Activity In Parkinson's Disease Research Articles

Associations between neuromelanin depletion and cortical rhythmic activity in Parkinson's disease.

Parkinson's disease (PD) is marked by the death of neuromelanin-rich dopaminergic and noradrenergic cells in the substantia nigra (SN) and the locus coeruleus (LC), respectively, resulting in motor and cognitive impairments. While SN dopamine dysfunction has clear neurophysiological effects, the association of reduced LC norepinephrine signaling with brain activity in PD remains to be established. We used neuromelanin-sensitive T1-weighted MRI (NPD = 58; NHC = 27) and task-free magnetoencephalography (NPD = 58; NHC = 65) to identify neuropathophysiological factors related to the degeneration of the LC and SN in patients with PD. We found pathological increases in rhythmic alpha (8-12 Hz) activity in patients with decreased LC neuromelanin, with a stronger association in patients with worse attentional impairments. This negative alpha-LC neuromelanin relationship is strongest in fronto-motor cortices, where alpha activity is inversely related to attention scores. Using neurochemical colocalization analyses with normative atlases of neurotransmitter transporters, we also show that this effect is more pronounced in regions with high densities of norepinephrine transporters. These observations support a noradrenergic association between LC integrity and alpha band activity. Our data also show that rhythmic beta (15-29 Hz) activity in the left somato-motor cortex decreases with lower levels of SN neuromelanin; the same regions where beta activity reflects axial motor symptoms. Together, our findings clarify the association of well-documented alterations of rhythmic neurophysiology in PD with cortical and subcortical neurochemical systems. Specifically, attention-related alpha activity is related to dysfunction of the noradrenergic system, and beta activity with relevance to motor impairments reflects dopaminergic dysfunction.

Association of synuclein alpha (SNCA) gene polymorphisms with spontaneous brain activity in patients with Parkinson's disease.

The synuclein alpha (SNCA) gene responsible for encoding alpha-synuclein, is believed to play a crucial role in the pathogenesis of Parkinson's disease (PD). However, the specific impact of SNCA gene single-nucleotide polymorphisms (SNPs) on brain function in PD remains unclear. Therefore, this cross-sectional retrospective study, particularly through use of imaging analysis, aimed to characterize the relationship between SNCA gene SNPs and spontaneous brain activity in PD in order to enhance our understanding of the mechanisms underlying PD pathogenesis. A total of 63 patients with PD and 73 sex- and age-matched healthy control (HC) participants were recruited from outpatient and inpatient clinics at Fujian Medical University Union Hospital from August 2017 to November 2019, and all underwent a resting-state functional magnetic resonance imaging (rs-fMRI) scanning. All participants were also examined to determine the correlation of different genotypes with regional brain activity measured by rs-fMRI using amplitude of low-frequency fluctuation (ALFF) analysis. Multivariate regression analysis was used to calculate the correlation between the brain function data and clinical features. All rs-fMRI data were analyzed with the SPM12 software and adjusted according to the false discovery rate (FDR) at the cluster level. This study included 63 patients with PD and 73 sex- and age-matched healthy participants were included in the study. The spontaneous brain activity in the right superior cerebellum (Cerebelum_Crus1_R), vermis (Vermis_7), and left supplementary motor area (Supp_Motor_Area_L) of patients in the PD group was weak compared to that in the HC group. The z-score ALFF of left central posterior gyrus was positively correlated with the Mini-Mental State Examination score (r=0.542; P<0.001) in the PD group. For rs11931074, the main genotypic effects were found in the left inferior cerebellum (Cerebellum_9_L) and right anterior cingulate and paracingulate gyri (Cingulum_Ant_R); for rs356219 and rs356165, the main genotypic effects were found in the left caudate nucleus (Caudate_L). An interaction effect of disease with genotype was found in the right inferior parietal gyrus (Parietal_Inf_R) only for rs356219. Our study found a correlation of the SNCA SNPs rs11931074, rs356219, and rs356165 with brain functional alterations in patients with PD. Furthermore, an interaction effect was found in the right inferior parietal gyrus only for rs356219. This study may contribute to furthering the understanding of the influence of SNCA gene SNPs on brain function in patients with PD.

Effects of motor and cognitive complex training on obstacle walking and brain activity in people with Parkinson's disease: a randomized controlled trial.

The difficulties in obstacle walking are significant in people with Parkinson's disease (PD) leading to an increased fall risk. Effective interventions to improve obstacle walking with possible training-related neuroplasticity changes are needed. We developed two different exercise programs, complex walking training and motor-cognitive training, both challenging motor and cognitive function for people with PD to improve obstacle walking. To investigate the effects of these two novel training programs on obstacle walking and brain activities in PD. A single-center randomized, single-blind controlled study. University laboratory; outpatient. Individuals with idiopathic PD. Thirty-two participants were randomly assigned to the complex walking training group (N.=11), motor-cognitive training group (N.=11) or control group (N.=10). Participants in training groups received exercises for 40 minutes/session, with a total of 12-session over 6 weeks. Control group did not receive additional training. Primary outcomes included obstacle walking, and brain activities (prefrontal cortex (PFC), premotor cortex (PMC), and supplementary motor area (SMA)) during obstacle walking by using functional near-infrared spectroscopy. Secondary outcomes included obstacle crossing, timed up and go test (TUG), cognitive function in different domains, and fall efficacy scale (FES-I). The motor-cognitive training group demonstrated greater improvements in obstacle walking speed and stride length, SMA activity, obstacle crossing velocity and stride length, digit span test, and TUG than the control group. The complex walking training did not show significant improvement in obstacle walking or change in brain activation compared with control group. However, the complex walking training resulted in greater improvements in Rey-Osterrieth Complex Figure test, TUG and FES-I compared with the control group. Our 12-session of the cognitive-motor training improved obstacle walking performance with increased SMA activities in people with PD. However, the complex walking training did not lead such beneficial effects as the cognitive-motor training. The cognitive-motor training is suggested as an effective rehabilitation program to improve obstacle walking ability in individuals with PD.

Association between Physical Activity and Parkinson's Disease: A Prospective Cohort Study.

The burden of Parkinson's disease (PD) is still increasing, and physical activity is a modifiable factor for health benefits. The benefits of physical activity in PD are not well established. Therefore, this study aimed to investigate the association between various types of physical activity and the risk of developing PD. Data from 432,497 participants in UK Biobank, who were free of PD at baseline, were analyzed. Physical activity levels were assessed by measuring the duration of walking for pleasure, light and heavy do-it-yourself (DIY) activities, strenuous sports, and other exercises. Physical activity was categorized into daily living activities (walking for pleasure, light DIY, and heavy DIY) and structured exercises (strenuous sports and other exercises). Association between different types of physical activity and PD risk was examined using multivariable adjusted restricted cubic splines and Cox proportional risk models. Over a median follow-up of 13.7 years, 2,350 PD cases were identified. Cubic spline analyses revealed negative linear associations between PD risk and total physical activity, daily living activities, and structured exercise. After multivariable adjustment, the hazard ratios and 95% confidence intervals for incident PD associated with the highest quartile of total physical activity, daily living activities, and structured exercise were 0.72 (0.64-0.81), 0.75 (0.67-0.84), and 0.78 (0.67-0.90), respectively, compared to those in the lowest quartile. Sensitivity analysis confirmed these findings. Higher levels of both daily living activities and structured exercise were associated with a reduced incidence of PD, underscoring the importance of maintaining physical activity to prevent PD.

Unraveling the characteristics of Parkinson's Disease through neuroimaging: Insights and future directions

Parkinson's disease (PD) is a neurodegenerative disease with a high degree of patient heterogeneity, and as of 2016 there are approximately 6.1 million PD patients worldwide. PD has a high proportion of patients with intermediate to advanced disease and a high rate of disability, and clinical diagnosis and treatment are difficult due to the lack of neuromarkers to identify disease states and the inability to quantify the effects of treatment in PD. In recent years, many researchers have explored specific changes in brain activity in PD based on electrophysiological and neuroimaging data. Electroencephalography, with its high temporal resolution and rich frequency domain information, and functional magnetic resonance imaging, with its high spatial resolution, have become the main tools to characterize the state of brain activity in PD in recent years. This paper analyses some of the available data on the characteristics of PD through two neuroimaging techniques commonly used in the disease. It concludes with the prospect of being able to establish uniform criteria for determining PD.

Parkinson's disease-derived α-synuclein assemblies combined with chronic-type inflammatory cues promote a neurotoxic microglial phenotype.

Parkinson's disease (PD) is a common age-related neurodegenerative disorder characterized by the aggregation of α-Synuclein (αSYN) building up intraneuronal inclusions termed Lewy pathology. Mounting evidence suggests that neuron-released αSYN aggregates could be central to microglial activation, which in turn mounts and orchestrates neuroinflammatory processes potentially harmful to neurons. Therefore, understanding the mechanisms that drive microglial cell activation, polarization and function in PD might have important therapeutic implications. Here, using primary microglia, we investigated the inflammatory potential of pure αSYN fibrils derived from PD patients. We further explored and characterized microglial cell responses to a chronic-type inflammatory stimulation combining PD patient-derived αSYN fibrils (FPD), Tumor necrosis factor-α (TNFα) and prostaglandin E2 (PGE2) (TPFPD). We showed that FPD hold stronger inflammatory potency than pure αSYN fibrils generated de novo. When combined with TNFα and PGE2, FPD polarizes microglia toward a particular functional phenotype departing from FPD-treated cells and featuring lower inflammatory cytokine and higher glutamate release. Whereas metabolomic studies showed that TPFPD-exposed microglia were closely related to classically activated M1 proinflammatory cells, notably with similar tricarboxylic acid cycle disruption, transcriptomic analysis revealed that TPFPD-activated microglia assume a unique molecular signature highlighting upregulation of genes involved in glutathione and iron metabolisms. In particular, TPFPD-specific upregulation of Slc7a11 (which encodes the cystine-glutamate antiporter xCT) was consistent with the increased glutamate response and cytotoxic activity of these cells toward midbrain dopaminergic neurons in vitro. Together, these data further extend the structure-pathological relationship of αSYN fibrillar polymorphs to their innate immune properties and demonstrate that PD-derived αSYN fibrils, TNFα and PGE2 act in concert to drive microglial cell activation toward a specific and highly neurotoxic chronic-type inflammatory phenotype characterized by robust glutamate release and iron retention.

Action Observation and Motor Imagery as a Treatment in Patients with Parkinson's Disease.

Action observation (AO) and motor imagery (MI) has emerged as promising tool for physiotherapy intervention in Parkinson's disease (PD). This narrative review summarizes why, how, and when applying AO and MI training in individual with PD. We report the neural underpinning of AO and MI and their effects on motor learning. We examine the characteristics and the current evidence regarding the effectiveness of physiotherapy interventions and we provide suggestions about their implementation with technologies. Neurophysiological data suggest a substantial correct activation of brain networks underlying AO and MI in people with PD, although the occurrence of compensatory mechanisms has been documented. Regarding the efficacy of training, in general evidence indicates that both these techniques improve mobility and functional activities in PD. However, these findings should be interpreted with caution due to variety of the study designs, training characteristics, and the modalities in which AO and MI were applied. Finally, results on long-term effects are still uncertain. Several elements should be considered to optimize the use of AO and MI in clinical setting, such as the selection of the task, the imagery or the video perspectives, the modalities of training. However, a comprehensive individual assessment, including motor and cognitive abilities, is essential to select which between AO and MI suite the best to each PD patients. Much unrealized potential exists for the use AO and MI training to provide personalized intervention aimed at fostering motor learning in both the clinic and home setting.

Microbiota-microglia crosstalk between Blautia producta and neuroinflammation of Parkinson's disease: A bench-to-bedside translational approach

Parkinson's disease (PD) is intricately linked to abnormal gut microbiota, yet the specific microbiota influencing clinical outcomes remain poorly understood. Our study identified a deficiency in the microbiota genus Blautia and a reduction in fecal short-chain fatty acid (SCFA) butyrate level in PD patients compared to healthy controls. The abundance of Blautia correlated with the clinical severity of PD. Supplementation with butyrate-producing bacterium B. producta demonstrated neuroprotective effects, attenuating neuroinflammation and dopaminergic neuronal death in mice, consequently ameliorating motor dysfunction. A pivotal inflammatory signaling pathway, the RAS-related pathway, modulated by butyrate, emerged as a key mechanism inhibiting microglial activation in PD. The change of RAS-NF-κB pathway in PD patients was observed. Furthermore, B. producta-derived butyrate demonstrated the inhibition of microglial activation in PD through regulation of the RAS-NF-κB pathway. These findings elucidate the causal relationship between specific gut microbiota and PD, presenting a novel microbiota-based treatment perspective for PD.

Novel Insights into Parkin-Mediated Mitochondrial Dysfunction and "Mito-Inflammation" in α-Synuclein Toxicity. The Role of the cGAS-STING Signalling Pathway.

The prevalence of age-related neurodegenerative diseases, such as Parkinson's disease (PD) and related disorders continues to grow worldwide. Increasing evidence links intracellular inclusions of misfolded alpha-synuclein (α-syn) aggregates, so-called Lewy bodies (LB) and Lewy neuritis, to the progressive pathology of PD and other synucleinopathies. Our previous findings established that α-syn oligomers induce S-nitrosylation and deregulation of the E3-ubiquitin ligase Parkin, leading to mitochondrial disturbances in neuronal cells. The accumulation of damaged mitochondria as a consequence, together with the release of mitochondrial-derived damage-associated molecular patterns (mtDAMPs) could activate the innate immune response and induce neuroinflammation ("mito-inflammation"), eventually accelerating neurodegeneration. However, the molecular pathways that transmit pro-inflammatory signals from damaged mitochondria are not well understood. One of the proposed pathways could be the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) (cGAS-STING) pathway, which plays a pivotal role in modulating the innate immune response. It has recently been suggested that cGAS-STING deregulation may contribute to the development of various pathological conditions. Especially, its excessive engagement may lead to neuroinflammation and appear to be essential for the development of neurodegenerative brain diseases, including PD. However, the precise molecular mechanisms underlying cGAS-STING pathway activation in PD and other synucleinopathies are not fully understood. This review focuses on linking mitochondrial dysfunction to neuroinflammation in these disorders, particularly emphasizing the role of the cGAS-STING signaling. We propose the cGAS-STING pathway as a critical driver of inflammation in α-syn-dependent neurodegeneration and hypothesize that cGAS-STING-driven "mito-inflammation" may be one of the key mechanisms promoting the neurodegeneration in PD. Understanding the molecular mechanisms of α-syn-induced cGAS-STING-associated "mito-inflammation" in PD and related synucleinopathies may contribute to the identification of new targets for the treatment of these disorders.

Cytokine activity in Parkinson's disease.

The contribution of the immune system to the pathophysiology of neurodegenerative Parkinson's disease (PD) is increasingly being recognised, with alterations in the innate and adaptive arms of the immune system underlying central and peripheral inflammation in PD. As chief modulators of the immune response, cytokines have been intensely studied in the field of PD both in terms of trying to understand their contribution to disease pathogenesis, and if they may comprise much needed therapeutic targets for a disease with no current modifying therapy. This review summarises current knowledge on key cytokines implicated in PD (TNFα, IL-6, IL-1β, IL-10, IL-4 and IL-1RA) that can modulate both pro-inflammatory and anti-inflammatory effects. Cytokine activity in PD is clearly a complicated process mediated by substantial cross-talk of signalling pathways and the need to balance pro- and anti-inflammatory effects. However, understanding cytokine activity may hold promise for unlocking new insight into PD and how it may be halted.

Medication-invariant resting aperiodic and periodic neural activity in Parkinson's disease.

Parkinson's disease (PD) has been associated with greater total power in canonical frequency bands (i.e., alpha, beta) of the resting electroencephalogram (EEG). However, PD has also been associated with a reduction in the proportion of total power across all frequency bands. This discrepancy may be explained by aperiodic activity (exponent and offset) present across all frequency bands. Here, we examined differences in the eyes-open (EO) and eyes-closed (EC) resting EEG of PD participants (N = 26) on and off medication, and age-matched healthy controls (CTL; N = 26). We extracted power from canonical frequency bands using traditional methods (total alpha and beta power) and extracted separate parameters for periodic (parameterized alpha and beta power) and aperiodic activity (exponent and offset). Cluster-based permutation tests over spatial and frequency dimensions indicated that total alpha and beta power, and aperiodic exponent and offset were greater in PD participants, independent of medication status. After removing the exponent and offset, greater alpha power in PD (vs. CTL) was only present in EO recordings and no reliable differences in beta power were observed. Differences between PD and CTL in the resting EEG are likely driven by aperiodic activity, suggestive of greater relative inhibitory neural activity and greater neuronal spiking. Our findings suggest that resting EEG activity in PD is characterized by medication-invariant differences in aperiodic activity which is independent of the increase in alpha power with EO. This highlights the importance of considering aperiodic activity contributions to the neural correlates of brain disorders.

Pinostrobin mitigates neurodegeneration through an up-regulation of antioxidants and GDNF in a rat model of Parkinson's disease.

Background: One of the most common neurodegenerative diseases is Parkinson's disease (PD); PD is characterized by a reduction of neurons containing dopamine in the substantia nigra (SN), which leads to a lack of dopamine (DA) in nigrostriatal pathways, resulting in motor function disorders. Oxidative stress is considered as one of the etiologies involved in dopaminergic neuronal loss. Thus, we aimed to investigate the neuroprotective effects of pinostrobin (PB), a bioflavonoid extracted from Boesenbergia rotunda with antioxidative activity in PD. Methods: Rats were treated with 40 mg/kg of PB for seven consecutive days before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. After completing the experiment, the brains including SN and striatum were used for histological studies and biochemical assays. Results: PB treatment demonstrated a reduction of free radicals in the SN as indicated by significantly decreased MDA levels, whereas the antioxidative enzymes (SOD and GSH) were significantly increased. Furthermore, PB treatment significantly increased glial cell line-derived neurotrophic factor (GDNF) immunolabelling which has neurotrophic and neuroprotective effects on the survival of dopaminergic neurons. Furthermore, PB treatment was shown to protect CA1 and CA3 neurons in the hippocampus and dopaminergic neurons in the SN. DA levels in the SN were increased after PB treatment, leading to the improvement of motor function of PD rats. Conclusions: These results imply that PB prevents MPTP-induced neurotoxicity via its antioxidant activities and increases GDNF levels, which may contribute to the therapeutic strategy for PD.

The Neuroprotective Effect of Isotetrandrine on Parkinson's Disease via Anti-Inflammation and Antiapoptosis In Vitro and In Vivo.

Parkinson's disease (PD) is one of the most influential diseases in the world, and the current medication only can relieve the clinical symptoms but not slow the progression of PD. Therefore, we intend to examine the neuroprotective activity of plant-derived compound isotetrandrine (ITD) in vitro and in vivo. In vitro, cells were cotreated with ITD and LPS to detect the inflammatory-related protein and mRNA. In vivo, zebrafish were pretreated with ITD and inhibitors prior to 6-OHDA treatment. Then, the behavior was monitored at 5 dpf. Our result showed ITD inhibited LPS-induced upregulation of iNOS, COX-2 protein expression, and iL-6, inos, cox-2, and cd11b mRNA expression in BV2 cells. The data in zebrafish also demonstrated a significant improvement of ITD on the 6-OHDA-induced locomotor deficiency. ITD also improved 6-OHDA-induced apoptosis in zebrafish PD. We also pharmacologically validated the mechanism with three inhibitors, including LY294002, PI3K inhibitor; LY32141996, ERK inhibitor, SnPP, and HO-1 inhibitors. All of these inhibitors could abolish the neuroprotective effect of ITD partially in locomotor activity. Besides, the molecular level also showed the same trend. Treatment of these inhibitors could significantly abolish ITD-induced antineuroinflammatory and antioxidative stress effects in zebrafish PD. Our study showed ITD possessed a neuroprotective activity in zebrafish PD. The mRNA level also supported our arguments. The neuroprotection of ITD might be through antineuroinflammation and antiapoptosis pathways via PI3K, ERK, and HO-1.

Elevated Expression of Two Pore Potassium Channel THIK-1 in Alzheimer's Disease: An Inflammatory Mechanism.

Tandem pore domain halothane-inhibited K+ channel 1 (THIK-1, coded by KCNK13) provides an upstream regulation of the activation of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, which has been suggested as one of the key mechanisms of the pathological process in neurodegeneration mainly from in vitro and in vivo model systems studies. However, unequivocal evidence from neurodegenerative disorders has been lacking. To investigate the involvement of the THIK-1/NLRP3 pathway in the pathological process of Alzheimer's disease (AD) and Parkinson's disease (PD). This study investigated gene expression of markers in the THIK-1/NLRP3 pathway in an animal model representing AD as well as in human postmortem brains of AD and PD by quantitative real-time PCR. THIK-1 protein expression was determined using automated capillary electrophoresis immunoblotting. Furthermore, DNA methylation of KCNK13 was analysed in AD cohort by pyrosequencing. A substantial upregulation of KCNK13, glial activation markers, NLRP3 inflammasome components, and IL1B was observed in the animal study. Increased expression of KCNK13 support an inflammatory glial cell activation in both advanced AD and PD. The increase in KCNK13 expression was also supported by downregulation in DNA methylation of KCNK13 in AD. The association between THIK-1 K+ channels expression and pathology changes indicates a THIK-1-induced activation of this glial subtype in AD and PD. Therefore, specific blocks of the microglial THIK-1 K+ channels at the early stage of AD and PD may be beneficial for the patients.

Cystathionine β-Synthase Suppresses NLRP3 Inflammasome Activation via Redox Regulation in Microglia.

Aims: Cystathionine β-synthase (CBS) is essential for homocysteine (Hcy) transsulfuration, yielding cysteine as a common precursor of hydrogen sulfide (H2S), glutathione (GSH), and other sulfur molecules, which produce neuroprotective effects in neurological conditions. We previously reported a disruption of microglial CBS/H2S signaling in a Parkinson's disease (PD) mouse model. Yet, it remains unclear whether CBS affects nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome activity and other pathologies in PD. Results: Microglial CBS expression decreased after lipopolysaccharide (LPS) stimulation. Elevated GSSG (the oxidized GSH) content and decreased H2S generation were found in the brains of microglial cbs conditional-knockout (cbscKO) mice, whereas serum and brain Hcy levels remained unaltered. Moreover, microglial cbscKO mice were susceptible to NLRP3 inflammasome activation and dopaminergic neuron losses caused by LPS injection into the substantia nigra, whereas cbs overexpression or activation produced opposite effects. In vitro studies showed that cbs overexpression or activation suppressed microglial NLRP3 inflammasome activation and interleukin (IL)-1β secretion by reducing mitochondrial reactive oxygen species (mitoROS) level. Conversely, ablation of cbs enhanced NLRP3 expression and mitoROS generation and augmented microglial NLRP3 inflammasome activity in response to adenosine triphosphate challenge, which was blocked by the mitoROS scavenger. Innovation and Conclusion: The study demonstrated an elevated GSSG level and reduced H2S generation, which correlated with a susceptible status of microglia in the brain of cbscKO mice. Our findings reveal a critical role of CBS in restraining the microglial NLRP3 inflammasome by controlling redox homeostasis and highlight that activation or upregulation of CBS may become a potential strategy for PD treatment.

Thioredoxin-1 inhibits the activation of IRE1 by targeting Hsp90/p-Cdc37 chaperone complex in Parkinson disease.

Endoplasmic reticulum stress is implicated in the etiopathogenesis of Parkinson disease (PD). Our previous study has revealed that thioredoxin-1 (Trx-1) attenuated IRE1 activation in 1-methyl-4-phenylpyridinium ion (MPP+)/1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models. However, its exact mechanism has been largely unclear. In this research, it was reported for the first time that the protein levels of heat shock protein 90 (Hsp90) and phosphorylated cell division cycle 37 (p-Cdc37) were significantly decreased and the interaction of Hsp90/p-Cdc37 complex with IRE1 was disturbed in MPP+/MPTP-induced PD models. Trx-1 overexpression reversed the expression of Hsp90 and p-Cdc37 in cultured cells and the substantia nigra pars compacta of mice. More importantly, Trx-1 overexpression enhanced the interaction of Hsp90/p-Cdc37 complex with IRE1. In conclusion, our data demonstrated that Trx-1 inhibited IRE1 activation in PD by elevating the expression of Hsp90 and p-Cdc37 and strengthening the interaction of Hsp90/p-Cdc37 complex and IRE1.

Plausible Role of Mitochondrial DNA Copy Number in Neurodegeneration-a Need for Therapeutic Approach in Parkinson's Disease (PD).

Parkinson's disease (PD) is an advancing age-associated progressive brain disorder which has various diverse factors, among them mitochondrial dysfunction involves in dopaminergic (DA) degeneration. Aging causes a rise in mitochondrial abnormalities which leads to structural and functional modifications in neuronal activity and cell death in PD. This ends in deterioration of mitochondrial function, mitochondrial alterations, mitochondrial DNA copy number (mtDNA CN) and oxidative phosphorylation (OXPHOS) capacity. mtDNA levels or mtDNA CN in PD have reported that mtDNA depletion would be a predisposing factor in PD pathogenesis. To maintain the mtDNA levels, therapeutic approaches have been focused on mitochondrial biogenesis in PD. The depletion of mtDNA levels in PD can be influenced by autophagic dysregulation, apoptosis, neuroinflammation, oxidative stress, sirtuins, and calcium homeostasis. The current review describes the regulation of mtDNA levels and discusses the plausible molecular pathways in mtDNA CN depletion in PD pathogenesis. We conclude by suggesting further research on mtDNA depletion which might show a promising effect in predicting and diagnosing PD.

Enzymatic properties and clinical associations of serum alpha-galactosidase A in Parkinson's disease.

Recent studies have revealed an association between Parkinson's disease (PD) and Fabry disease, a lysosomal storage disorder; however, the underlying mechanisms remain to be elucidated. This study aimed to investigate the enzymatic properties of serum alpha-galactosidase A (GLA) and compared them with the clinical parameters of PD. The study participants consisted of 66 sporadic PD patients and 52 controls. We measured serum GLA activity and calculated the apparent Michaelis constant (Km ) and maximal velocity (Vmax ) by Lineweaver-Burk plot analysis. Serum GLA protein concentration was measured by enzyme-linked immunosorbent assay. We examined the potential correlations between serum GLA activity and GLA protein concentration and clinical features and the plasma neurofilament light chain (NfL) level. Compared to controls, PD patients showed significantly lower serum GLA activity (P < 0.0001) and apparent Vmax (P = 0.0131), but no change in the apparent Km value. Serum GLA protein concentration was lower in the PD group (P = 0.0168) and was positively associated with GLA activity. Serum GLA activity and GLA protein concentration in the PD group showed a negative correlation with age. Additionally, serum GLA activity was negatively correlated with the motor severity score and the level of plasma NfL, and was positively correlated with the score of frontal assessment battery. This study highlights that the lower serum GLA activity in PD is the result of a quantitative decrement of GLA protein in the serum and that it may serve as a biomarker of disease severity.

The effects of AQP4 rs162009 on resting-state brain activity in Parkinson's disease.

We previously identified a significant association between Aquaporin-4 (AQP4) and Parkinson's disease (PD). To identify whether AQP4 single-nucleotide polymorphism (SNP) rs162009 affects regional brain activity and clinical phenotypes of PD. Low-frequency fluctuation amplitude (ALFF) was used to evaluate spontaneous brain activity, regional homogeneity (ReHo) was used to evaluate the pace of activity of adjacent voxel regions, and degree centrality (DC) was used to describe the functional connection strength between a voxel and the whole brain. Disease severity and PD stage were assessed with the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale and Hoehn and Yahr scales, and the Montreal Cognitive Assessment (MoCA) was used to assess the participants' cognitive function. In patients with PD, AQP4 SNP rs162009 was associated with a significant higher ALFF in the right caudate head and the left occipital gyrus, a significant lower ReHo in the right inferior frontal gyrus, a different DC in the right frontal gyrus, the left calcarine, and the right inferior temporal gyrus. A significant positive correlation between ALFF in the right caudate head and MoCA in rs162009_A carriers was found. A significant negative correlation between the DC at the left calcarine and MDS-UPDRS and MDS-UPDRS III in rs162009_A noncarriers was found. Our study further revealed the effect of AQP4 SNP rs162009 on brain activity in PD, indicating that AQP4 may play an important role in PD neuropathophysiology.

Striatal Dopamine Loss in Early Parkinson's Disease: Systematic Review and Novel Analysis of Dopamine Transporter Imaging.

Neuropathological studies, based on small samples, suggest that symptoms of Parkinson's disease (PD) emerge when dopamine/nigrostriatal loss is around 50-80%. Functional neuroimaging can be applied in larger numbers during life, which allows analysis of the extent of dopamine loss more directly. To quantify dopamine transporter (DaT) activity by neuroimaging in early PD. Systematic review and novel analysis of DaT imaging studies in early PD. In our systematic review, in 423 unique cases from 27 studies with disease duration of less than 6 years, mean age 58.0 (SD 11.5) years, and mean disease duration 1.8 (SD 1.2) years, striatal loss was 43.5% (95% CI 41.6, 45.4) contralaterally, and 36.0% (95% CI 33.6, 38.3) ipsilaterally. For unilateral PD, in 436 unique cases, mean age 57.5 (SD 10.2) years, and mean disease duration 1.8 (SD 1.4) years, striatal loss was 40.6% (95% CI 38.8, 42.4) contralaterally, and 31.6% (95% CI 29.4, 33.8) ipsilaterally. In our novel analysis of the Parkinson's Progressive Marker Initiative study, 413 cases had 1436 scans performed. For a disease duration of less than 1 year, age was 61.8 (SD 9.8) years, and striatal loss was 51.2% (95% CI 49.1, 53.3) contralaterally and 39.5% (36.9, 42.1) ipsilaterally, giving an overall striatal loss of 45.3% (43.0, 47.6). Loss of striatal DaT activity in early PD is less at 35-45%, rather than the 50-80% striatal dopamine loss estimated to be present at the time of symptom onset, based on backwards extrapolation from autopsy studies.