The Cerebellar Cognitive Affective/Schmahmann Syndrome Scale in Spinocerebellar Ataxias.

The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.

Longitudinal changes in white matter as measured with diffusion tensor imaging in adult-onset myotonic dystrophy type 1.

Myotonic dystrophy type 1 is characterized by neuromuscular degeneration. Our objective was to compare change in white matter microstructure (fractional anisotropy, radial and axial diffusivity), and functional/clinical measures. Participants underwent yearly neuroimaging and neurocognitive assessments over three-years. Assessments encompassed full-scale intelligence, memory, language, visuospatial skills, attention, processing speed, and executive function, as well as clinical symptoms of muscle/motor function, apathy, and hypersomnolence. Mixed effects models were used to examine differences. 69 healthy adults (66.2% women) and 41 DM1 patients (70.7% women) provided 156 and 90 observations, respectively. There was a group by elapsed time interaction for cerebral white matter, where DM1 patients exhibited declines in white matter (all p<0.05). Likewise, DM1 patients either declined (motor), improved more slowly (intelligence), or remained stable (executive function) for functional outcomes. White matter was associated with functional performance; intelligence was predicted by axial (r = 0.832; p<0.01) and radial diffusivity (r = 0.291, p<0.05), and executive function was associated with anisotropy (r = 0.416, p<0.001), and diffusivity (axial: r = 0.237, p = 0.05 and radial: r = 0.300, p<0.05). Indices of white matter health are sensitive to progression in DM1. These results are important for clinical trial design, which utilize short intervals to establish treatment efficacy.

Assisted annotation in Deep LOGISMOS: Simultaneous multi-compartment 3D MRI segmentation of calf muscles.

BACKGROUND: Automated segmentation of individual calf muscle compartments in 3D MR images is gaining importance in diagnosing muscle disease, monitoring its progression, and prediction of the disease course. Although deep convolutional neural networks have ushered in a revolution in medical image segmentation, achieving clinically acceptable results is a challenging task and the availability of sufficiently large annotated datasets still limits their applicability. PURPOSE: In this paper, we present a novel approach combing deep learning and graph optimization in the paradigm of assisted annotation for solving general segmentation problems in 3D, 4D, and generally n-D with limited annotation cost. METHODS: Deep LOGISMOS combines deep-learning-based pre-segmentation of objects of interest provided by our convolutional neural network, FilterNet+, and our 3D multi-objects LOGISMOS framework (layered optimal graph image segmentation of multiple objects and surfaces) that uses newly designed trainable machine-learned cost functions. In the paradigm of assisted annotation, multi-object JEI for efficient editing of automated Deep LOGISMOS segmentation was employed to form a new larger training set with significant decrease of manual tracing effort. RESULTS: We have evaluated our method on 350 lower leg (left/right) T1-weighted MR images from 93 subjects (47 healthy, 46 patients with muscular morbidity) by fourfold cross-validation. Compared with the fully manual annotation approach, the annotation cost with assisted annotation is reduced by 95%, from 8 h to 25 min in this study. The experimental results showed average Dice similarity coefficient (DSC) of 96.56 ± 0.26 % $96.56\pm 0.26 \%$ and average absolute surface positioning error of 0.63 pixels (0.44 mm) for the five 3D muscle compartments for each leg. These results significantly improve our previously reported method and outperform the state-of-the-art nnUNet method. CONCLUSIONS: Our proposed approach can not only dramatically reduce the expert's annotation efforts but also significantly improve the segmentation performance compared to the state-of-the-art nnUNet method. The notable performance improvements suggest the clinical-use potential of our new fully automated simultaneous segmentation of calf muscle compartments.

Longitudinal Clinical and Biological Characteristics in Juvenile-Onset Huntington's Disease.

BACKGROUND: Juvenile-onset Huntington's disease (JOHD) is a rare form of Huntington's disease (HD) characterized by symptom onset before the age of 21 years. Observational data in this cohort is lacking. OBJECTIVES: Quantify measures of disease progression for use in clinical trials of patients with JOHD. METHODS: Participants who received a motor diagnosis of HD before the age of 21 were included in the Kids-JOHD study. The comparator group consisted of children and young adults who were at-risk for inheriting the genetic mutation that causes HD, but who were found to have a CAG repeat in the non-expanded range (gene non-expanded [GNE]). RESULTS: Data were obtained between March 17, 2006, and February 13, 2020. There were 26 JOHD participants and 78 GNE participants who were comparable on age (16.03 vs. 14.43, respectively) and sex (53.8% female vs. 57.7% female, respectively). The mean annualized decrease in striatal volume in the JOHD group was -3.99% compared to -0.06% in the GNE (mean difference [MD], -3.93%; 95% confidence intervals [CI], [-4.98 to -2.80], FDR < 0.0001). The mean increase in the Unified Huntington's Disease Rating Scale Total Motor Score per year in the JOHD group was 7.29 points compared to a mean decrease of -0.21 point in the GNE (MD, 7.5; 95% CI, [5.71-9.28], FDR < 0·0001). CONCLUSIONS: These findings demonstrate that structural brain imaging and clinical measures in JOHD may be potential biomarkers of disease progression for use in clinical trials. Collaborative efforts are required to validate these results in a larger cohort of patients with JOHD. © 2022 International Parkinson and Movement Disorder Society.

The S-Factor, a New Measure of Disease Severity in Spinocerebellar Ataxia: Findings and Implications.

Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders, but there is no metric that predicts disease severity over time. We hypothesized that by developing a new metric, the Severity Factor (S-Factor) using immutable disease parameters, it would be possible to capture disease severity independent of clinical rating scales. Extracting data from the CRC-SCA and READISCA natural history studies, we calculated the S-Factor for 438 participants with symptomatic SCA1, SCA2, SCA3, or SCA6, as follows: ((length of CAG repeat expansion - maximum normal repeat length) /maximum normal repeat length) × (current age - age at disease onset) × 10). Within each SCA type, the S-Factor at the first Scale for the Assessment and Rating of Ataxia (SARA) visit (baseline) was correlated against scores on SARA and other motor and cognitive assessments. In 281 participants with longitudinal data, the slope of the S-Factor over time was correlated against slopes of scores on SARA and other motor rating scales. At baseline, the S-Factor showed moderate-to-strong correlations with SARA and other motor rating scales at the group level, but not with cognitive performance. Longitudinally the S-Factor slope showed no consistent association with the slope of performance on motor scales. Approximately 30% of SARA slopes reflected a trend of non-progression in motor symptoms. The S-Factor is an observer-independent metric of disease burden in SCAs. It may be useful at the group level to compare cohorts at baseline in clinical studies. Derivation and examination of the S-factor highlighted challenges in the use of clinical rating scales in this population.

Behavioral features in child and adolescent huntingtin gene-mutation carriers.

INTRODUCTION: We compared neuropsychiatric symptoms between child and adolescent huntingtin gene-mutation carriers and noncarriers. Given previous evidence of atypical striatal development in carriers, we also assessed the relationship between neuropsychiatric traits and striatal development. METHODS: Participants between 6 and 18 years old were recruited from families affected by Huntington's disease and tested for the huntingtin gene expansion. Neuropsychiatric traits were assessed using the Pediatric Behavior Scale and the Behavior Rating Inventory of Executive Function. Striatal volumes were extracted from 3T neuro-anatomical images. Multivariable linear regression models were conducted to evaluate the impact of group (i.e., gene nonexpanded [GNE] or gene expanded [GE]), age, and trajectory of striatal growth on neuropsychiatric symptoms. RESULTS: There were no group differences in any behavioral measure with the exception of depression/anxiety score, which was higher in the GNE group compared to the GE group (estimate = 4.58, t(129) = 2.52, FDR = 0.051). The growth trajectory of striatal volume predicted depression scores (estimate = 0.429, 95% CI 0.15:0.71, p = .0029), where a negative slope of striatal volume over time was associated with lower depression/anxiety. CONCLUSIONS: The current findings show that GE children may have lower depression/anxiety compared to their peers. Previously, we observed a unique pattern of early striatal hypertrophy and continued decrement in volume over time among GE children and adolescents. In contrast, GNE individuals largely show striatal volume growth. These findings suggest that the lower scores of depression and anxiety seen in GE children and adolescents may be associated with differential growth of the striatum.

Neurofilament Light Protein as a Potential Blood Biomarker for Huntington's Disease in Children.

BACKGROUND: Juvenile-onset Huntington's disease (JOHD) is a rare and particularly devastating form of Huntington's disease (HD) for which clinical diagnosis is challenging and robust outcome measures are lacking. Neurofilament light protein (NfL) in plasma has emerged as a prognostic biomarker for adult-onset HD. METHODS: We performed a retrospective analysis of samples and data collected between 2009 and 2020 from the Kids-HD and Kids-JHD studies. Plasma samples from children and young adults with JOHD, premanifest HD (preHD) mutation carriers, and age-matched controls were used to quantify plasma NfL concentrations using ultrasensitive immunoassay. RESULTS: We report elevated plasma NfL concentrations in JOHD and premanifest HD mutation-carrying children. In pediatric HD mutation carriers who were within 20 years of their predicted onset and patients with JOHD, plasma NfL level was associated with caudate and putamen volumes. CONCLUSIONS: Quantifying plasma NfL concentration may assist clinical diagnosis and therapeutic trial design in the pediatric population. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Cortical Features in Child and Adolescent Carriers of Mutant Huntingtin (mHTT).

BACKGROUND: Molecular studies provide evidence that mutant huntingtin (mHTT) affects early cortical development; however, cortical development has not been evaluated in child and adolescent carriers of mHTT. OBJECTIVE: To evaluate the impact of mHTT on the developmental trajectories of cortical thickness and surface area. METHODS: Children and adolescents (6-18 years) participated in the KidsHD study. mHTT carrier status was determined for research purposes only to classify participants as gene expanded (GE) and gene non-expanded (GNE). Cortical features were extracted from 3T neuroimaging using FreeSurfer. Nonlinear mixed effects models were conducted to determine if age, group, and CAG repeat were associated with cortical morphometry. RESULTS: Age-related changes in cortical morphometry were similar across groups. Expanded CAG repeat was not significantly associated with cortical features. CONCLUSION: While striatal development is markedly different in GE and GNE, developmental change of the cortex appears grossly normal among child and adolescent carrier of mHTT.

Associations between neurofilament light-chain protein, brain structure, and chronic kidney disease.

BACKGROUND: Neurofilament light-chain (NfL) protein is a blood-based marker of neuroaxonal injury. We sought to (1) compare plasma NfL levels in children with chronic kidney disease (CKD) and healthy peers, (2) characterize the relationship between NfL level and kidney function, and (3) evaluate NfL as a predictor of abnormal brain structure in CKD. METHODS: Sixteen children with CKD due to congenital kidney anomalies and 23 typically developing peers were included. Plasma NfL was quantified using single-molecule array immunoassay. Participants underwent structural magnetic resonance imaging. Multiple linear regression models were used to evaluate the association between plasma NfL levels, kidney function, and brain structure. RESULTS: An age × group interaction was identified whereby NfL levels increased with age in the CKD group only (estimate = 0.65; confidence interval (CI) = 0.08-1.22; p = 0.026). Decreased kidney function was associated with higher NfL levels (estimate = -0.10; CI = -0.16 to -0.04; p = 0.003). Lower cerebellar gray matter volume predicted increased plasma NfL levels (estimate = -0.00024; CI = -0.00039 to 0.00009; p = 0.004) within the CKD group. CONCLUSIONS: Children with CKD show accelerated age-related increases in NfL levels. NfL level is associated with lower kidney function and abnormal brain structure in CKD. IMPACT: NfL is a component of the neuronal cytoskeleton providing structural axonal support. Elevated NfL has been described in relation to gray and white matter brain volume loss. We have previously described the abnormal cerebellar gray matter in CKD. We explored the relationship between NfL, CKD, and brain volume. There is an accelerated, age-related increase in NfL level in CKD. Within the CKD sample, NfL level is associated with abnormal kidney function and brain structure. Decreased kidney function may be linked to abnormal neuronal integrity in pediatric CKD.

Global and Regional White Matter Fractional Anisotropy in Children with Chronic Kidney Disease.

OBJECTIVE: To investigate the associations between neurocognition and white matter integrity in children with chronic kidney disease (CKD). STUDY DESIGN: This cross-sectional study included 17 boys (age 6-16 years) with a diagnosis of mild to moderate (stages 1-3, nondialysis/nontransplant) CKD because of congenital anomalies of the kidney and urinary tract and 20 typically developing community controls. Participants underwent 3T neuroimaging and diffusion-weighted magnetic resonance imaging to assess white matter fractional anisotropy. Multivariable linear regression models were used to evaluate the impact of each group (controls vs CKD) on white matter fractional anisotropy, adjusting for age. Associations between white matter fractional anisotropy and neurocognitive abilities within the CKD group were also evaluated using regression models that were adjusted for age. The false discovery rate was used to account for multiple comparisons; wherein false discovery values <0.10 were considered significant. RESULTS: Global white matter fractional anisotropy was reduced in patients with CKD relative to controls (standardized estimate = -0.38, 95% CI -0.69:-0.07), driven by reductions within the body of the corpus callosum (standardized estimate = -0.44, 95% CI -0.75:-0.13), cerebral peduncle (SE = -0.37, 95% CI -0.67:-0.07), cingulum (hippocampus) (standardized estimate = -0.45, 95% CI -0.75:-0.14), and posterior limb of the internal capsule (standardized estimate = -0.46, 95% CI -0.76:-0.15). Medical variables and neurocognitive abilities were not significantly associated with white matter fractional anisotropy. CONCLUSIONS: White matter development is vulnerable in children with CKD because of congenital causes, even prior to the need for dialysis or transplantation.

Cognitive Deficits, Apathy, and Hypersomnolence Represent the Core Brain Symptoms of Adult-Onset Myotonic Dystrophy Type 1.

Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults, and is primarily characterized by muscle weakness and myotonia, yet some of the most disabling symptoms of the disease are cognitive and behavioral. Here we evaluated several of these non-motor symptoms from a cross-sectional time-point in one of the largest longitudinal studies to date, including full-scale intelligence quotient, depression, anxiety, apathy, sleep, and cerebral white matter fractional anisotropy in a group of 39 adult-onset myotonic dystrophy type 1 participants (27 female) compared to 79 unaffected control participants (46 female). We show that intelligence quotient was significantly associated with depression (P < 0.0001) and anxiety (P = 0.018), but not apathy (P < 0.058) or hypersomnolence (P = 0.266) in the DM1 group. When controlling for intelligence quotient, cerebral white matter fractional anisotropy was significantly associated with apathy (P = 0.042) and hypersomnolence (P = 0.034), but not depression (P = 0.679) or anxiety (P = 0.731) in the myotonic dystrophy type 1 group. Finally, we found that disease duration was significantly associated with apathy (P < 0.0001), hypersomnolence (P < 0.001), IQ (P = 0.038), and cerebral white matter fractional anisotropy (P < 0.001), but not depression (P = 0.271) or anxiety (P = 0.508). Our results support the hypothesis that cognitive deficits, hypersomnolence, and apathy, are due to the underlying neuropathology of myotonic dystrophy type 1, as measured by cerebral white matter fractional anisotropy and disease duration. Whereas elevated symptoms of depression and anxiety in myotonic dystrophy type 1 are secondary to the physical symptoms and the emotional stress of coping with a chronic and debilitating disease. Results from this work contribute to a better understanding of disease neuropathology and represent important therapeutic targets for clinical trials.

Association of CAG Repeat Length in the Huntington Gene With Cognitive Performance in Young Adults.

OBJECTIVE: To investigate the relationships between CAG repeat length in the huntingtin gene and cognitive performance in participants above and below the disease threshold for Huntington disease (HD), we performed a cross-sectional analysis of the Enroll-HD database. METHODS: We analyzed data from young, developing adults (≤30 years of age) without a history of depression, apathy, or cognitive deficits. We included participants with and without the gene expansion (CAG ≥36) for HD. All participants had to have a Total Functional Capacity Score of 13, a diagnostic confidence level of zero, and a total motor score of <10 and had to be >28.6 years from their predicted motor onset. We performed regression analyses to investigate the nonlinear relationship between CAG repeat length and various cognitive measures controlling for age, sex, and education level. RESULTS: There were significant positive relationships between CAG repeat length and the Symbol Digit Modalities, Stroop Color Naming, and Stroop Interference test scores. There were significant negative relationships between CAG repeat length and scores on Parts A and B of the Trails Making Test (p < 0.05), indicating that longer CAG repeat lengths were associated with better performance. DISCUSSION: An increasing number of CAG repeats in the huntingtin gene below disease threshold and low pathologic CAG ranges were associated with some improvements in cognitive performance. These findings outline the relationship between CAG repeats within the huntingtin gene and cognitive development. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that CAG repeat length is positively associated with cognitive function across a spectrum of CAG repeat lengths.

White matter microstructure relates to motor outcomes in myotonic dystrophy type 1 independently of disease duration and genetic burden.

Deficits in white matter (WM) integrity and motor symptoms are among the most robust and reproducible features of myotonic dystrophy type 1 (DM1). In the present study, we investigate whether WM integrity, obtained from diffusion-weighted MRI, corresponds to quantifiable motor outcomes (e.g., fine motor skills and grip strength) and patient-reported, subjective motor deficits. Critically, we explore these relationships in the context of other potentially causative variables, including: disease duration, elapsed time since motor symptom onset; and genetic burden, the number of excessive CTG repeats causing DM1. We found that fractional anisotropy (a measure of WM integrity) throughout the cerebrum was the strongest predictor of grip strength independently of disease duration and genetic burden, while radial diffusivity predicted fine motor skill (peg board performance). Axial diffusivity did not predict motor outcomes. Our results are consistent with the notion that systemic degradation of WM in DM1 mediates the relationship between DM1 progression and genetic burden with motor outcomes of the disease. Our results suggest that tracking changes in WM integrity over time may be a valuable biomarker for tracking therapeutic interventions, such as future gene therapies, for DM1.

DMPK mRNA Expression in Human Brain Tissue Throughout the Lifespan.

OBJECTIVE: Myotonic dystrophy is a multisystem disorder caused by a trinucleotide repeat expansion on the myotonic dystrophy protein kinase (DMPK) gene. To determine whether wildtype DMPK expression patterns vary as a function of age, we analyzed DMPK expression in the brain from 99 donors ranging from 5 postconceptional weeks to 80 years old. METHODS: We used the BrainSpan messenger RNA sequencing and the Yale Microarray data sets, which included brain tissue samples from 42 and 57 donors, respectively. Collectively, donors ranged in age from 5 postconceptional weeks to 80 years old. DMPK expression was normalized for each donor across regions available in both data sets. Restricted cubic spline linear regression models were used to analyze the effects of log-transformed age and sex on normalized DMPK expression data. RESULTS: Age was a statistically significant predictor of normalized DMPK expression pattern in the human brain in the BrainSpan (p < 0.005) and Yale data sets (p < 0.005). Sex was not a significant predictor. Across both data sets, normalized wildtype DMPK expression steadily increases during fetal development, peaks around birth, and then declines to reach a nadir around age 10. CONCLUSIONS: Peak expression of DMPK coincides with a time of dynamic brain development. Abnormal brain DMPK expression due to myotonic dystrophy may have implications for early brain development.

Blood-Based Markers of Neuronal Injury in Adult-Onset Myotonic Dystrophy Type 1.

INTRODUCTION: The present study had four aims. First, neuronal injury markers, including neurofilament light (NF-L), total tau, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), were compared between individuals with and without adult-onset myotonic dystrophy type 1 (DM1). Second, the impact of age and CTG repeat on brain injury markers was evaluated. Third, change in brain injury markers across the study period was quantified. Fourth, associations between brain injury markers and cerebral white matter (WM) fractional anisotropy (FA) were identified. METHODS: Yearly assessments, encompassing blood draws and diffusion tensor imaging on a 3T scanner, were conducted on three occasions. Neuronal injury markers were quantified using single molecule array (Simoa). RESULTS: The sample included 53 patients and 70 controls. NF-L was higher in DM1 patients than controls, with individuals in the premanifest phases of DM1 (PreDM1) exhibiting intermediate levels ( χ ( 2 ) 2 = 38.142, P < 0.001). Total tau was lower in DM1 patients than controls (Estimate = -0.62, 95% confidence interval [CI] -0.95: -0.28, P < 0.001), while GFAP was elevated in PreDM1 only (Estimate = 30.37, 95% CI 10.56:50.19, P = 0.003). Plasma concentrations of UCH-L1 did not differ between groups. The age by CTG interaction predicted NF-L: patients with higher estimated progenitor allelege length (ePAL) had higher NF-L at a younger age, relative to patients with lower CTG repeat; however, the latter exhibited faster age-related change (Estimate = -0.0021, 95% CI -0.0042: -0.0001, P = 0.045). None of the markers changed substantially over the study period. Finally, cerebral WM FA was significantly associated with NF-L (Estimate = -42.86, 95% CI -82.70: -3.02, P = 0.035). INTERPRETATION: While NF-L appears sensitive to disease onset and severity, its utility as a marker of progression remains to be determined. The tau assay may have low sensitivity to tau pathology associated with DM1.

Cognitive function and its relationship with brain structure in myotonic dystrophy type 1.

Studies have shown relationships between white matter abnormalities and cognitive dysfunction in myotonic dystrophy type 1 (DM1), but comprehensive analysis of potential structure-function relationships are lacking. Fifty adult-onset DM1 individuals (33 female) and 68 unaffected adults (45 female) completed the Wechsler Adult Intelligence Scale-IV (WAIS-IV) to determine the levels and patterns of intellectual functioning. Neuroimages were acquired with a 3T scanner and were processed with BrainsTools. Regional brain volumes (regions of interest, ROIs) were adjusted for inter-scanner variation and intracranial volume. Linear regression models were conducted to assess if group by ROI interaction terms significantly predicted WAIS-IV composite scores. Models were adjusted for age and sex. The DM1 group had lower Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI) scores than the unaffected group (PRI t(113)  = -3.28, p = 0.0014; WMI t(114)  = -3.49, p = 0.0007; PSI t(114)  = -2.98, p = 0.0035). The group by hippocampus interaction term was significant for both PRI and PSI (PRI (t(111)  = -2.82, p = 0.0057; PSI (t(112)  = -2.87, p = 0.0049)). There was an inverse association between hippocampal volume and both PRI and PSI in the DM1 group (the higher the volume, the lower the intelligence quotient scores), but no such association was observed in the unaffected group. Enlarged hippocampal volume may underlie some aspects of cognitive dysfunction in adult-onset DM1, suggesting that increased volume of the hippocampus may be pathological.

Early pediatric chronic kidney disease is associated with brain volumetric gray matter abnormalities.

BACKGROUND: The impact of pediatric chronic kidney disease (pCKD) on the brain remains poorly defined. The objective of this study was to compare brain morphometry between children with early-stage pCKD and typically developing peers using structural magnetic resonance imaging (MRI). METHODS: The sample age range was 6-16 years. A total of 18 children with a diagnosis of pCKD (CKD stages 1-3) due to congenital anomalies of the kidney and urinary tract and 24 typically developing peers were included. Volumetric data from MRI and neurocognitive testing were compared using linear models including pCKD status, age, maternal education level, and socioeconomic status. RESULTS: Cerebellar gray matter volume was significantly smaller in pCKD, t(38) = -2.71, p = 0.01. In contrast, cerebral gray matter volume was increased in pCKD, t(38) = 2.08, p = 0.04. Reduced cerebellum gray matter volume was associated with disease severity, operationalized as estimated glomerular filtration rate (eGFR), t(14) = 2.21, p = 0.04 and predicted lower verbal fluency scores in the pCKD sample. Enlarged cerebral gray matter in the pCKD sample predicted lower scores on mathematics assessment. CONCLUSIONS: This study provides preliminary evidence for a morphometric underpinning to the cognitive deficits observed in pCKD. IMPACT: The impact of pediatric chronic kidney disease (CKD) on the brain remains poorly defined, with no data linking brain morphometry and observed cognitive deficits noted in this population. We explored the relationship between brain morphometry (using structural magnetic resonance imaging), cognition, and markers of CKD. Cerebellar and cerebral gray matter volumes are different in early CKD. Volumetric decreases in cerebellar gray matter are predicted by lower eGFR, suggesting a link between disease and brain morphometry. Reduced cerebellar gray matter predicted lower verbal fluency for those with pCKD. Enlarged cerebral gray matter in the pCKD sample predicted lower mathematics performance.

Encoding of facial expressions in individuals with adult-onset myotonic dystrophy type 1.

Introduction: Emotional issues are often reported among individuals with myotonic dystrophy type 1 (DM1) and some studies have suggested that deficits in ability to quickly encode emotions may contribute to these problems. However, poor performance on emotion encoding tasks could also be explained by a more general cognitive deficit (Full Scale IQ [FSIQ]), rather than a specific deficit in emotional processing. Since individuals with DM1 are known to exhibit difficulties in general cognitive abilities, it is important to account for FSIQ when evaluating emotion encoding. The aim of this study was to compare emotion encoding abilities between individuals with and without DM1, while adjusting for the impact of general cognitive abilities (FSIQ). Methods: The sample included 35 individuals with adult-onset DM1 and 54 unaffected adults who completed assessments of emotion encoding abilities (Ekman faces test) and general cognitive abilities (Wechsler Adult Intelligence Scale-IV). Performance on the emotion encoding task was operationalized as proportion correct and response time. Group differences in proportion correct were evaluated with generalized linear regression, while linear regression models were used to determine the effect of group on response time. Models were adjusted for age, sex, and FSIQ. The false discovery rate (FDR) was applied to control false positives due to multiple comparisons (pfdr ). Results: No significant group differences were observed for emotion encoding abilities (all pfdr > 0.13). FSIQ was significantly associated with proportion correct and with response time (all pfdr < 0.05). Conclusions: Emotion encoding appears intact in individuals with DM1 and variation in the ability to encode facial expressions was associated with FSIQ. Further research is required to address the relationship between general cognitive abilities and emotion encoding abilities among DM1 patients.

Abnormal Brain Development in Huntington' Disease Is Recapitulated in the zQ175 Knock-In Mouse Model.

Emerging cellular and molecular studies are providing compelling evidence that altered brain development contributes to the pathogenesis of Huntington's disease (HD). There has been lacking longitudinal system-level data obtained from in vivo HD models supporting this hypothesis. Our human MRI study in children and adolescents with HD indicates that striatal development differs between the HD and control groups, with initial hypertrophy and more rapid volume decline in HD group. In this study, we aimed to determine whether brain development recapitulates the human HD during the postnatal period. Longitudinal structural MRI scans were conducted in the heterozygous zQ175 HD mice and their littermate controls. We found that male zQ175 HD mice recapitulated the region-specific abnormal volume development in the striatum and globus pallidus, with early hypertrophy and then rapidly decline in the regional volume. In contrast, female zQ175 HD mice did not show significant difference in brain volume development with their littermate controls. This is the first longitudinal study of brain volume development at the system level in HD mice. Our results suggest that altered brain development may contribute to the HD pathogenesis. The potential effect of gene therapies targeting on neurodevelopmental event is worth to consider for HD therapeutic intervention.