECT. Baseline PMD was associated with a smaller left caudate nucleus. One week after ECT, PMD improved and volume increases were detected bilaterally in the caudate nucleus and putamen, and in the right nucleus accumbens. Improved PMD after ECT did not relate to the significant volume increases in these structures, but was predicted by a nonsignificant volume change in the right globus pallidus. No volume differences were detected 6 months after ECT, compared to baseline. Although PMD is related to lower striatal volume in LLD, ECT-induced increase of striatal volume does not explain PMD improvement.

Ganglionic Eminence Anomalies and Coexisting Cerebral Developmental Anomalies on Fetal MR Imaging: Multicenter-Based Review of 60 Cases.

The ganglionic eminences are transient fetal brain structures that produce a range of neuron types. Ganglionic eminence anomalies have been recognized on fetal MR imaging and anecdotally found in association with a number of neurodevelopmental anomalies. The aim of this exploratory study was to describe and analyze the associations between ganglionic eminence anomalies and coexisting neurodevelopmental anomalies. This retrospective study includes cases of ganglionic eminence anomalies diagnosed on fetal MR imaging during a 20-year period from 7 centers in Italy and England. Inclusion criteria were cavitation or increased volume of ganglionic eminences on fetal MR imaging. The studies were analyzed for associated cerebral developmental anomalies: abnormal head size and ventriculomegaly, reduced opercularization or gyration, and abnormal transient layering of the developing brain mantle. The results were analyzed using χ2 and Fisher exact tests. Sixty fetuses met the inclusion criteria (21 females, 24 males, 15 sex unknown). Thirty-four had ganglionic eminence cavitations (29 bilateral and 5 unilateral), and 26 had increased volume of the ganglionic eminences (19 bilateral, 7 unilateral). Bilateral ganglionic eminence cavitations were associated with microcephaly (P = .01), reduced opercularization, (P < .001), reduced gyration (P < .001), and cerebellar anomalies (P = .01). Unilateral ganglionic eminence cavitations were not significantly associated with any particular feature. Bilateral increased volume of the ganglionic eminences showed an association with macrocephaly (P = .03). Unilateral increased volume was associated with macrocephaly (P = .002), abnormal transient layering (P = .001), unilateral polymicrogyria (P = .001), and hemimegalencephaly (P < .001). Ganglionic eminence anomalies are associated with specific neurodevelopmental anomalies with ganglionic eminence cavitations and increased ganglionic eminence volume apparently having different associated abnormalities.

Neurotoxicity studies with a tropomyosin-related kinase A inhibitor, ASP7962, on the sympathetic and sensory nervous systems in rats

ASP7962 is a small molecule inhibitor for the nerve growth factor (NGF) receptor, tropomyosin-related kinase A (TrkA). NGF contributes to the survival of sensory and sympathetic neurons through TrkA receptor activation. Gross, microscopic, and quantitative effects to the nervous system were evaluated following oral ASP7962 administration to Sprague Dawley rats for 4 weeks and 13 weeks and after a recovery period. Histopathological findings included reversible neuronal atrophy but no neuronal death in the sympathetic ganglia (cervicothoracic ganglion, cranial mesenteric ganglion or superior [cranial] cervical ganglion). Stereological analysis showed reversible decreased ganglion volume and/or decreased neuron size in the superior (cranial) cervical ganglion in both the 4-week and the 13-week repeated dose studies. There were no test article related changes in the brain, dorsal root ganglia with spinal nerve roots or trigeminal ganglia and no functional deficits. ASP7962 did not cause any detectable dysfunction of the sympathetic and sensory nervous system in either study.

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to examine age‐related trajectories inferred from cross‐sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter‐individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age‐related morphometric patterns.

Late-onset Huntington disease: An Italian cohort

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG expansion greater than 35 triplets in the IT-15 gene, with a clinical onset usually in the forties. Late-onset form of HD is defined as disease onset after the age of 59 years. The aim of the present study is to investigate the clinical-demographic features of Late-onset HD population (LoHD) in comparison to Classic-onset patients (CoHD).We analyzed a well-characterized Italian cohort of 127 HD patients, identifying 25.2% of LoHD cases. The mean age of onset was 65.9 and the mean length of pathological allele was 42.2. The 53.1% of LoHD patients had no family history of HD. No significant differences were observed in terms of gender, type of symptoms at disease onset, and clinical performance during the follow-up visits. The non-pathological allele resulted longer among LoHD patients. There is evidence that longer non-pathological allele is associated with a higher volume of basal ganglia, suggesting a possible protective role even in the onset of HD. In conclusion, LoHD patients in this Italian cohort were frequent, representing a quarter of total cases, and showed clinical features comparable to CoHD subjects. Due to the small sample size, further studies are needed to evaluate the influence of non-pathological alleles on disease onset.

Morphological Abnormalities in the Basal Ganglia of Dystonia Patients

Objective: The pathophysiology of dystonia is poorly understood. As opposed to secondary forms of dystonia, primary dystonia has long been believed to lack any neuroanatomical substrate. During trajectory planning for DBS, however, conspicuous T2-hyperinstensive signal alterations (SA) were registered within the target region, even in young patients, where ischemia is rare. Methods: Fifty MRIs of primary dystonia patients scheduled for DBS were analyzed. Total basal ganglia (BG) volumes, as well as proportionate SA volumes, were measured and compared to 50 age-matched control patients. Results: There was a 10-fold preponderance of percentaged SA within the globus pallidus (GP) in dystonia patients. The greatest disparity was in young patients <25 years. Also, total BG volume differences were observed with larger GP and markedly smaller putamen and caudate in the dystonia group. Conclusions: BG morphology in primary dystonia differed from a control population. Volume reductions of the putamen and caudate may reflect functional degeneration, while volume increases of the GP may indicate overactivity. T2-hyperintensive SA in the GP of young primary dystonia patients, where microvascular lesions are highly unlikely, are striking. Their pathogenic role remains unclear.

Assessment of Peripheral Nervous System Alterations in Patients with the Fabry Related GLA-Variant p.A143T.

The purpose of this study is to examine alterations of the peripheral nervous system (PNS) in oligo-symptomatic patients carrying the Fabry related GLA-gene variant p.A143T by Magnetic Resonance Neurography (MRN) and skin biopsy. This prospective study assessed dorsal root ganglia (DRG) volume L3 to S2, vascular permeability of the DRG L5, S1, and the spinal nerve L5 in five patients carrying p.A143T in comparison to patients with classical Fabry mutations and healthy controls. Moreover, skin punch biopsies above the lateral malleolus of the right foot were obtained in four patients and intraepidermal nerve fiber density (IENFD) was counted individually. Compared to controls, DRG volumes of p.A143T patients were enlarged by 30% (L3, p < 0.05), 35% (L4, p < 0.05), 29% (L5, p = 0.15), 36% (S1, p < 0.01), and 18% (S2, p < 0.05), but less pronounced compared to patients carrying a classical Fabry mutation. Compared to healthy controls, vascular permeability was decreased by 40% (L5 right), 49% (L5 left), 48% (S1 right), and 49% (S1) (p < 0.01–p < 0.001), but non-significant less than patients carrying a classical Fabry mutation. Compared to sex-matched 5% lower normative reference values per decade, IENFD was decreased in three of four patients. MRN and determination of IENFD is able to detect early alteration of the PNS segment in oligo-symptomatic patients with the disease-modifying GLA-variant p.A143T on an individual basis. This procedure might also help in further GLA-variants of uncertain significance for early identification of patients with single major organ manifestation.

Early parenting is associated with the developing brains of children born very preterm

Objective Examine relationships between parenting and brain structure and growth in children born very preterm (VPT). Methods Participants were 118 children born VPT (<30weeks’ gestation or <1,250 g birth weight) and their parents. Parenting behavior was observed at 2 years’ corrected age. Brain magnetic resonance imaging scans were performed at term equivalent age and 7 years’ corrected age with brain volumes and white matter microstructure analyzed. Results More sensitive parenting at 2 years was associated with larger basal ganglia volumes at 7 years for boys, greater growth in basal ganglia volume from term to 7 years, and greater growth in amygdala volume growth for boys. More intrusive parenting was associated with smaller intracranial and grey matter volumes at 7 years, as well as lower fractional anisotropy and higher radial diffusivity in the cerebellar white matter, cerebral peduncle, corticospinal tract, anterior thalamic radiation, and superior longitudinal fasciculus at 7. Conclusions Early positive parenting may be more strongly associated with subcortical brain development for boys born VPT, while early intrusive parenting may be associated with smaller cortical brain volumes and altered white matter microstructure in children born VPT.

MRI-based brain volumetry and retinal optical coherence tomography as the biomarkers of outcome in acute methanol poisoning

BackgroundBasal ganglia lesions are typical findings on magnetic resonance imaging (MRI) of the brain in survivors of acute methanol poisoning. However, no data are available on the association between the magnitude of damaged brain regions, serum concentrations of markers of acute methanol toxicity, oxidative stress, neuroinflammation, and the rate of retinal nerve ganglion cell loss. ObjectivesTo investigate the association between MRI-based volumetry of the basal ganglia, retinal nerve fibre layer (RNFL) thickness and prognostic laboratory markers of outcomes in acute methanol poisoning. MethodsMRI-based volumetry of putamen, nucleus caudatus and globus pallidus was performed and compared with laboratory parameters of severity of poisoning and acute serum markers of oxidative damage of lipids (8-isoprostan, MDA, HHE, HNE), nucleic acids (8−OHdG, 8−OHG, 5−OHMU), proteins (o-Thyr, NO-Thyr, Cl-Thyr) and leukotrienes (LTC4, LTD4, LTE4, LTB4), as well as with the results of RNFL measurements by optic coherence tomography (OCT) in 16 patients with acute methanol poisoning (Group I) and in 28 survivors of poisoning two years after discharge with the same markers measured within the follow-up examination (Group II). The control group consisted of 28 healthy subjects without methanol poisoning. ResultsThe survivors of acute methanol poisoning had significantly lower volumes of basal ganglia than the controls. The patients with MRI signs of methanol-induced toxic brain damage had significantly lower volumes of basal ganglia than those without these signs. A positive correlation was found between the volume of putamen and arterial blood pH on admission (r = 0.45; p = 0.02 and r = 0.44; p = 0.02 for left and right putamen, correspondingly). A negative correlation was present between the volumes of putamen and acute serum lactate (r = -0.63; p < 0.001 and r = -0.59; p = 0.01), creatinine (r = -0.53; p = 0.01 and r = -0.47; p = 0.01) and glucose (r = -0.55; p < 0.001 and r = -0.50; p = 0.01) concentrations.The volume of basal ganglia positively correlated with acute concentrations of markers of lipoperoxidation (8-isoprostan: r = 0.61; p < 0.05 and r = 0.59; p < 0.05 for left and right putamen, correspondingly) and inflammation (leukotriene LTB4: r = 0.61; p < 0.05 and r = 0.61; p < 0.05 for left and right putamen, correspondingly). The higher the volume of the basal ganglia, the higher the thickness of the RNFL, with the strongest positive association between global RNFL and the volume of putamen bilaterally (all p < 0.01). In the follow-up markers of oxidative stress and inflammation, only o-Thyr concentration negatively correlated with the volume of putamen bilaterally (r = –0.39; p < 0.05 and r = –0.37; p < 0.05 for left and right putamen, correspondingly). ConclusionIn survivors of acute methanol poisoning with signs of toxic brain damage, the magnitude of affected areas correlated with acute parameters of severity of poisoning, markers of oxidative stress and neuroinflammation. There was a positive association between the basal ganglia volume and the thickness of RNFL, making OCT an important screening test and MRI-based volumetry the confirmative diagnostic method for the detection of CNS sequelae of methanol poisoning.

Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) patients. We studied 38 children with NMDARE (median age = 12.9 years, range =1-18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed-effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity. Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid-attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed-effect models and z score transformation showed failure of age-expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31-9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51-17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68-24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47-9.82, p = 0.031) as independent predictors of poor clinical outcome. Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020 ANN NEUROL 2020;88:148-159.

Robust, 3-Dimensional Visualization of Human Colon Enteric Nervous System Without Tissue Sectioning

Small, 2-dimensional sections routinely used for human pathology analysis provide limited information about bowel innervation. We developed a technique to image human enteric nervous system (ENS) and other intramural cells in 3 dimensions. Using mouse and human colon tissues, we developed a method that combines tissue clearing, immunohistochemistry, confocal microscopy, and quantitative analysis of full-thickness bowel without sectioning to quantify ENS and other intramural cells in 3 dimensions. We provided 280 adult human colon confocal Z-stacks from persons without known bowel motility disorders. Most of our images were of myenteric ganglia, captured using a 20× objective lens. Full-thickness colon images, viewed with a 10× objective lens, were as large as 4× 5 mm2. Colon from 2 pediatric patients with Hirschsprung disease was used to show distal colon without enteric ganglia, as well as a transition zone and proximal pull-through resection margin where ENS was present. After testing a panel of antibodies with our method, we identified 16 antibodies that bind to molecules in neurons, glia, interstitial cells of Cajal, and muscularis macrophages. Quantitative analyses demonstrated myenteric plexus in 24.5% ± 2.4% of flattened colon Z-stack area. Myenteric ganglia occupied 34% ± 4% of myenteric plexus. Single myenteric ganglion volume averaged 3,527,678 ± 573,832 mm3 with 38,706 ± 5763 neuron/mm3 and 129,321 ± 25,356 glia/mm3. Images of large areas provided insight into why published values of ENS density vary up to 150-fold-ENS density varies greatly, across millimeters, so analyses of small numbers of thin sections from the same bowel region can produce varying results. Neuron subtype analysis revealed that approximately 56% of myenteric neurons stained with neuronal nitric oxide synthase antibody and approximately 33% of neurons produce and store acetylcholine. Transition zone regions from colon tissues of patients with Hirschsprung disease had ganglia in multiple layers and thick nerve fiber bundles without neurons. Submucosal neuron distribution varied among imaged colon regions. We developed a 3-dimensional imaging method for colon that provides more information about ENS structure than tissue sectioning. This approach could improve diagnosis for human bowel motility disorders and may be useful for other bowel diseases as well.