Kelly King

Language experience differentiates prefrontal and subcortical activation of the cognitive control network in novel word learning

The purpose of this study was to examine the cognitive control mechanisms in adult English speaking monolinguals compared to early sequential Spanish-English bilinguals during the initial stages of novel word learning. Functional magnetic resonance imaging during a lexico-semantic task after only 2h of exposure to novel German vocabulary flashcards showed that monolinguals activated a broader set of cortical control regions associated with higher-level cognitive processes, including the supplementary motor area (SMA), anterior cingulate (ACC), and dorsolateral prefrontal cortex (DLPFC), as well as the caudate, implicated in cognitive control of language. However, bilinguals recruited a more localized subcortical network that included the putamen, associated more with motor control of language. These results suggest that experience managing multiple languages may differentiate the learning strategy and subsequent neural mechanisms of cognitive control used by bilinguals compared to monolinguals in the early stages of novel word learning.

A longitudinal study of emotional adjustment, quality of life and adaptive function in attenuated MPS II

Objectives The behavioral, adaptive and quality of life characteristics of attenuated mucopolysaccharidosis type II (MPS II) have not been well studied. Understanding changes over time in the attenuated phenotype may assist in helping achieve better outcomes in long-term function. This longitudinal study investigates these outcomes in relation to age, somatic disease burden, and IQ. Specifically, somatic disease burden is a major challenge for these patients, even with treatment with enzyme replacement therapy. Methods 15 patients, 10 between ages 6 and < 12 and 5 between ages ≥ 12 and 18, were selected who had at least 2 yearly visits. The occurrence of physical signs, the Physical Symptom Score, and IQ in these two groups was studied as well as the longitudinal association of age with standardized measures of quality of life, adaptive function, and behavioral symptoms as rated by parents and the childs self-report. Slopes by age across and within patients were calculated for these measures. Results All but one child had hearing loss, most had joint contractures and short stature. Somatic disease burden increased with age. IQ, although normal for most, also improved with age in those under 12 years of age. Physical quality of life decreased while psychosocial quality of life increased with age. Although other adaptive skills were in the broad average range, daily living skills were low at baseline relative to normative data and decreased over time. Behavior ratings indicated improvement in attention and hyperactivity over time. No patient had severe psychopathology, but older children reported an increasing sense of inadequacy and low self-esteem on self-report, presumably due to increasing awareness of differences from peers over time. Conclusions Attenuated MPS II patients have increasing somatic disease burden and poor physical quality of life as they develop as well as decreasing self-esteem and sense of adequacy. Psychosocial quality of life, adaptive skills, and attention improve. Recognition of and intervention around these issues will be beneficial to MPS II attenuated patients who have the resources to use such assistance to improve their long-term outcomes.

Association of somatic burden of disease with age and neuropsychological measures in attenuated mucopolysaccharidosis types I, II and VI.

Introduction The mucopolysaccharidoses (MPSs) are a group of rare genetic lysosomal disorders with progressive multisystem involvement. An MPS-specific physical symptom scale was developed and introduced a Physical Symptom Score (PSS) to quantify the somatic disease burden across MPS I, II and VI. Hypothesis Somatic burden of disease in patients with attenuated MPS I, II and VI as measured by the PSS will be positively associated with age and negatively associated with neuropsychological functions [i.e. full scale intelligence quotient (FSIQ) and attention]. Materials and methods Forty-eight patients with attenuated MPS I (n = 24), II (n = 14), and VI (n = 10) aged 6 to 32 years on enzyme replacement therapy who were enrolled in “Longitudinal Studies of Brain Structure and Functions in MPS Disorders” across seven centers. Somatic disease burden was measured by the PSS. Neuropsychological functions were measured by the Wechsler Abbreviated Scale of Intelligence (WASI) and Test of Variables of Attention (TOVA). Results PSS was positively associated with age in attenuated MPS I (P < 0.001), MPS II (P < 0.01) and MPS VI (P < 0.05). There was a negative association of PSS with FSIQ in attenuated MPS I (P < 0.001) and in MPS VI (P < 0.001) but not with MPS II. Although attention scores were below average in all groups, a significant negative association between PSS and one measures of sustained attention (TOVA d prime) was found only in MPS VI. Conclusions Physical Symptom Score increased with age in attenuated MPS I, II and VI, reflecting progressive somatic burden of disease despite treatment with enzyme replacement therapy. Furthermore, the association of increased somatic disease burden with decreased neurocognitive ability suggests that both measures reflect disease severity and are not independent.

Infantile gangliosidoses: Mapping a timeline of clinical changes

BACKGROUND Infantile gangliosidoses include GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease). To date, natural history studies in infantile GM2 (iGM2) have been retrospective and conducted through surveys. Compared to iGM2, there is even less natural history information available on infantile GM1 disease (iGM1). There are no approved treatments for infantile gangliosidoses. Substrate reduction therapy using miglustat has been tried, but is limited by gastrointestinal side effects. Development of effective treatments will require identification of meaningful outcomes in the setting of rapidly progressive and fatal diseases. OBJECTIVES This study aimed to establish a timeline of clinical changes occurring in infantile gangliosidoses, prospectively, to: 1) characterize the natural history of these diseases; 2) improve planning of clinical care; and 3) identify meaningful future treatment outcome measures. METHODS Patients were evaluated prospectively through ongoing clinical care. RESULTS Twenty-three patients were evaluated: 8 infantile GM1, 9 infantile Tay-Sachs disease, 6 infantile Sandhoff disease. Common patterns of clinical change included: hypotonia before 6months of age; severe motor skill impairment within first year of life; seizures; dysphagia and feeding-tube placement before 18months of age. Neurodevelopmental testing scores reached the floor of the testing scale by 20 to 28months of age. Vertebral beaking, kyphosis, and scoliosis were unique to patients with infantile GM1. Chest physiotherapy was associated with increased survival in iGM1 (p=0.0056). Miglustat combined with a low-carbohydrate ketogenic diet (the Syner-G regimen) in patients who received a feeding-tube was associated with increased survival in infantile GM1 (p=0.025). CONCLUSIONS This is the first prospective study of the natural history of infantile gangliosidoses and the very first natural history of infantile GM1. The homogeneity of the infantile gangliosidoses phenotype as demonstrated by the clinical events timeline in this study provides promising secondary outcome measure candidates. This study indicates that overall survival is a meaningful primary outcome measure for future clinical trials due to reliable timing and early occurrence of this event. Combination therapy approaches, instead of monotherapy approaches, will likely be the best way to optimize clinical outcomes. Combination therapy approaches include palliative therapies (e.g., chest physiotherapy) along with treatments that address the underlying disease pathology (e.g. miglustat or future gene therapies).