Basal Ganglia Volumes Research Articles

Children had smaller brain volumes and cortical surface areas after prenatal opioid maintenance therapy exposure.

The studies have shown that infants with prenatal OMT exposure had smaller brain volumes than non-exposed controls, but long-term outcome data are lacking. We examined 5-13-year-old OMT-exposed children with brain MRI and tested motor and visual-motor functions and possible associations between brain morphology and outcome. To this retrospective cohort study, we recruited 55 children with prenatal OMT exposure and 59 age- and gender-matched controls. They were examined with brain MRI, Movement-ABC and Beery-VMI. MRI images were processed with the Free Surfer® software to obtain volumetrics and estimates of cortical surface area and thickness. We used a general linear regression model (GLM) to calculate group differences. The children in the OMT group had smaller mean total intracranial volume (ICV), 1407 cm3 (CI 95% 1379-1434) versus 1450 cm3 (CI 95% 1423-1476) in the control group (p = 0.026). After adjusting for ICV, significant group differences persisted for volumes of amygdala, basal ganglia and mid-posterior part of corpus callosum. Cortical surface area was smaller in the left caudal middle frontal gyrus and the right inferior parietal lobule in the OMT-group. Visual-motor function was significantly correlated with ICV. Prenatal OMT exposure may alter early brain development with possible negative long-term functional consequences.

The genetic landscape of basal ganglia and implications for common brain disorders

The basal ganglia are subcortical brain structures involved in motor control, cognition, and emotion regulation. We conducted univariate and multivariate genome-wide association analyses (GWAS) to explore the genetic architecture of basal ganglia volumes using brain scans obtained from 34,794 Europeans with replication in 4,808 white and generalization in 5,220 non-white Europeans. Our multivariate GWAS identified 72 genetic loci associated with basal ganglia volumes with a replication rate of 55.6% at P < 0.05 and 87.5% showed the same direction, revealing a distributed genetic architecture across basal ganglia structures. Of these, 50 loci were novel, including exonic regions of APOE, NBR1 and HLAA. We examined the genetic overlap between basal ganglia volumes and several neurological and psychiatric disorders. The strongest genetic overlap was between basal ganglia and Parkinson’s disease, as supported by robust LD-score regression-based genetic correlations. Mendelian randomization indicated genetic liability to larger striatal volume as potentially causal for Parkinson’s disease, in addition to a suggestive causal effect of greater genetic liability to Alzheimer’s disease on smaller accumbens. Functional analyses implicated neurogenesis, neuron differentiation and development in basal ganglia volumes. These results enhance our understanding of the genetic architecture and molecular associations of basal ganglia structure and their role in brain disorders.

Children’s exposure to chemical contaminants: Demographic disparities and associations with the developing basal ganglia

Children are regularly exposed to chemical contaminants that may influence brain development. However, relatively little is known about how these contaminants impact the developing human brain. Here, we combined silicone wristband exposure assessments with neuroimaging for the first time to examine how chemical contaminant mixtures are associated with the developing basal ganglia—a brain region key for the healthy development of emotion, reward, and motor processing, and which may be particularly susceptible to contaminant harm. Further, we examined demographic disparities in exposures to clarify which children were at highest risk for any contaminant-associated neurobiological changes. Participants included 62 community children (average age 7.00 years, 53% female, 66% White) who underwent structural neuroimaging to provide data on their basal ganglia structure and wore a silicone wristband for seven days to track their chemical contaminant exposure. 45 chemical contaminants—including phthalates and their alternatives, brominated flame retardants, organophosphate esters, pesticides, polycyclic aromatic hydrocarbons, and polychlorinated biphenyls—were detected in over 75% of wristbands. Notable demographic disparities in exposure were present, such that Non-White and lower-income children were more exposed to several contaminants. Exposure to chemical contaminant mixtures was not associated with overall basal ganglia volume; however, two organophosphate esters (2IPPDPP and 4IPPDPP) were both associated with a larger globus pallidus, a basal ganglia sub-region. Results highlight demographic disparities in exposure and suggest possible risks to a brain region key for healthy emotional development.

A Comparison of Pre- and Post-Treatment Cranial MRI Characteristics in Patients with Pediatric Epilepsy Receiving Levetiracetam.

Background and Objectives: This study was performed for the purpose of assessing whether antiepileptic levetiracetam treatment produces a change in brain volumes in children with epilepsy. To that end, we compared the volumes of the basal ganglia (caudate nucleus, putamen, globus, hip-pocampus, and thalamus) at magnetic resonance imaging (MRI) before and after treatment (months 18-24) in pediatric epilepsy patients using levetiracetam. Materials and Methods: This retrospective study involved a volumetric comparison of patients presenting to the Balikesir University Medical Faculty pediatric neurology clinic between 01.08.2019 and 01.11.2023 and diagnosed with epilepsy, and who underwent cranial MRI before and 18-24 months after treatment at the radiology department. The demographic and clinical characteristics (age, sex, family history of epilepsy, type of epilepsy, and EEG features (normal, abnormal, epileptiform)) of the patients included in the study were recorded. Results: The comparison of basal ganglia volumes at cranial MRI before and at months 18-24 of treatment revealed significant differences in the left caudate nucleus, right putamen, left putamen, left globus pallidus, right thalamus, left thalamus, and right hippocampal regions. Conclusions: In conclusion, differing findings are encountered at cranial imaging in patients with epilepsy, depending on the seizure frequency, activity, and the type of antiepileptic drugs used. This study compared basal ganglia volumes on cranial MRIs taken before and 18-24 months after treatment in pediatric epilepsy patients using levetiracetam. A significant increase was observed in the volumes of basal ganglia (caudate nucleus, putamen, globus pallidus, hippocampus, and thalamus) on the MRIs of pediatric epilepsy patients using levetiracetam.

The Relationship between Basal Ganglia Volume and Audiovisual Reaction Time in Turkish Elite Athletes

Background: In this study involving young adult elite athletes and healthy sedentary individuals, volumetric analyses were performed on basal ganglia (BG) involved in the coordination of motor movements. Aims and Objectives: In a group of athletes with high coordination speed, potential relationship between BG volumes and audiovisual reaction time of acquired-trained hand movements was explored by examining whether these individuals had significant differences in terms of BG volumes. Materials and Methods: Nineteen elite athletes aged between 19 and 25 years (9 male and 10 female) and 20 sedentary subjects (10 male, 10 female) were included. Gender, age, height, weight, and body-mass index (BMI) were recorded. In each group, audiovisual reaction time and stereological basal ganglia volumes were assessed and statistically analyzed. Results: Elite athletes react more rapidly to auditory stimuli than visual stimuli. As compared to sedentary individuals, elite athletes exhibited significantly shorter visual reaction time and only numerically shorter (statistically insignificant) visual reaction time. Left BG volume was higher in both groups, compared to right side). Conclusion: Our data may contribute to the construction of a database of normal BG morphology and provide useful information for clinicians and athletes.

Brain structure comparison among Parkinson disease, essential tremor, and healthy controls using 7T MRI.

Both Parkinson disease (PD) and Essential tremor (ET) are movement disorders causing tremors in elderly individuals. Although PD and ET are different disease, they often present with similar initial symptoms, making their differentiation challenging with magnetic resonance imaging (MRI) techniques. This study aimed to identify structural brain differences among PD, ET, and health controls (HCs) using 7-Tesla (T) MRI. We assessed the whole-brain parcellation in gray matter volume, thickness, subcortical volume, and small regions of basal ganglia in PD (n = 18), ET (n = 15), and HCs (n = 18), who were matched for age and sex. Brain structure analysis was performed automatic segmentation through Freesurfer software. Small regions of basal ganglia were manually segmented by ITK-SNAP. Additionally, we examined the associations between clinical indicators (symptom duration, unified Parkinson diseases rating scale (UPDRS), and clinical rating scale for tremor (CRST)) and brain structure. PD showed a significant reduction in gray matter volume in the postcentral region compared to ET. ET showed a significant reduction in cerebellum volume compared to HCs. There was a negative correlation between CRST scores (B and C) and gray matter thickness in right superior frontal in ET. This study demonstrated potential of 7T MRI in differentiating brain structure differences among PD, ET, and HCs. Specific findings, such as parietal lobe atrophy in PD compared to ET and cerebellum atrophy in ET compared to HCs, the importance of advanced imaging techniques in accurately diagnosing and distinguishing between movement disorders that present with similar initial symptoms.

Perivascular Spaces, Diffusivity Along Perivascular Spaces, and Free Water in Cerebral Small Vessel Disease.

Previous studies have linked the MRI measures of perivascular spaces (PVSs), diffusivity along the perivascular spaces (DTI-ALPS), and free water (FW) to cerebral small vessel disease (SVD) and SVD-related cognitive impairments. However, studies on the longitudinal associations between the three MRI measures, SVD progression, and cognitive decline are lacking. This study aimed to explore how PVS, DTI-ALPS, and FW contribute to SVD progression and cognitive decline. This is a cohort study that included participants with SVD who underwent neuroimaging and cognitive assessment, specifically measuring Mini-Mental State Examination (MMSE), cognitive index, and processing speed, at 2 time points. Three MRI measures were quantified: PVS in basal ganglia (BG-PVS) volumes, FW fraction, and DTI-ALPS. We performed a latent change score model to test inter-relations between the 3 MRI measures and linear regression mixed models to test their longitudinal associations with the changes of other SVD MRI markers and cognitive performances. In baseline assessment, we included 289 participants with SVD, characterized by a median age of 67.0 years and 42.9% women. Of which, 220 participants underwent the follow-up assessment, with a median follow-up time of 3.4 years. Baseline DTI-ALPS was associated with changes in BG-PVS volumes (β = -0.09, p = 0.030), but not vice versa (β = -0.08, p = 0.110). Baseline BG-PVS volumes were associated with changes in white matter hyperintensity (WMH) volumes (β = 0.33, p-corrected < 0.001) and lacune numbers (β = 0.28, p-corrected < 0.001); FW fraction was associated with changes in WMH volumes (β = 0.30, p-corrected < 0.001), lacune numbers (β = 0.28, p-corrected < 0.001), and brain volumes (β = -0.45, p-corrected < 0.001); DTI-ALPS was associated with changes in WMH volumes (β = -0.20, p-corrected = 0.002) and brain volumes (β = 0.23, p-corrected < 0.001). Furthermore, baseline FW fraction was associated with decline in MMSE score (β = -0.17, p-corrected = 0.006); baseline FW fraction and DTI-ALPS were associated with changes in cognitive index (FW fraction: β = -0.25, p-corrected < 0.001; DTI-ALPS: β = 0.20, p-corrected = 0.001) and processing speed over time (FW fraction: β = -0.29, p-corrected < 0.001; DTI-ALPS: β = 0.21, p-corrected < 0.001). Our results showed that increased BG-PVS volumes, increased FW fraction, and decreased DTI-ALPS are related to progression of MRI markers of SVD, along with SVD-related cognitive decline over time. These findings may suggest that the glymphatic dysfunction is related to SVD progression, but further studies are needed.

Cross-sectional associations between multisensory impairment and brain volumes in older adults: Baltimore Longitudinal Study of Aging

Sensory impairment and brain atrophy is common among older adults, increasing the risk of dementia. Yet, the degree to which multiple co-occurring sensory impairments (MSI across vision, proprioception, vestibular function, olfactory, and hearing) are associated with brain morphometry remain unexplored. Data were from 208 cognitively unimpaired participants (mean age 72 ± 10 years; 59% women) enrolled in the Baltimore Longitudinal Study of Aging. Multiple linear regression models were used to estimate cross-sectional associations between MSI and regional brain imaging volumes. For each additional sensory impairment, there were associated lower orbitofrontal gyrus and entorhinal cortex volumes but higher caudate and putamen volumes. Participants with MSI had lower mean volumes in the superior frontal gyrus, orbitofrontal gyrus, superior parietal lobe, and precuneus compared to participants with < 2 impairments. While MSI was largely associated with lower brain volumes, our results suggest the possibility that MSI was associated with higher basal ganglia volumes. Longitudinal analyses are needed to evaluate the temporality and directionality of these associations.

Alterations in the volume and shape of the basal ganglia and thalamus in schizophrenia with auditory hallucinations

Different lines of evidence indicate that the structure and physiology of the basal ganglia and the thalamus is disturbed in schizophrenia. However, it is unknown whether the volume and shape of these subcortical structures are affected in schizophrenia with auditory hallucinations (AH), a core positive symptom of the disorder. We took structural MRI from 63 patients with schizophrenia, including 36 patients with AH and 27 patients who had never experienced AH (NAH), and 51 matched healthy controls. We extracted volumes for the left and right thalamus, globus pallidus, putamen, caudate and nucleus accumbens. Shape analysis was also carried out. When comparing to controls, the volume of the right globus pallidus, thalamus, and putamen, was only affected in AH patients. The volume of the left putamen was also increased in individuals with AH, whereas the left globus pallidus was affected in both groups of patients. The shapes of right and left putamen and thalamus were also affected in both groups. The shape of the left globus pallidus was only altered in patients lacking AH, both in comparison to controls and to cases with AH. Lastly, the general PANSS subscale was correlated with the volume of the right thalamus, and the right and left putamen, in patients with AH. We have found volume and shape alterations of many basal ganglia and thalamus in patients with and without AH, suggesting in some cases a possible relationship between this positive symptom and these morphometric alterations.

Arterial spin‐labeling spatial coefficient of variation is associated with cerebral small vessel disease

AbstractBackgroundCerebral small vessel disease (SVD) is the most common pathology to co‐occur with Alzheimer’s disease but pathophysiologic mechanisms leading to SVD are poorly understood. The arterial spin‐labeling (ASL) spatial coefficient of variation (sCoV), a proxy marker of arterial transit time (ATT), may better reflect SVD‐related hemodynamic disturbances than ASL‐derived cerebral blood flow (CBF). We investigated whether grey matter CBF and grey matter sCoV each related to neuroimaging markers of SVD, including white matter hyperintensities (WMHs), basal ganglia enlarged perivascular spaces (ePVS), cerebral microbleeds (CMBs), and lacunes.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia and stroke at study entry (n = 312, 73±7 years, 39% mild cognitive impairment, 41% female) underwent multimodal 3T brain magnetic resonance imaging to quantify ASL parameters and SVD burden. Pseudo‐continuous ASL assessed CBF in total grey matter. Grey matter sCoV was calculated as σ(CBFGrey Matter)/μ(CBFGrey Matter). WMHs and ePVS volumes were quantified using automated methods and ePVS volumes were standardized to basal ganglia volume. CMBs and lacune counts were quantified by an expert rater. Ordinary least squares regression models cross‐sectionally related grey matter CBF and sCoV individually to log‐transformed burden of each SVD marker. Models were adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile (minus age), intracranial volume, grey matter volume, and apolipoprotein E‐ε4 status.ResultsGrey matter CBF was unrelated to all SVD outcomes (p‐values&gt;0.25). Higher grey matter sCoV was associated with greater WMHs (β = 2.1, p = 0.001), ePVS (β = 0.004, p = 0.0003), and lacunar infarcts (β = 1.4, p = 0.0006) but not CMBs (β = 1.0, p = 0.06).ConclusionsOur findings align with previous results showing that grey matter sCoV is a valuable marker of SVD. In contrast to previous work, we found an association between higher grey matter sCoV and higher basal ganglia ePVS burden. Potentially, our use of volumetric ePVS quantification rather than qualitative ePVS burden increased our ability to detect this association. As sCoV is a proxy marker of ATT, future work should consider quantifying sCoV or ATT in addition to CBF to better characterize SVD‐related hemodynamic disturbances. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, P20‐AG068082

PMPCA-Related Encephalopathy: Novel Variants, Phenotype Extension, and Mitochondrial Morphology.

The PMPCA gene encodes the α-subunit of mitochondrial processing peptidase (α-MPP), an enzyme responsible for cleavage of nuclear-encoded mitochondrial precursor proteins after their import into mitochondria. Mutations in this gene have been described in patients with nonprogressive or slow progressive cerebellar ataxia, with variable age at onset and severity. Cerebellar atrophy and striatum changes were found in severe cases. The patient was diagnosed using whole exome sequencing. Skin fibroblasts were used for confirmation of α-MPP levels using western blot and mitochondrial morphology assessment of immunofluorescent confocal microscopy images. Two novel compound heterozygous variants in the PMPCA gene (p.Tyr241Ser and p.Met251Val) were identified in an 8-year-old proband with progressive spastic quadriparesis, delayed psychomotor development, and intellectual disability, with onset at 13 months. The brain imaging showed cortical and cerebellar atrophy, reduced volume of basal ganglia with striatum hyperintensity, and periventricular white matter changes. The patient's fibroblasts showed a decreased α-MPP level and reduced and fragmented mitochondria. The described case contributes to the number of patients with progressive PMPCA-related disease with a severe intermediate phenotype. Moreover, we extend the phenotype to Leigh-like white matter changes that have not been described in previously reported cases.

Brain MRI Volumetric Assessment of Patients With Multiple Sclerosis: The Volume of Basal Ganglia, Thalamus, and Posterior Fossa.

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disorder of the central nervous system, which is associated with brain atrophy and volume changes in some brain structures. This study aimed to compare the volume of the basal ganglia, thalamus, cerebellum, and brainstem in patients with relapsing-remitting MS with that of the control group using magnetic resonance imaging (MRI). In this cross-sectional study, MRI brain scans were obtained from 25 patients with relapsing-remitting MS and 25 healthy control subjects. Volumetric analyses were performed using Brain Suite software. The mean age of the MS and the control groups was 33.96±8.75 and 40.40±8.72, respectively. No statistically significant difference was found in gender (P=0.747). The bilateral putamen and caudate nuclei volumes were significantly higher in the case group than in the control group (P<0.001). Moreover, lower the volume of the brainstem, cerebellum, bilateral thalamus, and globus pallidus were identified in the MS patients compared to the control group (P<0.001). There was an inverse correlation between the disease and treatment duration with the thalamus and cerebellum volume in MS patients (P=0.001). Treatment duration also had an inverse correlation with brainstem volume (P=0.047). The volume of some structures of the brain, including globus pallidus, thalamus, cerebellum, and brainstem is lower in MS and can be one of the markers of disease progression and disability among MS patients. Due to the degenerative process in multiple sclerosis, some cerebral structures may face volume change.The present study demonstrated that the volume of globus pallidus, thalamus, cerebellum, and brainstem is lower in MS patients compared to the controls. Multiple sclerosis (MS) is defined as an inflammatory disease involving the white matter of the brain, but experience has shown that many non-white matter structures also change in MS. In this study, we aimed to examine some parts of the brain, such as the thalamus, basal ganglia, brainstem, and cerebellum, for volume changes. The results showed that all these structures can have a smaller volume in MS patients than in healthy people. Especially in the case of the thalamus and cerebellum, this difference increases with increasing the disease duration. Changes in the size of these structures can be the result of degeneration of the neurons in these areas. These changes can cause significant disability in patients; however, there may not be significant changes in the number of plaques in patients. Attention to these changes can be essential in interpreting patients' clinical changes, including motor and cognitive disabilities.

Associations between sleep health and grey matter volume in the UK Biobank cohort (n = 33 356).

As suggested by previous research, sleep health is assumed to be a key determinant of future morbidity and mortality. In line with this, recent studies have found that poor sleep is associated with impaired cognitive function. However, to date, little is known about brain structural abnormalities underlying this association. Although recent findings link sleep health deficits to specific alterations in grey matter volume, evidence remains inconsistent and reliant on small sample sizes. Addressing this problem, the current preregistered study investigated associations between sleep health and grey matter volume (139 imaging-derived phenotypes) in the UK Biobank cohort (33 356 participants). Drawing on a large sample size and consistent data acquisition, sleep duration, insomnia symptoms, daytime sleepiness, chronotype, sleep medication and sleep apnoea were examined. Our main analyses revealed that long sleep duration was systematically associated with larger grey matter volume of basal ganglia substructures. Insomnia symptoms, sleep medication and sleep apnoea were not associated with any of the 139 imaging-derived phenotypes. Short sleep duration, daytime sleepiness as well as late and early chronotype were associated with solitary imaging-derived phenotypes (no recognizable pattern, small effect sizes). To our knowledge, this is the largest study to test associations between sleep health and grey matter volume. Clinical implications of the association between long sleep duration and larger grey matter volume of basal ganglia are discussed. Insomnia symptoms as operationalized in the UK Biobank do not translate into grey matter volume findings.

Cortical and subcortical brain morphometry abnormalities in youth at clinical high-risk for psychosis and individuals with early illness schizophrenia

Neuroimaging studies have documented morphometric brain abnormalities in schizophrenia, but less is known about them in individuals at clinical high-risk for psychosis (CHR-P), including how they compare with those observed in early schizophrenia (ESZ). Accordingly, we implemented multivariate profile analysis of regional morphometric profiles in CHR-P (n = 89), ESZ (n = 93) and healthy controls (HC; n = 122). ESZ profiles differed from HC and CHR-P profiles, including 1) cortical thickness: significant level reduction and regional non-parallelism reflecting widespread thinning, except for entorhinal and pericalcarine cortex, 2) basal ganglia volume: significant level increase and regional non-parallelism reflecting larger caudate and pallidum, and 3) ventricular volume: significant level increase with parallel regional profiles. CHR-P and ESZ cerebellar profiles showed significant non-parallelism with HC profiles. Regional profiles did not significantly differ between groups for cortical surface area or subcortical volume. Compared to CHR-P followed for ≥18 months without psychosis conversion (n = 31), CHR-P converters (n = 17) showed significant non-parallel ventricular volume expansion reflecting specific enlargement of lateral and inferolateral regions. Antipsychotic dosage in ESZ was significantly correlated with frontal cortical thinning. Results suggest that morphometric abnormalities in ESZ are not present in CHR-P, except for ventricular enlargement, which was evident in CHR-P who developed psychosis.

Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis

The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by progressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to unaffected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals.

A significant, functional and replicable risk KTN1 variant block for schizophrenia

Cortical and subcortical structural alteration has been extensively reported in schizophrenia, including the unusual expansion of gray matter volumes (GMVs) of basal ganglia (BG), especially putamen. Previous genome-wide association studies pinpointed kinectin 1 gene (KTN1) as the most significant gene regulating the GMV of putamen. In this study, the role of KTN1 variants in risk and pathogenesis of schizophrenia was explored. A dense set of SNPs (n = 849) covering entire KTN1 was analyzed in three independent European- or African-American samples (n = 6704) and one mixed European and Asian Psychiatric Genomics Consortium sample (n = 56,418 cases vs. 78,818 controls), to identify replicable SNP-schizophrenia associations. The regulatory effects of schizophrenia-associated variants on the KTN1 mRNA expression in 16 cortical or subcortical regions in two European cohorts (n = 138 and 210, respectively), the total intracranial volume (ICV) in 46 European cohorts (n = 18,713), the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258), and the surface areas (SA) and thickness (TH) of whole cortex and 34 cortical regions in 50 European cohorts (n = 33,992) and eight non-European cohorts (n = 2944) were carefully explored. We found that across entire KTN1, only 26 SNPs within the same block (r2 > 0.85) were associated with schizophrenia across ≥ 2 independent samples (7.5 × 10–5 ≤ p ≤ 0.048). The schizophrenia-risk alleles, which increased significantly risk for schizophrenia in Europeans (q < 0.05), were all minor alleles (f < 0.5), consistently increased (1) the KTN1 mRNA expression in 12 brain regions significantly (5.9 × 10–12 ≤ p ≤ 0.050; q < 0.05), (2) the ICV significantly (6.1 × 10–4 ≤ p ≤ 0.008; q < 0.05), (3) the SA of whole (9.6 × 10–3 ≤ p ≤ 0.047) and two regional cortices potentially (2.5 × 10–3 ≤ p ≤ 0.042; q > 0.05), and (4) the TH of eight regional cortices potentially (0.006 ≤ p ≤ 0.050; q > 0.05), and consistently decreased (1) the BG GMVs significantly (1.8 × 10–19 ≤ p ≤ 0.050; q < 0.05), especially putamen GMV (1.8 × 10–19 ≤ p ≤ 1.0 × 10–4; q < 0.05, (2) the SA of four regional cortices potentially (0.010 ≤ p ≤ 0.048), and (3) the TH of four regional cortices potentially (0.015 ≤ p ≤ 0.049) in Europeans. We concluded that we identified a significant, functional, and robust risk variant block covering entire KTN1 that might play a critical role in the risk and pathogenesis of schizophrenia.

MRI biomarkers of freezing of gait development in Parkinson’s disease

This study investigated longitudinal clinical, structural and functional brain alterations in Parkinson’s disease patients with freezing of gait (PD-FoG) and in those developing (PD-FoG-converters) and not developing FoG (PD-non-converters) over two years. Moreover, this study explored if any clinical and/or MRI metric predicts FoG development. Thirty PD-FoG, 11 PD-FoG-converters and 11 PD-non-converters were followed for two years. Thirty healthy controls were included at baseline. Participants underwent clinical and MRI visits. Cortical thickness, basal ganglia volumes and functional network graph metrics were evaluated at baseline and over time. In PD groups, correlations between baseline MRI and clinical worsening were tested. A ROC curve analysis investigated if baseline clinical and MRI measures, selected using a stepwise model procedure, could differentiate PD-FoG-converters from PD-non-converters. At baseline, PD-FoG patients had widespread cortical/subcortical atrophy, while PD-FoG-converters and non-converters showed atrophy in sensorimotor areas and basal ganglia relative to controls. Over time, PD-non-converters accumulated cortical thinning of left temporal pole and pallidum without significant clinical changes. PD-FoG-converters showed worsening of disease severity, executive functions, and mood together with an accumulation of occipital atrophy, similarly to PD-FoG. At baseline, PD-FoG-converters relative to controls and PD-FoG showed higher global and parietal clustering coefficient and global local efficiency. Over time, PD-FoG-converters showed reduced parietal clustering coefficient and sensorimotor local efficiency, PD-non-converters showed increased sensorimotor path length, while PD-FoG patients showed stable graph metrics. Stepwise prediction model including dyskinesia, postural instability and gait disorders scores and parietal clustering coefficient was the best predictor of FoG conversion. Combining clinical and MRI data, ROC curves provided the highest classification power to predict the conversion (AUC = 0.95, 95%CI: 0.86–1). Structural MRI is a useful tool to monitor PD progression, while functional MRI together with clinical features may be helpful to identify FoG conversion early.

The relationship between metabolic control and basal ganglia morphometry and function in individuals with early-treated phenylketonuria.

Abnormalities of the cortical white matter are the most prominent and widely-reported neurological findings in individuals with early-treated phenylketonuria (ETPKU). Much less is known regarding the effects of ETPKU on gray matter structures in the brain such as the basal ganglia. Previous findings on basal ganglia in ETPKU have been mixed. The current study was designed to further elucidate the effects of ETPKU and elevated phe levels on the morphometry of basal ganglia structures (i.e., putamen, caudate nucleus, nucleus accumbens, and globus pallidus). High resolution magnetic resonance imaging (MRI) data was collected from a sample of 37 adults with ETPKU and a demographically-matched comparison group of 33 individuals without PKU. No overall group differences (ETPKU vs. non-PKU) in basal ganglia volumes were observed. However, within the ETPKU group, poorer metabolic control (as reflected by higher blood phenylalanine levels) was associated with larger putamen volume. Vertex-wise shape analysis revealed that the volume increase was accompanied by shape changes in the middle left putamen. Consistent with this area's role in motor control, a significant correlation between left putamen volume and motor performance was also observed. Additional research is needed to fully understand the cellular level processes underlying this effect as well as to better understand the clinical impact of these morphometric changes and their potential relation to treatment response.

Obesity is associated with greater cognitive function in patients with type 2 diabetes mellitus.

The impact of obesity on cognitive function in patients with type 2 diabetes mellitus (T2DM) remains controversial. This study aimed to evaluate whether obesity, assessed by body mass index (BMI) was associated with cognitive function among T2DM patients and whether the effect of obesity on cognitive function was through brain structure. This was a post-hoc analysis of the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) study. The cognitive test battery included the Digit Symbol Substitution Test (DSST), Mini-Mental State Exam (MMSE), Rey Auditory Verbal Learning Test (RAVLT), and STROOP test, which were administered at baseline, and at 20, 40, and 80 months. A subgroup (n = 614) of the ACCORD-MIND study underwent MRI scanning at baseline and at 40 and 80 months. The total brain volume (TBV), abnormal white matter volume (AWM), abnormal gray matter volume (AGM), and abnormal basal ganglia volume (ABG) were estimated. The outcomes of this study were cognitive function and brain structure. In the adjusted analyses, BMI was positively associated with the MMSE (β:0.08, 95%CI,0.01-0.16, per standard deviation [SD] increase) and RAVLT scores (β:0.09, 95%CI,0.01-0.18). It was also associated with a greater TBV (β:7.48, 95%CI,0.29-14.67). BMI was not associated with the DSST or STROOP scores, and AWM, AGM, ABG. Mediation analysis found that the effect of BMI on MMSE/RAVLT was mediated through TBV. Obesity may be associated with greater cognitive function and the effect of BMI on cognitive function may be mediated by TBV among patients with T2DM. http://www.clinicaltrials.gov, identifier NCT00000620.

Quantitative susceptibility mapping of basal ganglia iron is associated with cognitive and motor functions that distinguish spinocerebellar ataxia type 6 and type 3.

In spinocerebellar ataxia type 3 (SCA3), volume loss has been reported in the basal ganglia, an iron-rich brain region, but iron content has not been examined. Recent studies have reported that patients with SCA6 have markedly decreased iron content in the cerebellar dentate, coupled with severe volume loss. Changing brain iron levels can disrupt cognitive and motor functions, yet this has not been examined in the SCAs, a disease in which iron-rich regions are affected. In the present study, we used quantitative susceptibility mapping (QSM) to measure tissue magnetic susceptibility (indicating iron concentration), structural volume, and normalized susceptibility mass (indicating iron content) in the cerebellar dentate and basal ganglia in people with SCA3 (n = 10) and SCA6 (n = 6) and healthy controls (n = 9). Data were acquired using a 7T Philips MRI scanner. Supplemental measures assessed motor, cognitive, and mood domains. Putamen volume was lower in both SCA groups relative to controls, replicating prior findings. Dentate susceptibility mass and volume in SCA6 was lower than in SCA3 or controls, also replicating prior findings. The novel finding was that higher basal ganglia susceptibility mass in SCA6 correlated with lower cognitive performance and greater motor impairment, an association that was not observed in SCA3. Cerebellar dentate susceptibility mass, however, had the opposite relationship with cognition and motor function in SCA6, suggesting that, as dentate iron is depleted, it relocated to the basal ganglia, which contributed to cognitive and motor decline. By contrast, basal ganglia volume loss, rather than iron content, appeared to drive changes in motor function in SCA3. The associations of higher basal ganglia iron with lower motor and cognitive function in SCA6 but not in SCA3 suggest the potential for using brain iron deposition profiles beyond the cerebellar dentate to assess disease states within the cerebellar ataxias. Moreover, the role of the basal ganglia deserves greater attention as a contributor to pathologic and phenotypic changes associated with SCA.