Journal of Neurodevelopmental Disorders最新文献

X-linked genetic causes of intellectual disability (ID) account for a substantial proportion of cases and remain poorly understood, in part due to the heterogeneous expression of X-linked genes in females. This is because most genes on the X chromosome are subject to random X chromosome inactivation (XCI) during early embryonic development, which results in a mosaic pattern of gene expression for a given X-linked mutant allele. This mosaic expression produces substantial complexity, especially when attempting to study the already complicated neural circuits that underly behavior, thus impeding the understanding of disease-related pathophysiology and the development of therapeutics. Here, we review a few selected X-linked forms of ID that predominantly affect heterozygous females and the current obstacles for developing effective therapies for such disorders. We also propose a genetic strategy to overcome the complexity presented by mosaicism in heterozygous females and highlight specific tools for studying synaptic and circuit mechanisms, many of which could be shared across multiple forms of intellectual disability.

Background: We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of "duration" processing. Given decrements in auditory processing abilities associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials.

Methods: We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system.

Results: Data from individuals with CLN3 disease (N = 21; range 6-28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N = 41; ages 6-26 years).

Conclusions: Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease.

Introduction: Evidence in the general population suggests that predictors of cardiovascular health such as moderate to vigorous physical activity (MVPA), cardiorespiratory fitness, and systolic blood pressure are associated with cognitive function. Studies supporting these associations in adults with Down syndrome (DS) are limited. The purpose of this study was to examine the associations between systolic blood pressure, cardiorespiratory fitness, and MVPA on cognition in adults with DS.

Methods: This is a cross-sectional analysis using baseline data from a trial in adults with DS. Participants attended a laboratory visit where resting blood pressure, cardiorespiratory fitness (VO_{2 Peak}), and cognitive function (CANTAB® DS Battery) were obtained. The cognitive battery included tests measuring multitasking, episodic memory, and reaction time. Physical activity (accelerometer) was collected over the week following the laboratory visit. Pearson correlations and linear regressions were used to measure the impact of systolic blood pressure, cardiorespiratory fitness, and MVPA on cognitive outcomes.

Results: Complete data was available for 72 adults with DS (26.8 ± 9.3 years of age, 57% female). At baseline, VO_{2 Peak} (21.1 ± 4.2 ml/kg/min) and MVPA were low (14.4 ± 14.4 min/day), and systolic blood pressure was 118.3 ± 13.3 mmHg. VO_{2 Peak} was correlated with simple movement time (rho =  - 0.28, p = 0.03) but was not significant using a linear regression controlling for age and sex. Systolic blood pressure was significantly associated with episodic memory (first attempt memory score: β =  - 0.11, p = 0.002; total errors: β = 0.58, p = 0.001) and reaction time (five-choice movement time: β = 4.11, p = 0.03; simple movement time: β = 6.14, p = 0.005) using age- and sex-adjusted linear regressions. No associations were observed between MVPA and multitasking, episodic memory, or reaction time.

Conclusion: Predictors of cardiovascular health, including cardiorespiratory fitness and systolic blood pressure, were associated with some aspects of cognition in adults with DS. While future research should examine the role of improved cardiovascular health on delaying decreases in cognitive function and dementia in adults with DS, we recommend that health care providers convey the importance of exercise and cardiovascular health to their patients with DS.

Trial registration: NCT04048759, registered on August 7, 2019.