PINK1 mutations in sporadic early-onset Parkinson's disease.

Pathogenic PINK1 mutations have been described in PARK6-linked Parkinson's disease (PD) patients of Asian origin. However, data on the frequency of PINK1 mutations in sporadic early-onset Parkinson's disease (EOPD) Asian patients are lacking. The objectives of this study were to report the frequency of PINK1 mutations of sporadic EOPD in an Asian cohort comprising of ethnic Chinese, Malays, and Indians, and to highlight a PINK1-positive patient who presented with restless legs symptoms. Eighty consecutive sporadic EOPD patients from the movement disorder clinics of two major tertiary institutions in the country were included. We performed sequence analysis of all the coding and exon-intron junctions of the PINK1 using specific primer sets. In addition, we genotyped polymorphisms detected from the analysis in a group of sporadic PD patients and controls. Three different mutations (two homozygous nonsense and one heterozygous missense) in the putative kinase domain were found in three patients, giving a 3.7% frequency of PINK1 mutations in our EOPD cohort. All the mutations were absent in 200 healthy controls. One patient with a novel homozygous nonsense PINK1 mutation presented unusually with restless legs symptoms. Separately, analysis of the frequency of four PINK1 polymorphisms in a group of sporadic PD and controls did not reveal any significant differences. We highlight a 3.7% frequency of PINK1 mutations in an Asian cohort (ethnic Chinese, Malay, and Indian) of EOPD. The phenotypic spectrum associated with PINK1-positive patients may be wider than previously reported. Polymorphisms of PINK1 do not appear to modulate risk of PD in our population.     

Functional redundancy of NSCL-1 and NeuroD during development of the petrosal and vestibulocochlear ganglia

To study the role of different members of the bHLH gene family for sensory organ development we have generated NSCL-1 and NeuroD compound-mutant mice. Double homozygous animals were characterized by a more severe reduction of the petrosal and vestibulocochlear ganglia than NeuroD-knockout mice. The more severe reduction of the petrosal and vestibulocochlear ganglia in double-knockout mice indicates overlapping functions of the two genes during neuronal development. Interestingly, we also found that the two genes are jointly regulated by thyroid hormone during sensory hair cell development. We further present a detailed expression analysis of NSCL-1 and NSCL-2 during sensory neuron development. NSCL-1 expression was detected in all developing cranial ganglia including the petrosal and vestibulocochlear ganglion, in inner and outer hair cells of the organ of Corti and in hair cells of the vestibular system. Expression domains in other sensory structures include the retina, Merkel cells of the developing skin and sensory cells of the tongue. The expression of NSCL-2 was restricted to developing cranial ganglia, the retina and the vestibular nerve. Both NSCL-1 and NSCL-2 genes are active only in postmitotic neurons, indicating a role for neuronal cell migration and/or differentiation within the sensory system.     

Personal characteristics and school contextual variables associated with student self-determination in Spanish context

Background: Most theoretical models of self-determination suggest that both environmental and personal factors influence the development of self-determination. The design and implementation of interventions must be conducted with foreknowledge of such mediating and moderating factors if the intervention is to be successful.

Methods: The purpose of this study was to examine the degree to which several personal factors and school characteristics affect and explain students’ self-determination. A total of 232 students with intellectual disability from Spain participated. Their self-determination level was assessed by the ARC-INICO Scale.

Results: Students with moderate levels of intellectual disability obtained significantly lower scores on self-determination than their peers with mild intellectual disability. There were significant differences in relation to the level of support needs and their experience with transition programs. The level of support needs was a significant predictor.

Conclusion: These findings contribute to current research in this field and practical implications were discussed.     

Serum neurofilaments increase at progressive multifocal leukoencephalopathy onset in natalizumab‐treated multiple sclerosis patients

This study analyzed serum neurofilament light chains (NfL) in 2 European cohorts of 312 multiple sclerosis (MS) patients to investigate whether NfL are biomarkers of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment. The cohort comprised 25 PML, 136 natalizumab‐treated, and 151 untreated MS patients. Patients subsequently developing PML had similar NfL to other natalizumab‐treated MS patients. At PML onset, NfL were 10‐fold higher than in the pre‐PML condition and in natalizumab‐treated or untreated MS patients, and NfL continued to increase until onset of immune reconstitution inflammatory syndrome. The results suggest that in natalizumab‐treated patients, NfL may represent an early and accessible marker of PML. Ann Neurol 2019;85:606–610     

Accumulation of prion protein in the vagus nerve in creutzfeldt–jakob disease

Disease‐associated proteins are thought to propagate along neuronal processes in neurodegenerative diseases. To detect disease‐associated prion protein (PrP^Sc) in the vagus nerve in different forms and molecular subtypes of Creutzfeldt–Jakob disease (CJD), we applied 3 different anti‐PrP antibodies. We screened the vagus nerve in 162 sporadic and 30 genetic CJD cases. Four of 31 VV‐2 type sporadic CJD and 7 of 30 genetic CJD cases showed vagal PrP^Sc immunodeposits with distinct morphology. Thus, PrP^Sc in CJD affects the vagus nerve analogously to α‐synuclein in Parkinson disease. The morphologically diverse deposition of PrP^Sc in genetic and sporadic CJD argues against uniform mechanisms of propagation of PrP^Sc. Ann Neurol 2019;85:782–787     

Longitudinally consistent estimates of intrinsic functional networks

Increasing numbers of neuroimaging studies are acquiring data to examine changes in brain architecture by investigating intrinsic functional networks (IFN) from longitudinal resting‐state functional MRI (rs‐fMRI). At the subject level, these IFNs are determined by cross‐sectional procedures, which neglect intra‐subject dependencies and result in suboptimal estimates of the networks. Here, a novel longitudinal approach simultaneously extracts subject‐specific IFNs across multiple visits by explicitly modeling functional brain development as an essential context for seeking change. On data generated by an innovative simulation based on real rs‐fMRI, the method was more accurate in estimating subject‐specific IFNs than cross‐sectional approaches. Furthermore, only group‐analysis based on longitudinally consistent estimates identified significant developmental effects within IFNs of 246 adolescents from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. The findings were confirmed by the cross‐sectional estimates when the corresponding group analysis was confined to the developmental effects. Those effects also converged with current concepts of neurodevelopment.     

Cognitive mapping style relates to posterior–anterior hippocampal volume ratio

As London taxi drivers acquire “the knowledge” and develop a detailed cognitive map of London, their posterior hippocampi (pHPC) gradually increase in volume, reflecting an increasing pHPC/aHPC volume ratio. In the mnemonic domain, greater pHPC/aHPC volume ratios in young adults have been found to relate to better recollection ability, indicating that the balance between pHPC and aHPC volumes might be reflective of cross‐domain individual differences. Here, we examined participants' self‐reported use of cognitive map‐based navigational strategies in relation to their pHPC/aHPC hippocampal volume ratio. We find that greater reported cognitive map use was related to significantly greater posterior, relative to anterior, hippocampal volume in two separate samples of young adults. Further, greater reported cognitive map usage correlated with better performance on a self‐initiated navigation task. Together, these data help to advance our understanding of differences between aHPC and pHPC and the greater role of pHPC in spatial mapping.     

Dyskinesia and FAB score predict future falling in Parkinson's disease

A growing body of research highlights the importance of cognition for prediction of falls in Parkinson's disease (PD). However, a previously proposed prediction model for future near falls and falls in PD, which includes history of near falls, tandem gait, and retropulsion, was developed without considering cognitive impairment. Therefore, by using a sample of 64 individuals with relatively mild PD and not excluding those with impaired cognition we aimed to externally validate the previously proposed model as well as to explore the value of additional predictors that also consider cognitive impairment. Since this validation study failed to support the proposed model in a PD sample including individuals with impaired global cognition, extended analyses generated a new model including dyskinesia (item 32 of Unified PD Rating Scale) and frontal lobe impairment (Frontal Assessment Battery—FAB) as significant independent predictors for future near falls and falls in PD. The discriminant ability of this new model was acceptable (AUC, 0. 80; 95% CI 0.68‐0.91). Replacing the continuous FAB scores by a dichotomized version of FAB with a cut‐off score ≤14 yielded slightly lower but still acceptable discriminant ability (AUC, 0. 79; 95% CI 0.68‐0.91). Further studies are needed to test our new model and the proposed cut‐off score of FAB in additional samples. Taken together, our observations suggest potentially important additions to the evidence base for clinical fall prediction in PD with concomitant cognitive impairment.     

Pushing attention to one side: Force field adaptation alters neural correlates of orienting and disengagement of spatial attention

Sensorimotor adaptation to wedge prisms can alter the balance of attention between left and right space in healthy adults, and improve symptoms of spatial neglect after stroke. Here we asked whether the orienting of spatial attention to visual stimuli is affected by a different form of sensorimotor adaptation that involves physical perturbations of arm movement, rather than distortion of visual feedback. Healthy participants performed a cued discrimination task before and after they made reaching movements to a central target. A velocity‐dependent force field pushed the hand aside during each reach, and required participants to apply compensatory forces toward the opposite side. We used event‐related potentials (ERPs) to determine whether electroencephalography (EEG) responses reflecting orienting (cue‐locked N1) and disengagement (target‐locked P1) of spatial attention are affected by adaptation to force fields. After adaptation, the cue‐locked N1 was relatively larger for stimuli presented in the hemispace corresponding to the direction of compensatory hand force. P1 amplitudes evoked by invalidly cued targets presented on the opposite side were reduced. This suggests that force field adaptation boosted attentional orienting responses toward the side of hand forces, and impeded attentional disengagement from that side, mimicking previously reported effects of prism adaptation. Thus, remapping between motor commands and intended movement direction is sufficient to bias ERPs, reflecting changes in the orienting of spatial attention in the absence of visuo‐spatial distortion or visuo‐proprioceptive mismatch. Findings are relevant to theories of how sensorimotor adaptation can modulate attention, and may open new avenues for treatment of spatial neglect.