Clinical value of video oculomotor evaluation in the differential diagnosis of multiple system atrophy and Parkinson's disease.

BACKGROUND: Multiple system atrophy (MSA) is a neurodegenerative disease that progresses rapidly and has a poor prognosis. This study aimed to assess the value of video oculomotor evaluation (VOE) in the differential diagnosis of MSA and Parkinson's disease (PD). METHODS: In total, 28 patients with MSA, 31 patients with PD, and 30 age- and sex-matched healthy controls (HC) were screened and included in this study. The evaluation consisted of a gaze-holding test, smooth pursuit eye movement (SPEM), random saccade, and optokinetic nystagmus (OKN). RESULTS: The MSA and PD groups had more abnormalities and decreased SPEM gain than the HC group (64.29%, 35.48%, 10%, p < .001). The SPEM gain in the MSA group was significantly lower than that in the PD group at specific frequencies. Patients with MSA and PD showed prolonged latencies in all saccade directions compared with those with HC. However, the two diseases had no significant differences in the saccade parameters. The OKN gain gradually decreased from the HC to the PD and the MSA groups (p < .05). Compared with the PD group, the gain in the MSA group was further decreased in the OKN test at 30°/s (Left, p = .010; Right p = .016). Receiver operating characteristic curves showed that the combination of oculomotor parameters with age and course of disease could aid in the differential diagnosis of patients with MSA and PD, with a sensitivity of 89.29% and a specificity of 70.97%. CONCLUSIONS: The combination of oculomotor parameters and clinical data may aid in the differential diagnosis of MSA and PD. Furthermore, VOE is vital in the identification of neurodegenerative diseases.

Synsvansker ved Parkinsons sykdom.

Parkinson's disease is characterised by the core motor symptoms: bradykinesia, rigidity and tremor. The disease also has a number of non-motor symptoms, such as visual impairment. Patients may experience blurred vision, sensitivity to light, difficulties in reading, and a subjective feeling of rapid eye fatigue. The visual impairments also affect the patients' motor skills, as vision compensates for poor postural control and difficulty initiating movement. It is important to identify common but frequently underdiagnosed visual impairment, and initiate measures that can increase quality of life and pattern of movement. In this clinical review we present the most common visual impairments in Parkinson's disease, as well as providing advice for improved visual function.

Speech, voice, and language outcomes following deep brain stimulation: A systematic review.

BACKGROUND: Deep brain stimulation (DBS) reliably ameliorates cardinal motor symptoms in Parkinson's disease (PD) and essential tremor (ET). However, the effects of DBS on speech, voice and language have been inconsistent and have not been examined comprehensively in a single study. OBJECTIVE: We conducted a systematic analysis of literature by reviewing studies that examined the effects of DBS on speech, voice and language in PD and ET. METHODS: A total of 675 publications were retrieved from PubMed, Embase, CINHAL, Web of Science, Cochrane Library and Scopus databases. Based on our selection criteria, 90 papers were included in our analysis. The selected publications were categorized into four subcategories: Fluency, Word production, Articulation and phonology and Voice quality. RESULTS: The results suggested a long-term decline in verbal fluency, with more studies reporting deficits in phonemic fluency than semantic fluency following DBS. Additionally, high frequency stimulation, left-sided and bilateral DBS were associated with worse verbal fluency outcomes. Naming improved in the short-term following DBS-ON compared to DBS-OFF, with no long-term differences between the two conditions. Bilateral and low-frequency DBS demonstrated a relative improvement for phonation and articulation. Nonetheless, long-term DBS exacerbated phonation and articulation deficits. The effect of DBS on voice was highly variable, with both improvements and deterioration in different measures of voice. CONCLUSION: This was the first study that aimed to combine the outcome of speech, voice, and language following DBS in a single systematic review. The findings revealed a heterogeneous pattern of results for speech, voice, and language across DBS studies, and provided directions for future studies.

Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson's Disease.

There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.

Association Analysis of Essential Tremor-Associated Genetic Variants in Sporadic Late-Onset Parkinson's Disease.

Background: Parkinson's disease (PD) and Essential tremor (ET) are the two most common tremor diseases with recognized genetic pathogenesis. The overlapping clinical features suggest they may share genetic predispositions. Our previous study systematically investigated the association between rare coding variants in ET-associated genes and early-onset PD (EOPD), and found the suggestive association between teneurin transmembrane protein 4 (TENM4) and EOPD. In the current research, we explored the potential genetic interplay between ET-associated genetic loci/genes and sporadic late-onset PD (LOPD). Methods: We performed whole-genome sequencing in the 1962 sporadic LOPD cases and 1279 controls from mainland China. We first used logistic regression analysis to test the top 16 SNPs identified by the ET genome-wide association study for the association between ET and LOPD. Then we applied the optimized sequence kernel association testing to explore the rare variant burden of 33 ET-associated genes in this cohort. Results: We did not observe a significant association between the included SNPs with LOPD. We also did not discover a significant burden of rare deleterious variants of ET-associated genes in association with LOPD risk. Conclusion: Our results do not support the role of ET-associated genetic loci and variants in LOPD. Highlights: 1962 cases and 1279 controls were recruited to study the potential genetic interplay between ET-associated genetic loci/variants and sporadic LOPD.No significant association between the ET-associated SNPs and LOPD were observed.No significant burden of rare deleterious variants of ET-associated gene in LOPD risk were found.

The correlation of orthostatic hypotension in Parkinson disease with the disease course and severity and its impact on quality of life.

We investigated the correlation of orthostatic hypotension (OH) in Parkinson disease (PD) with the disease course and severity, and its possible impact on quality of life. 171 PD patients were recruited and divided into the PD-NOH (n = 91) and PD-OH groups (n = 80). Clinical data were collected. The severity and quality of life of PD patients were evaluated. The impact of disease severity was analyzed using logistic regression analysis. The ROC curve was plotted. There were significant differences (P < .05) between PD-NOH and PD-OH groups in terms of the disease course, non-motor symptoms (somnipathy), Hoehn&Yahr stage, LEDD score, RBDSQ score, PDQ-39 score, MMSE score, MoCA, MDS-UPDRS Part III scores during off- and on-periods, and NMSS score. Hoehn&Yahr stage (OR 4.950, 95% CI 1.516-16.157, P = .008) was closely associated with the risk of OH in PD. PDQ-39 score (OR 1.079, 95% CI 1.033-1.127, P = .001) in PD patients with OH further decreased. Patients with PD-OH experienced severe impairment in 4 dimensions of quality of life, including motor function, cognitive function, physical discomfort, and activities of daily living. Different clinical symptoms of PD-OH were positively correlated with PDQ39 subscales. The area under the ROC curve of the Hoehn&Yahr stage in predicting the occurrence of OH was 0.679 (95% CI 0.600-0.758), and that of the Hoehn&Yahr stage combined with levodopa equivalent dose, and MDS-UPDRS Part III score during off-period was 0.793 (95% CI 0.727-0.862). Higher Hoehn&Yahr stage is associated with increased risk of OH in PD patients, and deteriorated quality of life of PD patients. Patients with different OH symptoms are affected in different dimensions of their quality of life. The Hoehn & Yahr stage can independently predict the risk of OH in PD patients.

Brain structure comparison among Parkinson disease, essential tremor, and healthy controls using 7T MRI.

Both Parkinson disease (PD) and Essential tremor (ET) are movement disorders causing tremors in elderly individuals. Although PD and ET are different disease, they often present with similar initial symptoms, making their differentiation challenging with magnetic resonance imaging (MRI) techniques. This study aimed to identify structural brain differences among PD, ET, and health controls (HCs) using 7-Tesla (T) MRI. We assessed the whole-brain parcellation in gray matter volume, thickness, subcortical volume, and small regions of basal ganglia in PD (n = 18), ET (n = 15), and HCs (n = 18), who were matched for age and sex. Brain structure analysis was performed automatic segmentation through Freesurfer software. Small regions of basal ganglia were manually segmented by ITK-SNAP. Additionally, we examined the associations between clinical indicators (symptom duration, unified Parkinson diseases rating scale (UPDRS), and clinical rating scale for tremor (CRST)) and brain structure. PD showed a significant reduction in gray matter volume in the postcentral region compared to ET. ET showed a significant reduction in cerebellum volume compared to HCs. There was a negative correlation between CRST scores (B and C) and gray matter thickness in right superior frontal in ET. This study demonstrated potential of 7T MRI in differentiating brain structure differences among PD, ET, and HCs. Specific findings, such as parietal lobe atrophy in PD compared to ET and cerebellum atrophy in ET compared to HCs, the importance of advanced imaging techniques in accurately diagnosing and distinguishing between movement disorders that present with similar initial symptoms.

Non-HLA angiotensin-type-1 receptor autoantibodies mediate the long-term loss of grafted neurons in Parkinson's disease models.

BACKGROUND: Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival. METHODS: In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection. RESULTS: At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats. CONCLUSIONS: The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.

Integrated bioinformatics analysis for exploring potential biomarkers related to Parkinson's disease progression.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disease with increasing prevalence. Effective diagnostic markers and therapeutic methods are still lacking. Exploring key molecular markers and mechanisms for PD can help with early diagnosis and treatment improvement. METHODS: Three datasets GSE174052, GSE77668, and GSE168496 were obtained from the GEO database to search differentially expressed circRNA (DECs), miRNAs (DEMis), and mRNAs (DEMs). GO and KEGG enrichment analyses, and protein-protein interaction (PPI) network construction were implemented to explore possible actions of DEMs. Hub genes were selected to establish circRNA-related competing endogenous RNA (ceRNA) networks. RESULTS: There were 1005 downregulated DECs, 21 upregulated and 21 downregulated DEMis, and 266 upregulated and 234 downregulated DEMs identified. The DEMs were significantly enriched in various PD-associated functions and pathways such as extracellular matrix organization, dopamine synthesis, PI3K-Akt, and calcium signaling pathways. Twenty-one hub genes were screened out, and a PD-related ceRNA regulatory network was constructed containing 31 circRNAs, one miRNA (miR-371a-3p), and one hub gene (KCNJ6). CONCLUSION: We identified PD-related molecular markers and ceRNA regulatory networks, providing new directions for PD diagnosis and treatment.

PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants.

Parkinson's disease (PD) is a common and incurable neurodegenerative disorder that arises from the loss of dopaminergic neurons in the substantia nigra and is mainly characterized by progressive loss of motor function. Monogenic familial PD is associated with highly penetrant variants in specific genes, notably the PRKN gene, where homozygous or compound heterozygous loss-of-function variants predominate. PRKN encodes Parkin, an E3 ubiquitin-protein ligase important for protein ubiquitination and mitophagy of damaged mitochondria. Accordingly, Parkin plays a central role in mitochondrial quality control but is itself also subject to a strict protein quality control system that rapidly eliminates certain disease-linked Parkin variants. Here, we summarize the cellular and molecular functions of Parkin, highlighting the various mechanisms by which PRKN gene variants result in loss-of-function. We emphasize the importance of high-throughput assays and computational tools for the clinical classification of PRKN gene variants and how detailed insights into the pathogenic mechanisms of PRKN gene variants may impact the development of personalized therapeutics.

A person-centered approach to characterizing longitudinal ambulatory impairment in Parkinson's disease.

Loss of ambulation is common and highly variable in Parkinson's disease (PD), and poorly understood from the perspectives of those with PD. Gaining insights to the anticipated perceived trajectories and their drivers, will facilitate patient-centered care. Latent class growth analysis, a person-centered mixture modelling approach, was applied to 16,863 people with PD stratified by early (N = 8612; < 3 years), mid (N = 6181; 3-10 years) and later (N = 2070; > 10 years) disease to discern clusters with similar longitudinal patterns of self-reported walking difficulty, measured by EuroQoL 5D-5L that is validated for use in PD. There were four clusters in early and mid-disease strata, with a fifth identified in later disease. Trajectories ranged from none to moderate walking difficulty, with small clusters with severe problems. The percentage of subjects with moderate (early = 17.5%, mid = 26.4%, later = 32.5%) and severe (early = 3.8%, mid = 7.4%, later = 15.4%) walking difficulty at baseline increased across disease duration groups. The trajectories tended to be stable with variability in moderate and severe groups. Across strata, clusters with moderate to severe problems were associated with more severe impairment, depression, anxiety, arthritis, higher BMI, lower income, and lower education, but no consistent race or gender differences. The findings reveal distinct longitudinal patterns in perceived difficulties in walking in PD.

Adenosine A2A Receptor Blockade Provides More Effective Benefits at the Onset Rather than after Overt Neurodegeneration in a Rat Model of Parkinson's Disease.

Adenosine A2A receptor (A2AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A2AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP+ in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP+ infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP+ infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A2AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A2AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.

Function and Mechanism of Abscisic Acid on Microglia-Induced Neuroinflammation in Parkinson's Disease.

Parkinson's disease (PD), as a neurologically implemented disease with complex etiological factors, has a complex and variable pathogenesis. Accompanying further research, neuroinflammation has been found to be one of the possible factors in its pathogenesis. Microglia, as intrinsic immune cells in the brain, play an important role in maintaining microenvironmental homeostasis in the brain. However, over-activation of neurotoxic microglia in PD promotes neuroinflammation, which further increases dopaminergic (DA) neuronal damage and exacerbates the disease process. Therefore, targeting and regulating the functional state of microglia is expected to be a potential avenue for PD treatment. In addition, plant extracts have shown great potential in the treatment of neurodegenerative disorders due to their abundant resources, mild effects, and the presence of multiple active ingredients. However, it is worth noting that some natural products have certain toxic side effects, so it is necessary to pay attention to distinguish medicinal ingredients and usage and dosage when using to avoid aggravating the progression of diseases. In this review, the roles of microglia with different functional states in PD and the related pathways inducing microglia to transform into neuroprotective states are described. At the same time, it is discussed that abscisic acid (ABA) may regulate the polarization of microglia by targeting them, promote their transformation into neuroprotective state, reduce the neuroinflammatory response in PD, and provide a new idea for the treatment of PD and the selection of drugs.

Role of Bioactives in Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) affect millions worldwide, with the two most prevalent being Alzheimer's and Parkinson disease [...].

Plasma exosomes impair microglial degradation of α-synuclein through V-ATPase subunit V1G1.

INTRODUCTION: Microglia are the main phagocytes in the brain and can induce neuroinflammation. Moreover, they are critical to alpha-synuclein (α-syn) aggregation and propagation. Plasma exosomes derived from patients diagnosed with Parkinson's disease (PD-exo) reportedly evoked α-syn aggregation and inflammation in microglia. In turn, microglia internalized and released exosomal α-syn, enhancing α-syn propagation. However, the specific mechanism through which PD-exo influences α-syn degradation remains unknown. METHODS: Exosomes were extracted from the plasma of patients with PD by differential ultracentrifugation, analyzed using electron microscopy (EM) and nanoparticle flow cytometry, and stereotaxically injected into the unilateral striatum of the mice. Transmission EM was employed to visualize lysosomes and autophagosomes in BV2 cells, and lysosome pH was measured with LysoSensor Yellow/Blue DND-160. Cathepsin B and D, lysosomal-associated membrane protein 1 (LAMP1), ATP6V1G1, tumor susceptibility gene 101 protein, calnexin, α-syn, ionized calcium binding adaptor molecule 1, and NLR family pyrin domain containing 3 were evaluated using quantitative polymerase chain reaction or western blotting, and α-syn, LAMP1, and ATP6V1G1 were also observed by immunofluorescence. Small interfering ribonucleic acid against V1G1 was transfected into BV2 cells and primary microglia using Lipofectamine® 3000. A PD mouse model was established via injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into mice. A lentiviral-mediated strategy to overexpress ATP6V1G1 in the brain of MPTP-treated mice was employed. Motor coordination was assessed using rotarod and pole tests, and neurodegeneration in the mouse substantia nigra and striatum tissues was determined using immunofluorescence histochemical and western blotting of tyrosine hydroxylase. RESULTS: PD-exo decreased the expression of V1G1, responsible for the acidification of intra- and extracellular milieu. This impairment of lysosomal acidification resulted in the accumulation of abnormally swollen lysosomes and decreased lysosomal enzyme activities, impairing lysosomal protein degradation and causing α-syn accumulation. Additionally, V1G1 overexpression conferred the mice neuroprotection during MPTP exposure. CONCLUSION: Pathogenic protein accumulation is a key feature of PD, and compromised V-type ATPase dysfunction might participate in PD pathogenesis. Moreover, V1G1 overexpression protects against neuronal toxicity in an MPTP-based PD mouse model, which may provide opportunities to develop novel therapeutic interventions for PD treatment.

Regional nigral neuromelanin degeneration in asymptomatic leucine-rich repeat kinase 2 gene carrier using MRI.

Asymptomatic Leucine-Rich Repeat Kinase 2 Gene (LRRK2) carriers are at risk for developing Parkinson's disease (PD). We studied presymptomatic substantia nigra pars compacta (SNc) regional neurodegeneration in asymptomatic LRRK2 carriers compared to idiopathic PD patients using neuromelanin-sensitive MRI technique (NM-MRI). Fifteen asymptomatic LRRK2 carriers, 22 idiopathic PD patients, and 30 healthy controls (HCs) were scanned using NM-MRI. We computed volume and contrast-to-noise ratio (CNR) derived from the whole SNc and the sensorimotor, associative, and limbic SNc regions. An analysis of covariance was performed to explore the differences of whole and regional NM-MRI values among the groups while controlling the effect of age and sex. In whole SNc, LRRK2 had significantly lower CNR than HCs but non-significantly higher volume and CNR than PD patients, and PD patients significantly lower volume and CNR compared to HCs. Inside SNc regions, there were significant group effects for CNR in all regions and for volumes in the associative region, with a trend in the sensorimotor region but no significant changes in the limbic region. PD had reduced volume and CNR in all regions compared to HCs. Asymptomatic LRRK2 carriers showed globally decreased SNc volume and CNR suggesting early nigral neurodegeneration in these subjects at risk of developing PD.

Association of dietary selenium intake and all-cause mortality of Parkinson's disease and its interaction with blood cadmium level: a retrospective cohort study.

BACKGROUND: Parkinson's disease (PD) is a slowly progressive neurodegenerating disease that may eventually lead to disabling condition and pose a threat to the health of aging populations. This study aimed to explore the association of two potential risk factors, selenium and cadmium, with the prognosis of Parkinson's disease as well as their interaction effect. METHODS: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 2005-2006 to 2015-2016 and National Death Index (NDI). Participants were classified as Parkinson's patients by self-reported anti-Parkinson medications usage. Cox regression models and restricted cubic spline models were applied to evaluate the association between PD mortality and selenium intake level as well as blood cadmium level. Subgroup analysis was also conducted to explore the interaction between them. RESULTS: A total of 184 individuals were included. In full adjusted cox regression model (adjusted for age, gender, race, hypertension, pesticide exposure, smoking status and caffeine intake), compared with participants with low selenium intake, those with normal selenium intake level were significantly associated with less risk of death (95%CI: 0.18-0.76, P = 0.005) while no significant association was found between low selenium intake group and high selenium group (95%CI: 0.16-1.20, P = 0.112). Restricted cubic spline model indicated a nonlinear relationship between selenium intake and PD mortality (P for nonlinearity = 0.050). The association between PD mortality and blood cadmium level was not significant (95%CI: 0.19-5.57, P = 0.112). However, the interaction term of selenium intake and blood cadmium showed significance in the cox model (P for interaction = 0.048). Subgroup analysis showed that the significant protective effect of selenium intake existed in populations with high blood cadmium but not in populations with low blood cadmium. CONCLUSION: Moderate increase of selenium intake had a protective effect on PD mortality especially in high blood cadmium populations.

Serum urate levels and neurodegenerative outcomes: a prospective cohort study and mendelian randomization analysis of the UK Biobank.

BACKGROUND: Previous studies on the associations between serum urate levels and neurodegenerative outcomes have yielded inconclusive results, and the causality remains unclear. This study aimed to investigate whether urate levels are associated with the risks of Alzheimer's disease and related dementias (ADRD), Parkinson's disease (PD), and neurodegenerative deaths. METHODS: This prospective study included 382,182 participants (45.7% men) from the UK Biobank cohort. Cox proportional hazards models were used to assess the associations between urate levels and risk of neurodegenerative outcomes. In the Mendelian randomization (MR) analysis, urate-related single-nucleotide polymorphisms were identified through a genome-wide association study. Both linear and non-linear MR approaches were utilized to investigate the potential causal associations. RESULTS: During a median follow-up period of 12 years, we documented 5,400 ADRD cases, 2,553 PD cases, and 1,531 neurodegenerative deaths. Observational data revealed that a higher urate level was associated with a decreased risk of ADRD (hazard ratio [HR]: 0.93, 95% confidence interval [CI]: 0.90, 0.96), PD (HR: 0.87, 95% CI: 0.82, 0.91), and neurodegenerative death (HR: 0.88, 95% CI: 0.83, 0.94). Negative linear associations between urate levels and neurodegenerative events were observed (all P-values for overall < 0.001 and all P-values for non-linearity > 0.05). However, MR analyses yielded no evidence of either linear or non-linear associations between genetically predicted urate levels and the risk of the aforementioned neurodegenerative events. CONCLUSION: Although the prospective cohort study demonstrated that elevated urate levels were associated with a reduced risk of neurodegenerative outcomes, MR analyses found no evidence of causality.

The Role of Oxygen Homeostasis and the HIF-1 Factor in the Development of Neurodegeneration.

Understanding the molecular underpinnings of neurodegeneration processes is a pressing challenge for medicine and neurobiology. Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent forms of neurodegeneration. To date, a substantial body of experimental evidence has strongly implicated hypoxia in the pathogenesis of numerous neurological disorders, including AD, PD, and other age-related neurodegenerative conditions. Hypoxia-inducible factor (HIF) is a transcription factor that triggers a cell survival program in conditions of oxygen deprivation. The involvement of HIF-1α in neurodegenerative processes presents a complex and sometimes contradictory picture. This review aims to elucidate the current understanding of the interplay between hypoxia and the development of AD and PD, assess the involvement of HIF-1 in their pathogenesis, and summarize promising therapeutic approaches centered on modulating the activity of the HIF-1 complex.

Role of virtual reality in examining the effect of fear of falling (FOF) on postural stability in individuals without and with Parkinson's disease in Egypt: a mixed-methods feasibility study protocol.

BACKGROUND: Falls are common in older people and individuals with neurological conditions. Parkinson's disease (PD) is known for postural instability causing mobility disabilities, falls and reduced quality of life. The fear of falling (FOF), a natural response to unstable balance, can worsen postural control problems. Evaluating FOF relies largely on affected persons' subjective accounts due to limited objective assessment methods available. The aim of this mixed-methods feasibility study is to develop an assessment method for FOF while in motion and walking within virtual environments. This study will assess a range of FOF-related responses, including cognitive factors, neuromuscular response and postural stability. METHODS AND ANALYSIS: This feasibility study will consist of four phases: the first two phases will include people without PD, while the other two will include people diagnosed with PD. Participants will be assessed for direct and indirect responses to real life, as well as virtual environment walking scenarios that may induce FOF. Data from questionnaires, different neurophysiological assessments, movement and gait parameters, alongside evaluations of usability and acceptability, will be collected. Semistructured interviews involving both participants and research assistants shall take place to elicit their experiences throughout different phases of the assessments undertaken. Demographic data, the scores of assessment scales, as well as feasibility, usability and acceptability of the measurement methods, will be illustrated via descriptive statistics. Movement and gait outcomes, together with neurophysiological data, will be extracted and calculated. Exploring relationships between different factors in the study will be achieved using a regression model. Thematic analysis will be the approach used to manage qualitative data. ETHICS AND DISSEMINATION: This feasibility study was approved by the Ethics Committee of the Faculty of Physical Therapy, Kafr El Sheikh University, Egypt (number: P.T/NEUR/3/2023/46). The results of this study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05931692).