Clinical features, disease progression, and nuclear imaging in ATXN2-related parkinsonism in a longitudinal cohort.

BACKGROUND: Spinocerebellar ataxia 2 (SCA2) with a low range of CAG repeat expansion of ATXN2 gene can present with predominant or isolated parkinsonism that closely resembles Parkinson's disease (PD). This study is aimed at comparing clinical features, disease progression, and nuclear imaging between ATXN2-related parkinsonism (ATXN2-P) and PD. METHODS: Three hundred and seventy-seven clinically diagnosed PD with family history were screened by multiplex ligation-dependent probe amplification, whole-exome sequencing or target sequencing, and dynamic mutation testing of 10 SCA subtypes. The baseline and longitudinal clinical features as well as the dual-tracer positron emission tomography (PET) imaging were compared between ATXN2-P and genetically undefined familial PD (GU-fPD). RESULTS: Fifteen ATXN2-P patients from 7 families and 50 randomly selected GU-fPD patients were evaluated. Significantly less resting tremor and more symmetric signs were observed in ATXN2-P than GU-fPD. No significant difference was found in motor progression and duration from onset to occurrence of fluctuation, dyskinesia, and recurrent falls between the two groups. Cognitive impairment and rapid-eye-movement sleep behavior disorder were more common in ATXN2-P. During follow-up, olfaction was relatively spared, and no obvious progression of cognition dysfunction evaluated by Mini-Mental State Examination scores was found in ATXN2-P. PET results of ATXN2-P demonstrated a symmetric, diffuse, and homogenous dopamine transporter loss of bilateral striatum and a glucose metabolism pattern inconsistent with that in PD. CONCLUSIONS: Symmetric motor signs and unique nuclear imaging might be the clues to distinguish ATXN2-P from GU-fPD.

Autosomal dominant Parkinson's disease caused by the recently identified LRRK2 N1437D mutation in a Chinese family: Clinical features, imaging findings, and functional impact.

INTRODUCTION: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of autosomal dominantly inherited Parkinson's disease (PD). Recently, a novel pathogenic variant (N1437D; c.4309A > G; NM_98578) in the LRRK2 gene has been identified in three Chinese families with PD. In this study, we describe a Chinese family with autosomal dominant PD that segregated with the N1437D mutation. A detailed clinical and neuroimaging characterization of the affected family members is reported. We also sought to investigate the functional mechanisms by which the detected mutation could cause PD. METHODS: We characterized the clinical and imaging phenotype of a Chinese pedigree with autosomal dominant PD. We searched for a disease-causing mutation by targeted sequencing and multiple ligation-dependent probe amplification. The functional impact of the mutation was investigated in terms of LRRK2 kinase activity, guanosine triphosphate (GTP) binding, and guanosine triphosphatase (GTPase) activity. RESULTS: The disease was found to co-segregate with the LRRK2 N1437D mutation. Patients in the pedigree exhibited typical parkinsonism (age at onset: 54.0 ± 5.9 years). One affected family member - who had evidence of abnormal tau accumulation in the occipital lobe on tau PET imaging - developed PD dementia at follow-up. The mutation markedly increased LRRK2 kinase activity and promoted GTP binding, without affecting GTPase activity. CONCLUSIONS: This study describes the functional impact of a recently identified LRRK2 mutation, N1437D, that causes autosomal dominant PD in the Chinese population. Further research is necessary to investigate the contribution of this mutation to PD in multiple Asian populations.

The genetic spectrum of a cohort of patients clinically diagnosed as Parkinson's disease in mainland China.

So far, over 20 causative genes of monogenic Parkinson's disease (PD) have been identified. Some causative genes of non-parkinsonian entities may also manifest with parkinsonism mimicking PD. This study aimed to investigate the genetic characteristics of clinically diagnosed PD with early onset age or family history. A total of 832 patients initially diagnosed with PD were enrolled, of which, 636 were classified into the early-onset group and 196 were classified into the familial late-onset group. The genetic testing included the multiplex ligation-dependent probe amplification and next generation sequencing (target sequencing or whole-exome sequencing). The dynamic variants of spinocerebellar ataxia were tested in probands with family history. In the early-onset group, 30.03% of patients (191/636) harbored pathogenic/likely pathogenic (P/LP) variants in known PD-related genes (CHCHD2, DJ-1, GBA (heterozygous), LRRK2, PINK1, PRKN, PLA2G6, SNCA and VPS35). Variants in PRKN were the most prevalent, accounting for 15.72% of the early-onset patients, followed by GBA (10.22%), and PLA2G6 (1.89%). And 2.52% (16/636) had P/LP variants in causative genes of other diseases (ATXN3, ATXN2, GCH1, TH, MAPT, GBA (homozygous)). In the familial late-onset group, 8.67% of patients (17/196) carried P/LP variants in known PD-related genes (GBA (heterozygous), HTRA2, SNCA) and 2.04% (4/196) had P/LP variants in other genes (ATXN2, PSEN1, DCTN1). Heterozygous GBA variants (7.14%) were the most common genetic cause found in familial late-onset patients. Genetic testing is of vital importance in differential diagnosis especially in early-onset and familial PD. Our findings may also provide some clues to the nomenclature of genetic movement disorders.

Association between Respiratory Function and Motor Function in Different Stages of Parkinson's Disease.

INTRODUCTION: Respiratory dysfunction in patients with Parkinson's disease (PD) could present in the early stage and worsen in the late stages. These changes could be a factor affecting the ability of daily living and quality of life of patients with PD. The primary objective of this study was to assess the respiratory function and its association with motor function in patients with different stages of PD. METHODS: This was a cross-sectional study conducted at the Huashan Hospital of Fudan University in Shanghai, China. The study included 65 patients diagnosed with PD (the Hoehn and Yahr scale between 1 and 4) and 20 healthy individuals of similar age, gender, weight, and height. The ventilatory function was assessed using the spirometry. Motor function was evaluated using subscale III of the United Parkinson's disease rating scale (UPDRS-III). After confirming the normality of data distribution, we performed one-way ANOVA with a Tukey's post hoc test. RESULTS: Compared with the healthy individuals, there was no statistical significance in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) in the H&Y 1 group and H&Y 2 group (p > 0.05) but reduced peak expiratory flow (PEF) in the H&Y 2 group (p = 0.002). Reduced FVC, FEV1, and PEF was seen in the H&Y 3 group (p = 0.002, p = 0.001, and p = 0.0001, respectively). Reduced FVC, FEV1, PEF, and FEF25-75% was seen in the H&Y 4 group (p = 0.001, p = 0.0001, p = 0.0001, and p = 0.025, respectively). The correlation analysis revealed that there was a significant negative correlation between FVC and UPDRS-III scores (r = -0.248, p = 0.046), disease duration (r = -0.276, p = 0.026), H&Y scale (r = -0.415, p = 0.001). FEV1 was negatively correlated with UPDRS-III scores (r = -0.277, p = 0.025), disease duration (r = -0.291, p = 0.019), H&Y scale (r = -0.434, p = 0.0001). FEF25-75% was negatively correlated with disease duration (r = -0.247, p = 0.047), H&Y scale (r = -0.278, p = 0.025). CONCLUSION: Our findings revealed that respiratory impairment is present in moderate and advanced PD patients, and directly related to the severity of the disease. It is important to conduct respiratory function test in the clinical practice.

In Vivo 18 F-APN-1607 Tau Positron Emission Tomography Imaging in MAPT Mutations: Cross-Sectional and Longitudinal Findings.

BACKGROUND: Frontotemporal lobar degeneration with tauopathy caused by MAPT (microtubule-associated protein tau) mutations is a highly heterogenous disorder. The ability to visualize and longitudinally monitor tau deposits may be beneficial to understand disease pathophysiology and predict clinical trajectories. OBJECTIVE: The aim of this study was to investigate the cross-sectional and longitudinal 18 F-APN-1607 positron emission tomography/computed tomography (PET/CT) imaging findings in MAPT mutation carriers. METHODS: Seven carriers of MAPT mutations (six within exon 10 and one outside of exon 10) and 15 healthy control subjects were included. All participants underwent 18 F-APN-1607 PET/CT at baseline. Three carriers of exon 10 mutations received follow-up 18 F-APN-1607 PET/CT scans. Standardized uptake value ratio (SUVR) maps were obtained using the cerebellar gray matter as the reference region. SUVR values observed in MAPT mutation carriers were normalized to data from healthy control subjects. A regional SUVR z score ≥ 2 was used as the criterion to define positive 18 F-APN-1607 PET/CT findings. RESULTS: Although the seven study patients had heterogenous clinical phenotypes, all showed a significant 18 F-APN-1607 uptake characterized by high-contrast signals. However, the anatomical localization of tau deposits differed in patients with distinct clinical symptoms. Follow-up imaging data, which were available for three patients, demonstrated worsening trends in patterns of tau accumulation over time, which were paralleled by a significant clinical deterioration. CONCLUSIONS: Our data represent a promising step in understanding the usefulness of 18 F-APN-1607 PET/CT imaging for detecting tau accumulation in MAPT mutation carriers. Our preliminary follow-up data also suggest the potential value of 18 F-APN-1607 PET/CT for monitoring the longitudinal trajectories of frontotemporal lobar degeneration caused by MAPT mutations. © 2021 International Parkinson and Movement Disorder Society.

Disease progression in Parkinson's disease patients with subjective cognitive complaint.

OBJECTIVE: Little is known about the disease progression of Parkinson's disease patients with subjective cognitive complaint (PD-SCC). This longitudinal cohort study aims to compare the progression of clinical features and quality of life (QoL) in PD patients with normal cognition (NC), SCC, and mild cognitive impairment (MCI). METHODS: A total of 383 PD patients were enrolled, including 189 PD-NC patients, 59 PD-SCC patients, and 135 PD-MCI patients, with 1-7 years of follow-up. Linear mixed models were applied to evaluate longitudinal changes in motor symptoms, nonmotor features (cognitive impairment, depression, and excessive daytime sleepiness), and QoL in PD. RESULTS: At baseline, PD-SCC patients had lower Beck Depression Inventory (BDI) scores and Parkinson's Disease Questionnaire-39 (PDQ-39) scores than PD-NC patients (all p < 0.05). Longitudinal analyses revealed that the PD-SCC group exhibited faster progression in terms of BDI scores (p = 0.042) and PDQ-39 scores (p = 0.035) than the PD-NC group. The PD-MCI group exhibited faster progression rates in the Epworth Sleepiness Scale scores (p = 0.001) and PDQ-39 scores (p = 0.005) than the PD-NC group. In addition, the PD-SCC group exhibited a greater reduction in attention (Trail Making Test Part A, p = 0.047) and executive function (Stroop Color-Word Test, p = 0.037) than the PD-NC group. INTERPRETATION: PD-SCC patients exhibited faster deterioration of depression and QoL than PD-NC patients, and SCC may be an indicator of initial attention and executive function decline in PD. Our findings provided a more accurate prognosis in PD-SCC patients.

Neuroprotection of Exendin-4 by Enhanced Autophagy in a Parkinsonian Rat Model of α-Synucleinopathy.

Glucagon-like peptide-1 (GLP-1) receptor stimulation ameliorates parkinsonian motor and non-motor deficits in both experimental animals and patients; however, the disease-modifying mechanisms of GLP-1 receptor activation have remained unknown. The present study investigated whether exendin-4 (a GLP-1 analogue) can rescue motor deficits and exert disease-modifying effects in a parkinsonian rat model of α-synucleinopathy. This model was established by unilaterally injecting AAV-9-A53T-α-synuclein into the right substantia nigra pars compacta, followed by 4 or 8 weeks of twice-daily intraperitoneal injections of exendin-4 (5 µg/kg/day) starting at 2 weeks after AAV-9-A53T-α-synuclein injections. Positron emission tomography/computed tomography (PET/CT) scanning and immunostaining established that treatment with exendin-4 attenuated tyrosine-hydroxylase-positive neuronal loss and terminal denervation and mitigated the decrease in expression of vesicular monoamine transporter 2 within the nigrostriatal dopaminergic systems of rats injected with AAV-9-A53T-α-synuclein. It also mitigated the parkinsonian motor deficits assessed in behavioral tests. Furthermore, through both in vivo and in vitro models of Parkinson's disease, we showed that exendin-4 promoted autophagy and mediated degradation of pathological α-synuclein, the effects of which were counteracted by 3-methyladenine or chloroquine, the autophagic inhibitors. Additionally, exendin-4 attenuated dysregulation of the PI3K/Akt/mTOR pathway in rats injected with AAV-9-A53T-α-synuclein. Taken together, our results demonstrate that exendin-4 treatment relieved behavioral deficits, dopaminergic degeneration, and pathological α-synuclein aggregation in a parkinsonian rat model of α-synucleinopathy and that these effects were mediated by enhanced autophagy via inhibiting the PI3K/Akt/mTOR pathway. In light of the safety and tolerance of exendin-4 administration, our results suggest that exendin-4 may represent a promising disease-modifying treatment for Parkinson's disease.

Disease Progression in Patients with Parkin-Related Parkinson's Disease in a Longitudinal Cohort.

BACKGROUND: There was a paucity of follow-up studies in the disease progression of early-onset PD patients with Parkin mutations (Parkin-EOPD). Here we conducted a longitudinal study to investigate the progression of motor and cognitive features of Parkin-EOPD patients. METHODS: Genetic analysis was performed via target sequencing and multiplex ligation-dependent probe amplification. Thirty patients carrying homozygous or compound heterozygous Parkin mutations with at least 2 follow-up revisions were investigated as the Parkin-EOPD group. Fifty-two patients with at least 2 follow-up revisions, who did not have any known causative PD mutations, GBA or LRRK2 risk variants, a heterozygous Parkin mutation or 2 Parkin mutations without a segregation test, were defined as the genetically undefined EOPD (GU-EOPD) group. A linear mixed-effect model was implemented to evaluate longitudinal changes in motor symptoms and cognition. RESULTS: At baseline, the Parkin-EOPD group had a lower Unified Parkinson's Disease Rating Scale score (UPDRS-III) (off-medication) than the GU-EOPD group, without significant differences in cognition. A longitudinal study showed the estimated progression rate per year (standard error) of the UPDRS-III score (off-medication) was lower in the Parkin-EOPD group (0.203 [0.3162] points per year) than in the GU-EOPD group (1.056 [0.3001] points per year). The difference in the UPDRS-III score rate between the 2 groups was 0.853 (0.4183) (P = 0.042). The Parkin-EOPD group showed better maintenance of spatial processing ability compared with the GU-EOPD group (P = 0.027). CONCLUSION: Parkin-EOPD patients showed a slower deterioration of motor symptoms and a better spatial processing ability than GU-EOPD patients, which suggests that subtyping according to genetic features can help predict PD progression. © 2020 International Parkinson and Movement Disorder Society.

Propagated α-synucleinopathy recapitulates REM sleep behaviour disorder followed by parkinsonian phenotypes in mice.

Idiopathic rapid eye movement sleep behaviour disorder (RBD) is now recognized as an early manifestation of α-synucleinopathies. Increasing experimental studies demonstrate that manipulative lesion or inactivation of the neurons within the sublaterodorsal tegmental nucleus (also known as the subcoeruleus nucleus in humans) can induce RBD-like behaviours in animals. As current RBD animal models are not established on the basis of α-synucleinopathy, they do not represent the pathological substrate of idiopathic RBD and thus cannot model the phenoconversion to Parkinson's disease. The purpose of this study was therefore to establish an α-synucleinopathy-based RBD animal model with the potential to convert to parkinsonian disorder. To this end, we first determined the functional neuroanatomical location of the sublaterodorsal tegmental nucleus in wild-type C57BL/6J mice and then validated its function by recapitulating RBD-like behaviours based on this determined nucleus. Next, we injected preformed α-synuclein fibrils into the sublaterodorsal tegmental nucleus and performed regular polysomnographic recordings and parkinsonian behavioural and histopathological studies in these mice. As a result, we recapitulated RBD-like behaviours in the mice and further showed that the α-synucleinopathy and neuron degeneration identified within the sublaterodorsal tegmental nucleus acted as the neuropathological substrates. Subsequent parkinsonian behavioural studies indicated that the α-synucleinopathy-based RBD mouse model were not stationary, but could further progress to display parkinsonian locomotor dysfunction, depression-like disorder, olfactory dysfunction and gastrointestinal dysmotility. Corresponding to that, we determined α-synuclein pathology in the substantia nigra pars compacta, olfactory bulb, enteral neuroplexus and dorsal motor nucleus of vagus nerve, which could underlie the parkinsonian manifestations in mice. In conclusion, we established a novel α-synucleinopathy-based RBD mouse model and further demonstrated the phenoconversion of RBD to Parkinson's disease in this animal model.

Fasudil Promotes α-Synuclein Clearance in an AAV-Mediated α-Synuclein Rat Model of Parkinson's Disease by Autophagy Activation.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, but the disease-modifying therapies focusing on the core pathological changes are still unavailable. Rho-associated protein kinase (ROCK) has been suggested as a promising target for developing neuroprotective therapies in PD. OBJECTIVE: We aimed to explore the promotion of α-synuclein (α-syn) clearance in a rat model. METHODS: In a rat model induced by unilateral injection of adeno-associated virus of serotype 9 (AAV9) expressing A53T α-syn (AAV9-A53T-α-syn) into the right substantia nigra, we aimed to investigate whether Fasudil could promote α-syn clearance and thereby attenuate motor impairments and dopaminergic deficits. RESULTS: In our study, treatment with Fasudil (5 mg/kg rat weight/day) for 8 weeks significantly improved the motor deficits in the Cylinder and Rotarod tests. In the in vivo positron emission tomography imaging with the ligand 18F-dihydrotetrabenazine, Fasudil significantly enhanced the dopaminergic imaging in the injected striatum of the rat model (p < 0.05 vs. vehicle group, p < 0.01 vs. left striatum in Fasudil group). The following mechanistic study confirmed that Fasudil could promote the autophagic clearance of α-syn by Becline 1 and Akt/mTOR pathways. CONCLUSION: Our study suggested that Fasudil, the ROCK2 inhibitor, could attenuate the anatomical and behavioral lesions in the Parkinsonian rat model by autophagy activation. Our results identify Fasudil as a drug with high translational potential as disease-modifying treatment for PD and other synucleinopathies.

Non-motor Symptoms in Parkinson's Disease Patients with Parkin Mutations: More Depression and Less Executive Dysfunction.

The purpose of this study was to identify differences between genetically undefined (GU) early-onset Parkinson's disease (EOPD) patients and carriers of Parkin mutations on non-motor symptoms (NMSs). EOPD patients (N = 261) underwent targeted sequencing of Parkinson's disease (PD) related genes. Among them, 53 cases carried homozygous or compound heterozygous Parkin mutations (Parkin group) while 208 did not carry known causative PD mutations or risk factors of GBA or Parkin heterozygous mutations (GU group). NMSs were evaluated by face-to-face interviews, self-completed questionnaires and results on a neuropsychological battery. Linear regression and logistic regression models were applied to assess the predictors of NMSs. Parkin patients had younger ages of onset (AOO) (p < 0.001), longer disease durations (p < 0.001) and lower grades of Hoehn and Yarh (H&Y) (p = 0.007). Results on the neuropsychological battery showed a shorter time in Trail Making Test (TMT) (part B) in Parkin patients (p = 0.034) compared to GU patients. After adjusting for AOO, disease duration, H&Y, and levodopa equivalent daily dose (LEDD), there was a higher depression index on the Beck Depression Inventory (BDI) (p = 0.013) and better performance (p = 0.038) on executive function in the Parkin group compared to the GU group. No significant differences were found for autonomic functions, sleep-wake problems or other domains of cognitive function. Our study showed that the Parkin mutation status might be a good predictor of symptoms of depression without an impact on executive function. While these findings need to be confirmed in larger cohorts, they identify a need to screen for depression. Graphical Abstract Flow chart of genetic tests.

Quality of Life in Newly Diagnosed Patients With Parkin-Related Parkinson's Disease.

Introduction: Mutations in the Parkin gene are the most common cause of autosomal recessive early-onset Parkinson's disease (PD). However, little is known about the quality of life (QoL) in Parkin-related PD. Here, we investigated the patterns of QoL in newly diagnosed Parkin-related PD patients. Methods: Newly diagnosed PD patients (diagnosis made within 12 months) who had an age of onset (AOO) below 40 and underwent a PD-related genetic testing, were recruited (n = 148). Among them, 24 patients carried bi-allelic variants in Parkin (PD-Parkin) and 24 patients did not have any known causative PD mutations, or risk variants (GU-EOPD). The clinical materials, relevant factors and determinants of QoL were analyzed. Results: PD-Parkin patients had a younger AOO (p = 0.003) and longer disease duration (p = 0.005). After adjustment for AOO and disease duration, more dystonia (p = 0.034), and worse scores of non-motor symptoms including Beck depression inventory (BDI, p = 0.035), Epworth sleepiness scale (ESS, p = 0.044), and subdomains of depression/anxiety (p = 0.015) and sleep disorders (p = 0.005) in Non-motor symptoms questionnaire, were found in PD-Parkin comparing with GU-EOPD. PD-Parkin patients had poorer QoL (adjusted p = 0.045), especially in the mobility (adjusted p = 0.025), emotional well-being (adjusted p = 0.015) and bodily discomfort dimensions (adjusted p = 0.016). BDI scores (p = 0.005) and ESS scores (p = 0.047) were significant determinants of QoL in PD-Parkin. Conclusion: Newly diagnosed PD-Parkin patients showed worse QoL. More depression and excessive daytime sleepiness predicted worse QoL. For clinicians, management of depression and excessive daytime sleepiness is suggested to better improve QoL in patients with Parkin mutations.

Cognitive characteristics in Chinese non-demented PD patients based on gender difference.

BACKGROUND: Cognitive impairment is one of the non-motor symptoms in Parkinson's disease (PD). In the present study, we aim to examine the cognitive function of non-demented Parkinson's disease patients and compare the results between male and female patients as well as control groups in search of any gender effect. METHODS: Sixty PD Patients (30 males and 30 females) from the Movement Disorders Clinic at Huashan Hospital Affiliated to Fudan University were recruited to participate in the study. One hundred age and gender matched control subjects without neurological or psychiatric disorders were voluntarily recruited. The participants were administered measures of cognition in five domains including memory, language, spatial processing abilities, attention and executive function. RESULTS: PD patients attained significantly lower scores in the visual spatial function, language and attention/executive function compared with the control group. Anti-parkinsonian treated patients performed worse in Rey-copy score, Clock Drawing Test (CDT) and Verbal Fluency-City than untreated ones. In regard to gender differences, though no general cognitive differences were found in Mini-mental State Examination (MMSE), men surpassed women on Boston naming test (BNT) while women were superior on Auditory Verbal Learning Test-long (AVLT) delayed cued recall test. CONCLUSIONS: Cognitive impairments were common in PD patients even in the absence of dementia. PD patients with anti-parkinsonian medication had worse cognitive impairment than untreated patients. Genders may have different manifestations of cognitive impairment in PD patients.

Clinical characteristics of cognitive impairment in patients with Parkinson's disease and its related pattern in 18 F-FDG PET imaging.

This study aimed to characterize the clinical features and the related cerebral glucose metabolism pattern of cognitive impairments in Parkinson's disease (PD) with positron emission tomography (PET) imaging. We recruited 168 PD patients and 100 age-matched healthy controls of similar education and gender distribution. All of those enrolled underwent clinical assessment including the unified Parkinson's disease rating scale motor score, Hoehn and Yahr scale, and comprehensive neuropsychological tests including domains of executive function, attention, memory, visuospatial function, and language. Demographics and the results of cognitive measures were compared between patients and healthy controls. Cognition status was classified as PD patients with dementia (PD-D), PD patients with mild cognitive impairment (PD-MCI), or PD patients with normal cognition (PD-NC). In 53 PD patients who underwent 18 F-fluorodeoxyglucose (18 F-FDG) PET imaging, correlations between Z-score values of the different cognitive domains and cerebral 18 F-FDG uptake were assessed using statistical parametric mapping (SPM8) corrected for age and motor severity. A total of 23.2% of PD patients were PD-MCI and 8.9% were PD-D. In the group of PD-MCI, 96.3% showed multiple-domain deficits, with executive function and attention impairment most predominantly involved. All the cognitive domain scores with the exception of language correlated with 18 F-FDG metabolisms, primarily in posterior temporo-parieto-occipital association cortical areas. This study found that cognitive impairment in PD particularly encompasses frontal/executive deficits. Posterior cortical areas, containing multiple neurotransmitters and neural circuits, may play an important role in the pathogenesis of cognitive impairment in PD.

Depressive Symptoms Are Associated With Color Vision but not Olfactory Function in Patients With Parkinson's Disease.

Depressive symptoms and sensory dysfunction, such as reduction in visual and olfactory function, are common in Parkinson's disease (PD). Previous studies have suggested that depressive symptoms are associated with visual impairments and potentially with hyposmia in several types of mood disorders. However, the relationship between depressive symptoms and sensory dysfunction remains unclear in PD. To examine the association of depressive symptoms with color vision and olfactory function in PD, the authors conducted a cross-sectional study in 159 patients with PD. Depressive symptoms were measured with the Beck Depression Inventory-II (BDI-II) and the 30-item Geriatric Depression Scale (GDS-30); color vision was tested with the Farnsworth-Munsell 100 Hue Test (FMT); and olfactory function was tested with the Sniffin' Sticks Screening 12 Test. Results showed that the total error score (TES) for the FMT was significantly and independently correlated with scores on both the BDI-II and GDS-30 in a positive manner, suggesting that more severe depressive symptoms are associated with poorer color vision in PD. In addition, both somatic and effective subscores for the BDI-II were correlated with the TES on the FMT, while no significant correlation was observed between total scores on the Sniffin' Sticks Screening 12 Test and BDI-II or GDS-30. The decrease in color vision but not olfactory function was found to be associated with the severity of depressive symptoms in PD patients, supporting the idea that the occurrence of depressive symptoms in PD is linked with disruption of the visual system.

A homozygous missense variant in HSD17B4 identified in a consanguineous Chinese Han family with type II Perrault syndrome.

BACKGROUND: Perrault syndrome is a rare multisystem disorder that manifests with sensorineural hearing loss in both sexes, primary ovarian insufficiency in females and neurological features. The syndrome is heterogeneous both genetically and phenotypically. CASE PRESENTATION: We reported a consanguineous family (two affected sisters) with Perrault syndrome. The proband had the characteristics of Perrault syndrome: ovarian dysgenesis, bilateral hearing loss and obvious neurological signs. Target genetic sequencing and triplet repeat primed PCR (TP-PCR) plus capillary electrophoresis was conducted to detect causative mutations in the proband. The detected variant was further confirmed in the proband and tested in other family members by Sanger sequencing. Both the proband and her sister were found homozygous for the novel variant HSD17B4 c.298G > T (p.A100S) with their parents heterozygous. Detected by western blot, the protein expression of HSD17B4 mutant was much lower than that of the wild type in SH-SY5Y cells transfected by HSD17B4 wild type or mutant plasmid, which indicated the pathogenicity of the HSD17B4 mutation. CONCLUSIONS: Our findings supported that HSD17B4 was one of the genes contributing to Perrault syndrome with the likely pathogenic variant c.298G > T (p.A100S). Special manifestations of cerebellar impairment were found in cases caused by HSD17B4 mutations. Besides, attention should be paid to distinguish Perrault syndrome from D-bifunctional protein deficiency and hereditary ataxia.

Fasudil, a Rho kinase inhibitor, promotes the autophagic degradation of A53T α-synuclein by activating the JNK 1/Bcl-2/beclin 1 pathway.

Accumulation of α-synuclein (α-syn) is pivotally implicated in the pathogenesis of Parkinson׳s disease (PD), and enhancing its clearance might be a promising strategy in PD treatment. It has recently been shown that Rho kinase (ROCK) activation is involved in many neurodegenerative diseases, and some ROCK inhibitors might promote the degradation of abnormal protein aggregates. However, it is not known if fasudil, the only ROCK inhibitor available in clinical setting, could promote the degradation of α-syn, and ameliorate the α-syn induced neurotoxicity. In this regard, we investigated the effect of fasudil on neurite injury caused by A53T α-syn overexpression and the implicated pathway it might mediate. In the current study, we found that under the condition of A53T α-syn overexpression, the neurite outgrowth decreased significantly with the increasing expression of ROCK2. Fasudil, the ROCK inhibitor, ameliorated such neurotoxicity and promoted the clearance of A53T α-syn. Its underlying mechanism was supported by that fasudil could increase the macroautophagy activation via JNK 1 and Bcl-2 phosphorylation and beclin 1/Vps34 complex formation. Taken together, fasudil might be able to provide a novel and promising strategy for PD treatment by enhancing α-syn clearance and activating the JNK 1/Bcl-2/beclin 1 pathway.

Trehalose alleviates PC12 neuronal death mediated by lipopolysaccharide-stimulated BV-2 cells via inhibiting nuclear transcription factor NF-κB and AP-1 activation.

Inflammation is implicated in the pathogenesis of Parkinson's disease (PD). Trehalose is a disaccharide which exhibits a variety of effects like anti-aggregation, autophagy enhancement in PD. It has also been known to suppress inflammation in many experimental models, involving endotoxin shock, murine dry eye and subarachnoid hemorrhage. However, whether trehalose has an anti-inflammation effect on PD is largely unknown. In the present study, we found trehalose inhibited generation of interleukin-1ß, interleukin-6, tumor necrosis factor-α, and nitric oxide in the conditioned medium released from lipopolysaccharide (LPS)-stimulated BV-2 cells. LPS-induced nuclear transcription factors of NF-κB and AP-1 activation were also inhibited by trehalose. Then the conditioned medium of BV-2 cells was applied to PC12 neurons. As a result, both MTT and LDH indicated that trehalose decreased PC12 neuronal death. TUNEL assay showed that trehalose suppressed apoptosis of PC12 neurons. These results implied that trehalose exerted a protective effect on PC12 neurons against the neurotoxic effect triggered by BV-2 microglial activation through inhibiting NF-κB and AP-1 activation and inflammatory mediators and cytokines production in BV-2 cells.