Does 22q11.2 deletion syndrome contribute to the genetic aetiology of Parkinson’s disease?

Journal of Neurology -     

How might stress contribute to increased risk for schizophrenia in children with chromosome 22q11.2 deletion syndrome?

The most common human microdeletion occurs at chromosome 22q11.2. The associated syndrome (22q11.2DS) has a complex and variable phenotype with a high risk of schizophrenia. While the role of stress in the etiopathology of schizophrenia has been under investigation for over 30 years (Walker et al. 2008), the stress–diathesis model has yet to be investigated in children with 22q11.2DS. Children with 22q11.2DS face serious medical, behavioral, and socioemotional challenges from infancy into adulthood. Chronic stress elevates glucocorticoids, decreases immunocompetence, negatively impacts brain development and function, and is associated with psychiatric illness in adulthood. Drawing knowledge from the extant and well-developed anxiety and stress literature will provide invaluable insight into the complex etiopathology of schizophrenia in people with 22q11.2DS while suggesting possible early interventions. Childhood anxiety is treatable and stress coping skills can be developed thereby improving quality of life in the short-term and potentially mitigating the risk of developing psychosis.     

Visual memory profile in 22q11.2 microdeletion syndrome: are there differences in performance and neurobiological substrates between tasks linked to ventral and dorsal visual brain structures? A cross-sectional and longitudinal study

Background

Children affected by the 22q11.2 deletion syndrome (22q11.2DS) have a specific neuropsychological profile with strengths and weaknesses in several cognitive domains. Specifically, previous evidence has shown that patients with 22q11.2DS have more difficulties memorizing faces and visual-object characteristics of stimuli. In contrast, they have better performance in visuo-spatial memory tasks. The first focus of this study was to replicate these results in a larger sample of patients affected with 22q11.2DS and using a range of memory tasks. Moreover, we analyzed if the deficits were related to brain morphology in the structures typically underlying these abilities (ventral and dorsal visual streams). Finally, since the longitudinal development of visual memory is not clearly characterized in 22q11.2DS, we investigated its evolution from childhood to adolescence.

Methods

Seventy-one patients with 22q11.2DS and 49 control individuals aged between 9 and 16 years completed the Benton Visual Retention Test (BVRT) and specific subtests assessing visual memory from the Children’s Memory Scale (CMS). The BVRT was used to compute spatial and object memory errors. For the CMS, specific subtests were classified into ventral, dorsal, and mixed subtests. Longitudinal data were obtained from a subset of 26 patients and 22 control individuals.

Results

Cross-sectional results showed that patients with 22q11.2DS were impaired in all visual memory measures, with stronger deficits in visual-object memory and memory of faces, compared to visuo-spatial memory. No correlations between morphological brain impairments and visual memory were found in patients with 22q11.2DS. Longitudinal findings revealed that participants with 22q11.2DS made more object memory errors than spatial memory errors at baseline. This difference was no longer significant at follow-up.

Conclusions

Individuals with 22q11.2DS have impairments in visual memory abilities, with more pronounced difficulties in memorizing faces and visual-object characteristics. From childhood to adolescence, the visual cognitive profile of patients with 22q11.2DS seems globally stable even though some processes show an evolution with time. We hope that our results will help clinicians and caregivers to better understand the memory difficulties of young individuals with 22q11.2DS. This has a particular importance at school to facilitate recommendations concerning intervention strategies for these young patients.

     

Visual scanpath abnormalities in 22q11.2 deletion syndrome: is this a face specific deficit?

People with 22q11.2 deletion syndrome (22q11DS) have deficits in face emotion recognition. However, it is not known whether this is a deficit specific to faces, or represents maladaptive information processing strategies to complex stimuli in general. This study examined the specificity of face emotion processing deficits in 22q11DS by exploring recognition accuracy and visual scanpath performance to a Faces task compared to a Weather Scene task. Seventeen adolescents with 22q11DS (11 = females, age = 17.4) and 18 healthy controls (11 = females, age = 17.7) participated in the study. People with 22q11DS displayed an overall impoverished scanning strategy to face and weather stimuli alike, resulting in poorer accuracy across all stimuli for the 22q11DS participants compared to controls. While the control subjects altered their information processing in response to faces, a similar change was not present in the 22q11DS group indicating different visual scanpath strategies to identify category within each of the tasks, of which faces appear to represent a particularly difficult subcategory. To conclude, while this study indicates that people with 22q11DS have a general visual processing deficit, the lack of strategic change between tasks suggest that the 22q11DS group did not adapt to the change in stimuli content as well as the controls, indicative of cognitive inflexibility rather than a face specific deficit.     

Is theory of mind related to social dysfunction and emotional problems in 22q11.2 deletion syndrome (velo-cardio-facial syndrome)?

Social dysfunction is intrinsically involved in severe psychiatric disorders such as depression and psychosis and linked with poor theory of mind. Children with 22q11.2 deletion syndrome (22q11DS, or velo-cardio-facial syndrome) have poor social competence and are also at a particularly high risk of developing mood (40%) and psychotic (up to 30%) disorders in adolescence and young adulthood. However, it is unknown if these problems are associated with theory of mind skills, including underlying social-cognitive and social-perceptual mechanisms. The present cross-sectional study included classic social-cognitive false-belief and mentalising tasks and social-perceptual face processing tasks. The performance of 50 children with 22q11DS was compared with 31 age-matched typically developing sibling controls. Key findings indicated that, while younger children with 22q11DS showed impaired acquisition of social-cognitive skills, older children with 22q11DS were not significantly impaired compared with sibling controls. However, children with 22q11DS were found to have social-perceptual deficits, as demonstrated by difficulties in matching faces on the basis of identity, emotion, facial speech and gaze compared with sibling controls. Furthermore, performance on the tasks was associated with age, language ability and parentally rated social competence and emotional problems. These results are discussed in relation to the importance of a better delineation of social competence in this population.     

Verbal short-term memory in individuals with chromosome 22q11.2 deletion: specific deficit in serial order retention capacities?

Many researchers have recently explored the cognitive profile of velocardiofacial syndrome (VCFS), a neurodevelopmental disorder linked to a 22q11.2 deletion. However, verbal short-term memory has not yet been systematically investigated. We explored verbal short-term memory abilities in a group of 11 children and adults presenting with VCFS and two control groups, matched on either CA or vocabulary knowledge, by distinguishing short-term memory for serial order and item information. The VCFS group showed impaired performance on the serial order short-term memory tasks compared to both control groups. Relative to the vocabulary-matched control group, item short-term memory was preserved. The implication of serial order short-term memory deficits on other aspects of cognitive development in VCFS (e.g., language development, numerical cognition) is discussed.     

Are hemianopic reading and visual exploration impairments visually elicited? New insights from eye movements in simulated hemianopia

Hemianopic reading and visual exploration impairments are well-known clinical phenomena. Yet, it is unclear whether they are primarily caused by the hemianopic visual field defect itself or by additional brain injury preventing efficient spontaneous oculomotor adaptation. To establish the extent to which these impairments are visually elicited we simulated unilateral homonymous hemianopia in healthy participants, using a gaze-contingent display paradigm, and investigated its effect on reading and visual exploration. We demonstrate that simulated hemianopia induces the reading and visual exploration impairments of hemianopic patients. Over time, however, all participants showed efficient spontaneous oculomotor adaptation to the visual-sensory loss which improved their reading and visual exploration performance. Our results suggest that the hemianopic visual field defect is a major component of the chronic impairments of reading and visual and exploration found in hemianopic patients although it may not be their sole cause.     

Does luminance‐contrast contribute to a saliency map for overt visual attention?

In natural environments, humans select a subset of visual stimuli by directing their gaze to locations attended. In previous studies it has been found that at fixation points luminance-contrast is higher than average. This led to the hypothesis that luminance-contrast makes a major contribution to a saliency map of visual overt attention, consistent with a computation of stimulus saliency in early visual cortical areas. We re-evaluate this hypothesis by using natural and modified natural images to uncover the causal effects of luminance-contrast to human overt visual attention and: (i) we confirm that when viewing natural images, contrasts are elevated at fixation points. This, however, only holds for low spatial frequencies and in a limited temporal window after stimulus onset; (ii) however, despite this correlation between overt attention and luminance-contrast, moderate modifications of contrast in natural images do not measurably affect the selection of fixation points. Furthermore, strong local reductions of luminance-contrast do not repel but attract fixation; (iii) neither contrast nor contrast modification is correlated to fixation duration; and (iv), even the moderate contrast modifications used fall into the physiologically relevant range, and subjects are well able to detect them in a forced choice paradigm. In summary, no causal contribution of luminance-contrast to a saliency map of human overt attention is detectable. In conjunction with recent results on the relation of contrast sensitivity of neuronal activity to the level in the visual cortical hierarchy, the present study provides evidence that, for natural scenes, saliency is computed not early but late during processing.     

Do visual attentional factors contribute to phonological ability? studies in adult dyslexia

A case study approach was taken to examine the role of visual attention and auditory memory processes in eight adults with dyslexia, all of whom demonstrated phonological difficulties. The participants were administered a battery of neuropsychological tests and participated in an attentional cueing experiment. Individual data revealed that, although one adult with dyslexia showed overt visual attention deficits on a visual search task, and five showed auditory working memory deficits, the difficulty that all of the adults with dyslexia had in common was with covert shifts of attention toward and away from fixation. These results indicate that deficits in overt visual attentional processing and working memory can be present with dyslexia, but neither is a necessary requirement. Overall, the results suggest that covert visual attention makes a significant contribution to phonological ability, which thus has implications for reading ability.     

Does cardiovascular autonomic dysfunction contribute to fatigue in Parkinson's disease?

Patients with Parkinson's disease often complain of fatigue, and although cardiac sympathetic denervation is thought to be associated with fatigue, this link remains unclear. Previously, we detected cardiac sympathetic denervation in patients with Parkinson's disease using dobutamine, a selective beta‐1 stimulant. To clarify the involvement of autonomic dysfunction in fatigue in Parkinson's disease, we conducted autonomic function tests on 33 patients with Parkinson's disease (mean age, 66.1 ± 5.6 years; 20 men, 13 women) and evaluated their relationships to fatigue. We divided patients into 2 groups, fatigued (n = 12) and nonfatigued (n = 21), based on an average score ≥ 3.3 on the Parkinson fatigue scale. Autonomic function tests included the coefficient of variation of R–R intervals, head‐up tilt test, norepinephrine and dobutamine infusion tests, and cardiac ¹²³I‐metaiodobenzylguanidine scintigraphy. The coefficient of variation of R–R intervals and the systolic blood pressure changes accompanying the head‐up tilt test did not show significant differences between the 2 groups; however, the pressor responses in the norepinephrine and dobutamine infusion tests were significantly greater in the fatigued group than in the nonfatigued group. The ¹²³I‐metaiodobenzylguanidine heart‐to‐mediastinal uptake ratio was lower in the fatigued group than in the nonfatigued group. Partial correlation analyses, using disease duration and Hoehn and Yahr stage as control variables, also demonstrated significant correlations between the Parkinson fatigue scale score and the results of the autonomic function tests and cardiac ¹²³I‐metaiodobenzylguanidine uptake. Our results suggest that autonomic dysfunction, including cardiac sympathetic denervation, is associated with fatigue in patients with Parkinson's disease. © 2011 Movement Disorder Society     

Does motoneuron adaptation contribute to muscle fatigue?

To help reduce the gap between the cellular physiology of motoneurons (MNs) as studied "bottom-up" in animal preparations and the "top-down" study of the firing patterns of human motor units (MUs), this article addresses the question of whether motoneuron adaptation contributes to muscle fatigue. Findings are reviewed on the intracellularly recorded electrophysiology of spinal MNs as studied in vivo and in vitro using animal preparations, and the extracellularly recorded discharge of MUs as studied in conscious humans. The latter "top-down" approach, combined with kinetic measurements, has provided most of what is currently known about the neurobiology of muscle fatigue, including its task and context dependencies. It is argued that although the question addressed is still open, it should now be possible to design new "bottom-up" research paradigms using animal preparations that take advantage of what has been learned with the use of relatively noninvasive quantitative procedures in conscious humans.     

Does cardiac conduction pathology contribute to sudden unexpected death in epilepsy?

Heart weights have been reported to be increased in those dying suddenly and unexpectedly from epilepsy (SUDEP) and it has been suggested that cardiac pathology including cardiac conduction pathology and coronary artery atheroma may contribute to SUDEP. The purpose of this study was to perform a detailed controlled study of the microscopic pathology of the cardiac conduction system in SUDEP cases, in addition to assessing coronary artery atheroma and other cardiac pathology. The hearts of ten SUDEPs and ten control subjects (no history of epilepsy and a cause of death not primarily cardiac) were examined macroscopically and microscopically by two pathologists blinded to the patient group. Morphological abnormalities of the cardiac conduction system that could have possibly contributed to death were not increased in the SUDEP group (four cases showed such changes in the SUDEP group vs. six in the control). There was no significant difference between the maximal percentage coronary artery stenoses between the two groups and no increased prevalence of other cardiac pathology in the SUDEP group. However, since subtle abnormalities of the conduction system were identified in some of the epileptic deaths, it is still feasible that these may contribute to death by causing cardiac arrhythmia, when associated with apnoea, bradycardia or other cardiac arrhythmia related to an epileptic seizure.     

Does the fusion pore contribute to synaptic plasticity?

How synapses change their strength in response to impinging neural activity is a fundamental issue for understanding how the brain molds its circuitry in response to behavioral experience. Although a growing number of studies reveal the involvement of postsynaptic changes contributing to synaptic plasticity in brain circuits, the involvement of presynaptic factors has been implied by several studies. Most recently, several works point to the mechanism of vesicle fusion as a new possible locus for the modification of presynaptic synaptic strength. However, it is not yet clear to what extent such changes affect the simplest form of information transfer in the brain--the transmission of a single action potential.     

Does visual impairment lead to additional disability in adults with intellectual disabilities?

Background   This study addresses the question to what extent visual impairment leads to additional disability in adults with intellectual disabilities (ID).
Method   In a multi-centre cross-sectional study of 269 adults with mild to profound ID, social and behavioural functioning was assessed with observant-based questionnaires, prior to expert assessment of visual function. With linear regression analysis the percentage of variance, explained by levels of visual function, was calculated for the total population and per ID level.
Results   A total of 107/269 participants were visually impaired or blind (WHO criteria). On top of the decrease by ID visual impairment significantly decreased daily living skills, communication & language, recognition/communication. Visual impairment did not cause more self-absorbed and withdrawn behaviour or anxiety. Peculiar looking habits correlated with visual impairment and not with ID. In the groups with moderate and severe ID this effect seems stronger than in the group with profound ID.
Conclusion   Although ID alone impairs daily functioning, visual impairment diminishes the daily functioning even more. Timely detection and treatment or rehabilitation of visual impairment may positively influence daily functioning, language development, initiative and persistence, social skills, communication skills and insecure movement.