Association analyses of apolipoprotein E genotypes and cognitive performance in patients with Parkinson's disease.

BACKGROUND: Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD). The apolipoprotein E (APOE) ε4 genotype increases the risk of Alzheimer's disease (AD). However, the effect of APOEε4 on cognitive function of PD patients remains unclear. In this study, we aimed to understand whether and how carrying APOEε4 affects cognitive performance in patients with early-stage and advanced PD. METHODS: A total of 119 Chinese early-stage PD patients were recruited. Movement Disorder Society Unified Parkinson's Disease Rating Scale, Hamilton anxiety scale, Hamilton depression scale, non-motor symptoms scale, Mini-mental State Examination, Montreal Cognitive Assessment, and Fazekas scale were evaluated. APOE genotypes were determined by polymerase chain reactions and direct sequencing. Demographic and clinical information of 521 early-stage and 262 advanced PD patients were obtained from Parkinson's Progression Marker Initiative (PPMI). RESULTS: No significant difference in cognitive performance was found between ApoEε4 carriers and non-carriers in early-stage PD patients from our cohort and PPMI. The cerebrospinal fluid (CSF) Amyloid Beta 42 (Aß42) level was significantly lower in ApoEε4 carrier than non-carriers in early-stage PD patients from PPMI. In advanced PD patients from PPMI, the BJLOT, HVLT retention and SDMT scores seem to be lower in ApoEε4 carriers without reach the statistical significance. CONCLUSIONS: APOEε4 carriage does not affect the cognitive performance of early-stage PD patients. However, it may promote the decline of CSF Aß42 level and the associated amyloidopathy, which is likely to further contribute to the cognitive dysfunction of PD patients in the advanced stage.

Carpets with visual cues can improve gait in Parkinson's disease patients: may be independent of executive function.

BACKGROUND: Gait impairment is common in Parkinson's disease (PD) patients, which greatly reduces their quality of life. Executive dysfunction is associated with gait impairment. Compensatory strategies, including visual cues, have been shown to be effective in improving PD gait. In this study, we aimed to understand whether carpets with visual cues could improve PD gait, and how the improvement varies across patients with different executive function state. METHODS: We designed carpets with chessboard and stripe cues. A total of 65 Chinese PD patients were recruited. Movement Disorder Society Unified Parkinson's Disease Rating Scale, L-dopa equivalent daily dosage, Hoehn & Yahr stage, Frontal Assessment Battery, Mini Mental State Examination Scale, Hamilton Anxiety Scale, and Hamilton Depression Scale were evaluated. Gait parameters including stride length, gait speed and fall risk were recorded by a wearable electronic device. RESULTS: The stride length and gait speed were significantly improved and the fall risk was significantly mitigated when PD patients walked on carpets with chessboard and stripe patterns. Further analysis showed the amelioration of gait parameters was independent of executive dysfunction. CONCLUSIONS: Our study demonstrates that carpets with visual cues can improve the gait of PD patients even in those with mild executive dysfunction.

Isolated unilateral oculomotor palsy caused by pure midbrain infarction: a case report.

Purpose: Multiple etiologies may cause oculomotor nerve palsies. Identification of different etiologies is very important for subsequent treatment. Midbrain infarction is a rare cause of oculomotor nerve palsy. Materials and methods: We herein present a case of isolated unilateral oculomotor paresis caused by pure midbrain infarction. Results: Her pupillary sphincter and inferior rectus muscles were selectively spared. The symptoms were completely relieved after two months of antiplatelet therapy. We proposed that fibers from Edinger-Westphal nucleus and inferior rectus nucleus do not course through the paramedian area of the midbrain. Conclusions: Our report adds to the understanding of fascicles arrangement in the midbrain.

Reduced platelet 5-HT content is associated with rest tremor in Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is highly heterogeneous in manifestations and pathogenesis. Serotonergic neurotransmitter system dysfunction is frequently implicated in PD tremor. Serotonin (5-HT) content in platelets is highly correlated with that in cerebrospinal fluid. In this study, we aimed to understand whether and how platelet 5-HT content reflects tremor in PD. METHOD: A total of 139 Chinese PD patients met with inclusion criteria were recruited. Motor and non-motor scores, and disease severity were evaluated. Patients were classified into subtypes of tremor-dominant (TD) and non-tremor-dominant (NTD). Peripheral platelets were isolated, and platelet 5-HT levels were measured. RESULTS: Platelet 5-HT content was lower in PD patients of TD subtype than in NTD subtype. Multifactor risk analysis showed that this lower content was independently associated with the TD phenotype. Platelet 5-HT level was inversely correlated with total tremor score, rest tremor amplitude score, rest tremor constancy score, and index of rest tremor, but not with postural tremor score, and kinetic tremor score. CONCLUSION: The cross-sectional study demonstrates that reduced platelet 5-HT content is associated with PD rest tremor. Our results support the involvement of serotonergic disturbance in PD rest tremor and indicate that 5-HT reduction can be manifested in peripheral platelets.

Parkinsonism-Hyperpyrexia Syndrome and Dyskinesia-Hyperpyrexia Syndrome in Parkinson's Disease: Two Cases and Literature Review.

Parkinsonism-hyperpyrexia syndrome (PHS) and dyskinesia-hyperpyrexia syndrome (DHS) are rare but exhibit life-threatening complications in Parkinson's disease (PD). We herein presented two cases of PD patients and performed a comprehensive and comparative literature review for these two syndromes. The first case was diagnosed as PHS with cerebral salt wasting syndrome caused by abrupt withdrawal of antiparkinsonian medication. Her symptoms were gradually remitted with reinstitution of the medication. The second one was an early-stage PD patient diagnosed as DHS in association with abuse of antiparkinsonian drugs. Her symptoms were gradually remitted with reduced dosage of dopaminergic drugs. Results of literature reviews revealed a total of 56 and 13 cases of PHS and DHS, respectively, and they were more likely to occur in elderly and long-term PD patients. These two syndromes showed different female-to-male ratio, similar mortality, and different recovery time. There were stark differences between PHS and DHS, including triggers (abrupt drug stoppage versus drug abuse), symptoms (worsened tremor and rigidity versus continuous dyskinesia), and treatment (drug reinstitution versus drug reduction). In summary, our reports and the review provide new insights into PHS and DHS in association with PD and may facilitate rapid discrimination of the syndromes for timely and proper treatment to reduce mortality.

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants. METHODS: Primary astrocytes were isolated and cultured using neurobasal-based serum-free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor α, and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses, and the underlying mechanisms were analyzed. RESULTS: All the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1ß (IL-1ß). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1ß but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity. CONCLUSIONS: The study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes.

Association Analyses of Autonomic Dysfunction and Sympathetic Skin Response in Motor Subtypes of Parkinson's Disease.

Introduction: Autonomic dysfunction is a common and disabling non-motor symptom of Parkinson's disease (PD). We aimed to understand autonomic dysfunction in PD motor subtypes, the pattern of sympathetic skin response (SSR) to motor asymmetry, and the association of SSR with autonomic and motor dysfunctions. Methods: A total of 101 PD patients of Han Chinese were included. Unified PD rating scale (UPDRS), scales for outcomes in PD-autonomic symptoms (SCOPA-AUT), orthostatic hypotension, and SSR were evaluated. Results: SCOPA-AUT and incidences of orthostatic hypotension and absent SSR were worse in the subtype of postural instability gait disorder (PIGD) than the subtypes of tremor dominant and intermediate. SSR latency and amplitude were asymmetrical corresponding to the accentuation of motor severity. Patients with absent SSR had worse UPDRS and SCOPA-AUT scores. SSR parameters of the severe side in patients with SSR showed no independent association with the scores. Conclusion: Our results support that autonomic dysfunction is more severe in the PIGD than other subtypes and demonstrate an asymmetry of SSR in PD patients. Absent SSR may indicate worse autonomic and motor symptoms, but SSR parameters are not sufficient to evaluate the severity of the dysfunctions.

Prioritized brain selenium retention and selenoprotein expression: Nutritional insights into Parkinson's disease.

Selenium (Se), an essential trace mineral, confers its physiological functions mainly through selenoproteins, most of which are oxidoreductases. Results from animal, epidemiological, and human genetic studies link Parkinson's disease to Se and certain selenoproteins. Parkinson's disease is characterized by multiple motor and non-motor symptoms that are difficult to diagnose at early stages of the pathogenesis. While irreversible, degenerative and age-related, the onset of Parkinson's disease may be delayed through proper dietary and environmental controls. One particular attribute of Se biology is that brain has the highest priority to receive and retain this nutrient even in Se deficiency. Thus, brain Se deficiency is rare; however, a strong body of recent evidence implicates selenoprotein dysfunction in Parkinson's disease. Direct and indirect evidence from mouse models implicate selenoprotein T, glutathione peroxidase 1, selenoprotein P and glutathione peroxidase 4 in counteracting Parkinson's disease through Se transportation to the brain and reduced oxidative stress. It is of future interest to further characterize the full selenoproteomes in various types of brain cells and elucidate the mechanism of their actions in Parkinson's disease.

[Effect of Shouwu Shudi Yin on dopaminegic neurons in MPTP induced Parkinson's disease mouse model].

In order to investigate the effect of Shouwu Shudi Yin on dopaminegic neurons in MPTP induced Parkinson's disease mouse model and the possible mechamism, the experimental mice were randomly divided into 4 groups: control, Shouwu Shudi Yin, MPTP and the treatment (MPTP+Shouwu Shudi Yin) groups. The number of tyrosine hydroxylase (TH) positive cells in the substantia nigra was measured by immunohistochemistry, and mRNA expression of TH and glutathione peroxidase (GPX) were detected by PCR. The results showed that the number of TH positive cells and mRNA expression of TH were significantly reduced in MPTP group compared with the control (P<0.05), and pretreated with Shouwu Shudi Yin didn't show protective effect. Compared to MPTP group, the mRNA expression of four subtypes of GPX were increased in various degrees in the treatment group pretreated with Shouwu Shudi Yin, although the difference was not statistically significant. These indicated that the preventive medication of Shouwu Shudi Yin don't have protective effect on the mice with Parkinson' s disease induced by MPTP, but it may enhance the antioxidant capacity through increasing the expression of GPX.

Paroxetine ameliorates lipopolysaccharide-induced microglia activation via differential regulation of MAPK signaling.

BACKGROUND: Paroxetine, a selective serotonin reuptake inhibitor for counteracting depression, has been recently suggested as having a role in prevention of dopaminergic neuronal degeneration in substantia nigra, a hallmark of Parkinson's disease (PD). The pathogenesis of this type of neurological disorders often involves the activation of microglia and associated inflammatory processes. Thus in this study we aimed to understand the role of paroxetine in microglia activation and to elucidate the underlying mechanism(s). METHODS: BV2 and primary microglial cells were pretreated with paroxetine and stimulated with lipopolysaccharide (LPS). Cells were assessed for the responses of pro-inflammatory mediator and cytokines, and the related signaling pathways were evaluated and analyzed in BV2 cells. RESULTS: Paroxetine significantly inhibited LPS-induced production of nitric oxide (NO) and pro-inflammatory cytokines such as TNF-α and IL-1ß. Further analysis showed inducible nitric oxide synthase (iNOS) and mRNA expression of TNF-α and IL-1ß were attenuated by paroxetine pretreatment. Analyses in signaling pathways demonstrated that paroxetine led to suppression of LPS-induced JNK1/2 activation and baseline ERK1/2 activity, but had little effect on the activation of p38 and p65/NF-κB. Interference with specific inhibitors revealed that paroxetine-mediated suppression of NO production was via JNK1/2 pathway while the cytokine suppression was via both JNK1/2 and ERK1/2 pathways. Furthermore, conditioned media culture showed that paroxetine suppressed the microglia-mediated neurotoxicity. CONCLUSIONS: Paroxetine inhibits LPS-stimulated microglia activation through collective regulation of JNK1/2 and ERK1/2 signaling. Our results indicate a potential role of paroxetine in neuroprotection via its anti-neuroinflammatory effect besides targeting for depression.

Association analysis of PARK16-18 variants and Parkinson's disease in a Chinese population.

Genome-wide association studies identified PARK16 variants rs823128 and rs947211, PARK17/GAK rs11248051 and PARK18/HLA-DRA rs3129882 as risk factors for Parkinson's disease (PD). However the susceptibility of these loci to predisposing individuals for PD, particularly rs11248051, remains under investigation in Chinese populations. A total of 323 PD patients and 345 age and sex matched controls were recruited in eastern China. Our results show that minor allele frequencies of rs11248051 (odds ratio [OR] 1.522; p=0.016) and rs3129882 (OR 1.294; p=0.03), but not rs823128 and rs947211, were associated with risk for PD. Genetic interaction analysis revealed that subjects simultaneously carrying the T allele (TC or TT) of rs11248051 and the A allele (AG or AA) of rs3129882 had an aggravated risk (OR 1.91; p=0.016) of PD. However, rs11248051 or rs3129882 displayed no association with PD phenotypes or clinical scores. Our results suggest that rs11248051 and rs3129882 are risk factors for sporadic PD in a Chinese population, and their genetic interplay contributes to an elevated risk for PD predisposition. Our data provide a novel insight and further information regarding PARK16-18 loci in PD susceptibility.