Shirley Yin-Yu Pang

The default mode network is disrupted in parkinson's disease with visual hallucinations

Background: Visual hallucinations (VH) are one of the most striking nonmotor symptoms in Parkinsons disease (PD), and predict dementia and mortality. Aberrant default mode network (DMN) is associated with other psychoses. Here, we tested the hypothesis that DMN dysfunction contributes to VH in PD. Methods: Resting state functional data was acquired from individuals with PD with VH (PDVH) and without VH (PDnonVH), matched for levodopa drug equivalent dose, and a healthy control group (HC). Independent component analysis was used to investigate group differences in functional connectivity within the DMN. In addition, we investigated whether the functional changes associated with hallucinations were accompanied by differences in cortical thickness. Results: There were no group differences in cortical thickness but functional coactivation within components of the DMN was significantly lower in both PDVH and PDnonVH groups compared to HC. Functional coactivation within the DMN was found to be greater in PDVH group relative to PDnonVH group. Conclusion: Our study demonstrates, for the first time that, within a functionally abnormal DMN in PD, relatively higher “connectivity” is associated with VH. We postulate that aberrant connectivity in a large scale network affects sensory information processing and perception, and contributes to “positive” symptom generation in PD. Hum Brain Mapp 35:5658–5666, 2014.

Multimodal MRI of the hippocampus in Parkinson’s disease with visual hallucinations

Visual hallucinations carry poor prognosis in Parkinson’s disease. Here we tested the hypothesis that the hippocampus and visuospatial memory impairment play a central role in the pathology of PD with visual hallucinations. Multimodal magnetic resonance imaging of the brain was carried out in 12 people with PD and visual hallucinations; 15 PD individuals without hallucinations; and 14 healthy controls. Age, gender, cognitive ability, and education level were matched across the three groups. PD patients were taking dopaminergic medication. Hippocampal volume, shape, mean diffusivity (MD), and functional connectivity within the whole brain were examined. Visuospatial memory was compared between groups, and correlations with hippocampal MD, functional connectivity, and the severity of hallucinations were explored. There were no macrostructural differences across groups, but individuals with hallucinations had higher diffusivity in posterior hippocampus than the other two groups. Visuospatial memory was poorer in both PD groups compared to controls, and was correlated with hallucinations. Finally, hippocampal functional connectivity in the visual cortices was lower in those with hallucinations than other groups, and this correlated with visuospatial memory impairment. In contrast, functional connectivity between the hippocampus and default mode network regions and frontal regions was greater in the PD hallucinators compared to other groups. We suggest that hippocampal pathology, which disrupts visuospatial memory, makes a key contribution to visual hallucinations in PD. These findings may pave the way for future studies of imaging biomarkers to measure treatment response in those with PD who are most at risk of poor outcomes.

PMCA4 (ATP2B4) Mutation in Familial Spastic Paraplegia

Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. In this study, we identified a novel missense mutation (c.803G>A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP using whole-exome sequencing and confirmed with Sanger sequencing. This mutation co-segregated with the phenotype in the six family members studied and is predicted to be pathogenic when multiple deleteriousness predictions were combined. This novel R268Q mutation was not present in over 7,000 subjects in public databases, and over 1,000 Han Chinese in our database. Prediction of potential functional consequence of R268Q mutation on PMCA4 by computational modeling revealed that this mutation is located in protein aggregation-prone segment susceptible to protein misfolding. Analysis for thermodynamic protein stability indicated that this mutation destabilizes the PMCA4 protein structure with higher folding free energy. As PMCA4 functions to maintain neuronal calcium homeostasis, our result showed that calcium dysregulation may be associated with the pathogenesis of FSP.

PMCA4 (ATP2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion

Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. Recently, we described a novel missense mutation (c.803G>A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP. Further to this finding, here we describe the functional effect of this mutation.

LRRK2 R1441G mice are more liable to dopamine depletion and locomotor inactivity

Mutations in leucine‐rich repeat kinase 2 (LRRK2) pose a significant genetic risk in familial and sporadic Parkinsons disease (PD). R1441 mutation (R1441G/C) in its GTPase domain is found in familial PD. How LRRK2 interacts with synaptic proteins, and its role in dopamine (DA) homeostasis and synaptic vesicle recycling remain unclear.

Single-nucleotide polymorphism of transient axonal glycoprotein-1 and its correlation with clinical features and prognosis in chronic inflammatory demyelinating polyneuropathy

The single‐nucleotide polymorphism (SNP) rs2275697 in the transient axonal glycoprotein‐1 (TAG‐1) gene was reported to be associated with responsiveness to intravenous immunoglobulin (IVIG) treatment in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). However, it is not known if this SNP is associated with long‐term prognosis. We examined the case records of 32 Chinese CIDP patients. The overall response rate to IVIG, prednisolone, or plasmapheresis was 83%. After 5.4 years, 57% of patients were on maintenance immunotherapy. Patients with higher modified Rankin score and more prolonged distal motor latencies in the upper limbs on presentation had a higher risk (odds ratio [OR] 3.86, 95% confidence interval [CI] 1.23–12.11 and OR 1.04, 95% CI 1.01–1.07, respectively) of being on maintenance immunotherapy. Blood samples from 24 patients and 147 controls were examined for their genotypes of four non‐synonymous SNPs (rs41264871, rs36074532, rs5611135, and rs2275697) in the coding region of TAG‐1. The G allelic frequency of rs2275697 was similar between CIDP patients and controls (56% and 50%, respectively) and was not associated with treatment responsiveness, treatment dependence, disability, or mortality.

Combined LRRK2 mutation, aging and chronic low dose oral rotenone as a model of Parkinson’s disease

Aging, genetics and environmental toxicity are important etiological factors in Parkinson’s disease (PD). However, its pathogenesis remains unclear. A major obstacle is the lack of an appropriate experimental model which incorporates genetic susceptibility, aging and prolonged environmental toxicity. Here, we explored the interplay amongst these factors using mutant LRRK2R1441G (leucine-rich-repeat-kinase-2) knockin mice. We found that mutant primary cortical and mesencephalic dopaminergic neurons were more susceptible to rotenone-induced ATP deficiency and cell death. Compared with wild-type controls, striatal synaptosomes isolated from young mutant mice exhibited significantly lower dopamine uptake after rotenone toxicity, due to reduced striatal synaptosomal mitochondria and synaptic vesicular proton pump protein (V-ATPase H) levels. Mutant mice developed greater locomotor deficits in open-field tests than wild-type mice following low oral rotenone doses given twice weekly over 50 weeks (half their lifespan). The increased locomotor deficit was associated with specific reduction in striatal mitochondrial Complex-I (NDUFS4) in rotenone-treated mutant but not in similarly treated wild-type mice. Our unique experimental model which incorporates genetic effect, natural aging and prolonged oral environmental toxicity administered to mutant knockin LRRK2 mice over half their life span, with observable and measurable phenotype, is invaluable in further studies of the pathogenic process and therapeutics of PD.

The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review

The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms. It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder. The advent of next generation sequencing (NGS) has allowed for a system-wide, unbiased approach to identify all gene variants in the genome simultaneously. With the plethora of new genes being identified, genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia (SCA), hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth disease (CMT) has become widely accepted. It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). The observation of pleiotropy has emerged, with mutations in the same gene giving rise to diverse phenotypes, which further increases the complexity of phenotype-genotype correlation. Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene, presence of modifier genes, and oligogenic inheritance. Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms, translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies, and ultimately finding disease-modifying therapies for neurodegenerative disorders.

Visuomotor control in patients with Parkinson's disease

Previous studies have suggested that the deteriorated visuomotor control in patients with PD (Parkinsons disease) is due to deficits in various aspects of the sensory-motor processing rather than motor control itself. In the current study, by taking a control-theoretic approach, we systematically examined how PD and antiparkinsonian medication affect visuomotor control and the underlying sensory-motor system. We tested 20 PD patients in both ON and OFF medication states and 20 demographically matched healthy controls with a commonly used manual control task. Specifically, in each 95-s trial, participants were instructed to use a joystick to control a randomly moving target to keep it centered on a computer display. We found that although antiparkinsonian medication improved visuomotor control in PD patients, they still showed significantly decreased control precision (measured by RMS error) and response amplitude (gain) as well as increased response delay (phase lag) compared with healthy controls. Our model-driven analysis revealed that PD impairs the responsiveness and the predicting ability of the sensory-motor system as well as the stability of the neuromuscular system. Taking antiparkinsonian medication improves the responsiveness of the sensory-motor system. More importantly, it improves the ability of the sensory-motor system to make sensory predictions of the current control actions (see Wolpert et al., 1995) to anticipate the input error signals and generate control responses ahead of time up to the level of healthy controls. However, taking antiparkinsonian medication does not improve the stability of the neuromuscular system. These results support the claim that the effect of antiparkinsonian medication on visuomotor control is mainly through improving visual-stimulus-dependent sensory-motor processing. The present study provides the first quantitative examination of the effects of PD and antiparkinsonian medication on the visual-stimulus-dependent sensory-motor and visual-stimulus-independent neuromuscular systems underlying visuomotor control. The findings have practical implications for developing sensitive assessment tools to evaluate the efficacy of different therapies for PD and preliminary screening and training tools for fitness-to-drive in PD patients.

Quantitative susceptibility mapping as an indicator of subcortical and limbic iron abnormality in Parkinson's disease with dementia

Late stage Parkinsons disease (PD) patients were commonly observed with other non-motor comorbidities such as dementia and psychosis. While abnormal iron level in the substantia nigra was clinically accepted as a biomarker of PD, it was also suggested that the increased iron deposition could impair other brain regions and induce non-motor symptoms. A new Magnetic Resonance Imaging (MRI) called Quantitative Susceptibility Mapping (QSM) has been found to measure iron concentration in the grey matter reliably. In this study, we investigated iron level of different subcortical and limbic structures of Parkinsons disease (PD) patients with and without dementia by QSM. QSM and volumetric analysis by MRI were performed in 10 PD dementia (PDD) patients (73 ± 6 years), 31 PD patients (63 ± 8 years) and 27 healthy controls (62 ± 7 years). No significant differences were observed in the L-Dopa equivalent dosage for the two PD groups (p = 0.125). Putative iron content was evaluated in different subcortical and limbic structures of the three groups, as well as its relationship with cognitive performance. One-way ANCOVA with FDR adjustment at level of 0.05, adjusted for age and gender, showed significant group differences for left and right hippocampus (p = 0.015 & 0.032, respectively, BH-corrected for multiple ROIs) and right thalamus (p = 0.032, BH-corrected). Post-hoc test with Bonferronis correction suggested higher magnetic susceptibility in PDD patients than healthy controls in the left and right hippocampus (p = 0.001 & 0.047, respectively, Bonferronis corrected), while PD patients had higher magnetic susceptibility than the healthy controls in right hippocampus and right thalamus (p = 0.006 & 0.005, respectively, Bonferronis corrected). PDD patients also had higher susceptibility than the non-demented PD patients in left hippocampus (p = 0.046, Bonferronis corrected). The magnetic susceptibilities of the left and right hippocampus were negatively correlated with the Mini-Mental State Examination score (r = −0.329 & -0.386, respectively; p < 0.05). This study provides support for iron accumulation in limbic structures of PDD and PD patients and its correlation with cognitive performance, however, its putative involvement in development of non-motor cognitive dysfunction in PD pathogenesis remains to be elucidated.