α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies.

Spread and aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn protein conformations, often termed "strains" for their distinct biological properties, it is unclear whether PD and DLB result from aSyn strain differences, and biomarkers that differentiate PD and DLB are lacking. Moreover, while pathological forms of aSyn have been detected outside the brain ( e.g., in skin, gut, blood), the functional significance of these peripheral aSyn species is unclear. Here, we developed assays using monoclonal antibodies selective for two different aSyn species generated in vitro - termed Strain A and Strain B - and used them to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma, through immunohistochemistry, enzyme-linked immunoassay, and immunoblotting. Surprisingly, we found that plasma aSyn species detected by these antibodies differentiated individuals with PD vs. DLB in a discovery cohort (UPenn, n=235, AUC 0.83) and a multi-site replication cohort (Parkinson's Disease Biomarker Program, or PDBP, n=200, AUC 0.72). aSyn plasma species detected by the Strain A antibody also predicted rate of cognitive decline in PD. We found no evidence for aSyn strains in CSF, and ability to template aSyn fibrillization differed for species isolated from plasma vs. brain, and in PD vs. DLB. Taken together, our findings suggest that aSyn conformational differences may impact clinical presentation and cortical spread of pathological aSyn. Moreover, the enrichment of these aSyn strains in plasma implicates a non-central nervous system source.

Public perceptions of air pollution and its impacts on fertility desire: a nationwide study in China.

Over the past few years, there has been a significant focus on air pollution due to its various detrimental effects on human health. However, its influence on people's tendency to have children remains uncertain, as only a few studies have examined the correlation between public perception of air pollution and the desire to start a family. This article introduces a theoretical framework utilizing a two-stage interval iteration model to explore the connection between children's relative utility and the perception of air pollution. Data for this study were gathered from the "Chinese General Social Survey" (CGSS 2013). The CGSS 2013 project employed a four-stage stratified random sampling technique and conducted household interviews using questionnaires. The sample covered 28 provincial-level cities across China. The hypothesis was tested using a Probit regression model. The findings indicate that individuals considering air pollution a significant issue are 8.62% less likely to have more than one child. The variation in fertility desire sensitivity to air pollution points to heterogeneity among residents, such as registered residents and those living in various residential areas, as well as individuals with different characteristics like education levels. The study concludes that air quality significantly influences human fertility desire, highlighting the urgent necessity to raise awareness of environmental protection issues among both the public and authorities. In particular, there are two key steps to address this issue. Firstly, the government should establish clear air pollution control objectives and refine policies to enhance governance efficiency. Secondly, there is a need to encourage environmentally friendly behaviours among the public, promote more significant involvement in public environmental matters, and ensure effective oversight of the government's responsibilities in managing air pollution.

Is air pollution detrimental to regional innovation? An empirical heterogeneity test based on Chinese cities.

Nowadays, innovation seems to be the inevitable choice to achieve stable economic growth. However, the negative impact of air pollution on health and economy makes air pollution an important factor in regional innovation, which deserves our discussion. The overall regional innovation level from 2014 to 2019 has an upward trend, while the overall air pollution has a downward trend during the period, which provides foundation for our research. Based on the data of 285 prefecture-level cities in China from 2014 to 2019, this paper uses the fixed effect and mediation model to verify the impact and mechanism of air pollution on regional innovation. The results show that the increase in air pollution, measured by the air quality index, significantly inhibits regional innovation. Air pollution has significant funds crowding-out effect and human capital loss effect, thereby decreasing the regional innovation level, which means innovation funds and researchers play a conductive role between air pollution and regional innovation. In heterogeneity analysis, it is found that the detrimental effect of air pollution on regional innovation is significant in eastern and central China, in large- and medium-sized cities, and in cities with poor or general air quality. It indicates that developed and large-scale regions should pay more attention to air pollution control. For polluted regions, more emphasis and endeavors are needed to address air pollution problems. Besides, the inhibitory effect is more severe on incremental innovation rather than on radical innovation, which deserves the attention of enterprises engaged in incremental innovation. Therefore, we propose that targeted environmental policies and effective measures should be developed to improve air quality in the long run. Moreover, policymakers could provide strong support for innovation grants, talent subsidies, and rewards and encourage clean technological innovation through short-term trade-offs between heavily polluting and low polluting enterprises.

Novel THAP1 missense variant with incomplete penetrance in a case of generalized young onset dystonia showing good response to deep brain stimulation.

We describe a case of young onset generalized dystonia, harboring a previously unreported likely pathogenic THAP1 missense variant (c.109 G > A; p.Glu37Lys) that was inherited from her unaffected father. Moreover, we report a positive effect of deep brain stimulation, particularly on the cervical component of dystonia.

Novel bi-allelic FBXO7 variants in a family with early-onset typical Parkinson's disease.

Bi-allelic mutations in FBXO7 are classically associated with a complex phenotype, known as parkinsonian-pyramidal syndrome. We describe two brothers affected by typical early onset Parkinson's disease (EOPD), who carry novel compound heterozygous variants in FBXO7. Our report highlights that typical EOPD can be part of an expanding FBXO7-related phenotype.

Design of fractional evolutionary processing for reactive power planning with FACTS devices.

Reactive power dispatch is a vital problem in the operation, planning and control of power system for obtaining a fixed economic load expedition. An optimal dispatch reduces the grid congestion through the minimization of the active power loss. This strategy involves adjusting the transformer tap settings, generator voltages and reactive power sources, such as flexible alternating current transmission systems (FACTS). The optimal dispatch improves the system security, voltage profile, power transfer capability and overall network efficiency. In the present work, a fractional evolutionary approach achieves the desired objectives of reactive power planning by incorporating FACTS devices. Two compensation arrangements are possible: the shunt type compensation, through Static Var compensator (SVC) and the series compensation through the Thyristor controlled series compensator (TCSC). The fractional order Darwinian Particle Swarm Optimization (FO-DPSO) is implemented on the standard IEEE 30, IEEE 57 and IEEE 118 bus test systems. The power flow analysis is used for determining the location of TCSC, while the voltage collapse proximity indication (VCPI) method identifies the location of the SVC. The superiority of the FO-DPSO is demonstrated by comparing the results with those obtained by other techniques in terms of measure of central tendency, variation indices and time complexity.

Whole Clinic Research Enrollment in Parkinson's Disease: The Molecular Integration in Neurological Diagnosis (MIND) Study.

BACKGROUND: Observational studies in Parkinson's disease (PD) have focused on relatively small numbers of research participants who are studied extensively. The Molecular Integration in Neurological Diagnosis Initiative at the University of Pennsylvania aims to characterize molecular and clinical features of PD in every patient in a large academic center. OBJECTIVE: To determine the feasibility and interest in a global-capture biomarker research protocol. Additionally, to describe the clinical characteristics and GBA and LRRK2 variant carrier status among participants. METHODS: All patients at UPenn with a clinical diagnosis of PD were eligible. Informed consent included options for access to the medical record, future recontact, and use of biosamples for additional studies. A blood sample and a completed questionnaire were obtained from participants. Targeted genotyping for four GBA and eight LRRK2 variants was performed, with plasma and DNA banked for future research. RESULTS: Between September 2018 and December 2019, 704 PD patients were approached for enrollment; 652 (92.6%) enrolled, 28 (3.97%) declined, and 24 (3.41%) did not meet eligibility criteria. Median age was 69 (IQR 63_75) years, disease duration was 5.41 (IQR 2.49_9.95) years, and 11.10%of the cohort was non-white. Disease risk-associated variants in GBA were identified in 39 participants (5.98%) and in LRRK2 in 16 participants (2.45%). CONCLUSIONS: We report the clinical and genetic characteristics of PD patients in an all-comers, global capture protocol from an academic center. Patient interest in participation and yield for identification of GBA and LRRK2 mutation carriers is high, demonstrating feasibility of PD clinic-wide molecular characterization.

Subjective Cognitive Complaint in Parkinson's Disease Patients With Normal Cognition: Canary in the Coal Mine?

OBJECTIVE: The objective of this study was to determine the frequency and impact of subjective cognitive complaint (SCC) in Parkinson's disease (PD) patients with normal cognition. METHODS: Patients with PD with expert consensus-determined normal cognition at baseline were asked a single question regarding the presence of SCC. Baseline (N = 153) and longitudinal (up to 4 follow-up visits during a 5-year period; N = 121) between-group differences in patients with PD with (+SCC) and without (-SCC) cognitive complaint were examined, including cognitive test performance and self-rated and informant-rated functional abilities. RESULTS: A total of 81 (53%) participants reported a cognitive complaint. There were no between-group differences in global cognition at baseline. Longitudinally, the +SCC group declined more than the -SCC group on global cognition (Mattis Dementia Rating Scale-2 total score, F1,431 = 5.71, P = 0.02), processing speed (Symbol Digit Modalities Test, F1,425 = 7.52, P = 0.006), and executive function (Trail Making Test Part B, F1,419 = 4.48, P = 0.04), although the results were not significant after correction for multiple testing. In addition, the +SCC group was more likely to progress to a diagnosis of cognitive impairment over time (hazard ratio = 2.61, P = 0.02). The +SCC group also demonstrated significantly lower self-reported and knowledgeable informant-reported cognition-related functional abilities at baseline, and declined more on an assessment of global functional abilities longitudinally. CONCLUSIONS: Patients with PD with normal cognition, but with SCC, report poorer cognition-specific functional abilities, and are more likely to be diagnosed with cognitive impairment and experience global functional ability decline long term. These findings suggest that SCC and worse cognition-related functional abilities may be sensitive indicators of initial cognitive decline in PD. © 2020 International Parkinson and Movement Disorder Society.

Using scalp EEG and intracranial EEG signals for predicting epileptic seizures: Review of available methodologies.

Patients suffering from epileptic seizures are usually treated with medication and/or surgical procedures. However, in more than 30% of cases, medication or surgery does not effectively control seizure activity. A method that predicts the onset of a seizure before it occurs may prove useful as patients might be alerted to make themselves safe or seizures could be prevented with therapeutic interventions just before they occur. Abnormal neuronal activity, the preictal state, starts a few minutes before the onset of a seizure. In recent years, different methods have been proposed to predict the start of the preictal state. These studies follow some common steps, including recording of EEG signals, preprocessing, feature extraction, classification, and postprocessing. However, online prediction of epileptic seizures remains a challenge as all these steps need further refinement to achieve high sensitivity and low false positive rate. In this paper, we present a comparison of state-of-the-art methods used to predict seizures using both scalp and intracranial EEG signals and suggest improvements to existing methods.

Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders.

OBJECTIVE: To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD. METHODS: Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN-AD = 35). Digital measures of tau, ß-amyloid (Aß), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing. RESULTS: SYN burden was higher in SYN + AD than SYN-AD in each neocortical region (F1, 54 = 5.6-6.0, p < 0.02) but was equivalent in entorhinal cortex and putamen (F1, 43-49 = 0.7-1.7, p > 0.2). SYN + AD performed worse than SYN-AD on a temporal lobe-mediated naming task (t27 = 2.1, p = 0.04). Antemortem cognitive test scores inversely correlated with tau burden (r = -0.39 to -0.68, p < 0.05). AD had higher tau than SYN + AD in all regions (F1, 43 = 12.8-97.2, p < 0.001); however, SYN + AD had a greater proportion of tau in the temporal neocortex than AD (t41 = 2.0, p < 0.05), whereas AD had a greater proportion of tau in the frontal neocortex than SYN + AD (t41 = 3.3, p < 0.002). SYN + AD had similar severity and distribution of neocortical Aß compared to AD (F1, 40-43 = 1.6-2.0, p > 0.1). INTERPRETATION: LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1-13 ANN NEUROL 2019;85:259-271.

Measurements of auto-antibodies to α-synuclein in the serum and cerebral spinal fluids of patients with Parkinson's disease.

Biomarkers for α-synuclein are needed for diagnosis and prognosis in Parkinson's disease (PD). Endogenous auto-antibodies to α-synuclein could serve as biomarkers for underlying synucleinopathy, but previous assessments of auto-antibodies have shown variability and inconsistent clinical correlations. We hypothesized that auto-antibodies to α-synuclein could be diagnostic for PD and explain its clinical heterogeneity. To test this hypothesis, we developed an enzyme-linked immunosorbent assay for measuring α-synuclein auto-antibodies in human samples. We evaluated 69 serum samples (16 healthy controls (HC) and 53 PD patients) and 145 CSF samples (52 HC and 93 PD patients) from our Institution. Both serum and CSF were available for 24 participants. Males had higher auto-antibody levels than females in both fluids. CSF auto-antibody levels were significantly higher in PD patients as compared with HC, whereas serum levels were not significantly different. CSF auto-antibody levels did not associate with amyloid-ß1-42 , total tau, or phosphorylated tau. CSF auto-antibody levels correlated with performance on the Montreal Cognitive Assessment, even when controlled for CSF amyloidß1-42 . CSF hemoglobin levels, as a proxy for contamination of CSF by blood during lumbar puncture, did not influence these observations. Using recombinant α-synuclein with N- and C-terminal truncations, we found that CSF auto-antibodies target amino acids 100 through 120 of α-synuclein. We conclude that endogenous CSF auto-antibodies are significantly higher in PD patients as compared with HC, suggesting that they could indicate the presence of underlying synucleinopathy. These auto-antibodies associate with poor cognition, independently of CSF amyloidß1-42 , and target a select C-terminal region of α-synuclein. Read the Editorial Highlight for this article on page 433.

CSF tau and ß-amyloid predict cerebral synucleinopathy in autopsied Lewy body disorders.

OBJECTIVE: To test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD). METHODS: Patients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN - AD = 14). Ordinal pathology scores for tau, ß-amyloid (Aß), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology. CSF total tau (t-tau), phosphorylated tau at threonine181, and Aß1-42 levels were compared between LBD and control groups and correlated with global cerebral pathology scores in LBD with linear regression. Diagnostic accuracy for postmortem categorization of LBD into SYN + AD vs SYN - AD or neocortical vs brainstem/limbic SYN stage was tested with receiver operating curves. RESULTS: SYN + AD had higher CSF t-tau (mean difference 27.0 ± 8.6 pg/mL) and lower Aß1-42 (mean difference -84.0 ± 22.9 g/mL) compared to SYN - AD (p < 0.01, both). Increasing global cerebral tau and plaque scores were associated with higher CSF t-tau (R2 = 0.15-0.16, p < 0.05, both) and lower Aß1-42 (R2 = 0.43-0.49, p < 0.001, both), while increasing cerebral SYN scores were associated with lower CSF Aß1-42 (R2 = 0.31, p < 0.001) and higher CSF t-tau/Aß1-42 ratio (R2 = 0.27, p = 0.01). CSF t-tau/Aß1-42 ratio had 100% specificity and 90% sensitivity for SYN + AD, and CSF Aß1-42 had 77% specificity and 82% sensitivity for neocortical SYN stage. CONCLUSIONS: Higher antemortem CSF t-tau/Aß1-42 and lower Aß1-42 levels are predictive of increasing cerebral AD and SYN pathology. These biomarkers may identify patients with LBD vulnerable to cortical SYN pathology who may benefit from both SYN and AD-targeted disease-modifying therapies.

Regional brain amyloid-ß accumulation associates with domain-specific cognitive performance in Parkinson disease without dementia.

Parkinson disease patients develop clinically significant cognitive impairment at variable times over their disease course, which is often preceded by milder deficits in memory, visuo-spatial, and executive domains. The significance of amyloid-ß accumulation to these problems is unclear. We hypothesized that amyloid-ß PET imaging by 18F-florbetapir, a radiotracer that detects fibrillar amyloid-ß plaque deposits, would identify subjects with global cognitive impairment or poor performance in individual cognitive domains in non-demented Parkinson disease patients. We assessed 61 non-demented Parkinson disease patients with detailed cognitive assessments and 18F-florbetapir PET brain imaging. Scans were interpreted qualitatively (positive or negative) by two independent nuclear medicine physicians blinded to clinical data, and quantitatively by a novel volume-weighted method. The presence of mild cognitive impairment was determined through an expert consensus process using Level 1 criteria from the Movement Disorder Society. Nineteen participants (31.2%) were diagnosed with mild cognitive impairment and the remainder had normal cognition. Qualitative 18F-florbetapir PET imaging was positive in 15 participants (24.6%). Increasing age and presence of an APOE ε4 allele were associated with higher composite 18F-florbetapir binding. In multivariable models, an abnormal 18F-florbetapir scan by expert rating was not associated with a diagnosis of mild cognitive impairment. However, 18F-florbetapir retention values in the posterior cingulate gyrus inversely correlated with verbal memory performance. Retention values in the frontal cortex, precuneus, and anterior cingulate gyrus retention values inversely correlated with naming performance. Regional cortical amyloid-ß amyloid, as measured by 18F-florbetapir PET, may be a biomarker of specific cognitive deficits in non-demented Parkinson disease patients.

Hyponatraemia: Epidemiology and aetiology in a tertiary care centre in Pakistan.

OBJECTIVE: To determine the incidence, aetiology and epidemiology of hospitalized patients with hyponatraemia. METHODS: Subjects were identified through hospital information system for two consecutive low sodium values (< 130 mEq/L) and charts were reviewed retrospectively. Possible etiologic factors were identified and co-morbidities documented. Management plans were also noted. RESULTS: Among the hospitalized patients the incidence of hyponatraemia was 6.72%. The mean age was 54.8±14.8 years and there were 50% males. The mean serum sodium at presentation was 122 mEq/L. Most common causes were volume depletion (30.6%) and chronic kidney disease (22.6%). Most of the patients had two or more co morbidities. Hyponatraemia at presentation and improvement or worsening during hospital stay did not affect survival of patients. CONCLUSIONS: Hypervolaemic hyponatraemia was the most common presentation in our study.

Amyloid-Beta Positron Emission Tomography Imaging of Alzheimer's Pathology in Parkinson's Disease Dementia.

BACKGROUND: Neuronal loss and α-synuclein (α-syn) pathology are diagnostic of PD in the appropriate clinical context. However, some PD patients have co-morbid Alzheimer's disease (AD) pathology on autopsy, including amyloid-ß (Aß) plaques and neurofibrillary tangles. Florbetapir(18F) is a PET ligand that detects Aß pathology. We hypothesized that florbetapir(18F) imaging could detect Aß pathology in Parkinson disease dementia (PDD) patients prior to death. OBJECTIVE: To determine the utility of florbetapir(18F) PET imaging in detecting Aß pathology in patients with autopsy-confirmed PDD. METHODS: Five participants with PDD had florbetapir(18F) PET imaging prior to death as a part of a longitudinal research study of cognitive decline in PD. PET scans were evaluated by expert raters blinded to clinical and neuropathological information. At autopsy, all five participants underwent semi-quantitative assessments of regional Aß and tau immunohistochemistry. RESULTS: All participants met neuropathological criteria for PD. Two had both positive florbetapir(18F) scans and Aß-positive plaques in multiple brain regions. Regional florbetapir(18F) binding correlated with regional semi-quantitative Aß pathology in these cases. Three cases had negative florbetapir(18F) scans. Two of these had significant tau pathology without Aß pathology, consistent with progressive supranuclear palsy (PSP) in one case and argyrophilic grain disease (AGD) in the other. The last case had a low level of AD neuropathological change. CONCLUSIONS: Florbetapir(18F) Aß imaging can detect the presence of Aß neuropathology in patients with PDD. This imaging technique may aid the clinical evaluation of PDD patients to determine if cognitive decline is occurring in the setting of Aß accumulation.

Diagnostic Accuracy of Anti-Endomysial Antibody in Celiac Disease.

The objective of the study was to determine the diagnostic accuracy of anti-EMA antibody in comparison to histopathological findings in patients suspected of CD. This cross-sectional study was conducted at Gastroenterology Department, Fatima Memorial Hospital, Lahore, from March to October 2014. One hundred and twenty-one patients aged between 5 - 60 years of either gender were recruited in the study. Every patient went through serological testing and biopsy specimens were obtained from second part of the duodenum. Histopathological evaluation was done according to the Modified Marsh classification. The overall sensitivity of anti-EMAcame out to be 85.7% which varied with the histological lesions being 75.0%, 83.3%, and 100% for Marsh IIIA, IIIB and IIIC, respectively. Although anti-EMAhas high sensitivity but serological tests as a sole mean of diagnosis are currently unable to replace the biopsy.

Longitudinal study of normal cognition in Parkinson disease.

OBJECTIVE: To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods. METHODS: A prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.9%) of eligible patients seen at year 6. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors. RESULTS: We enrolled 141 patients, who averaged 68.8 years of age, 63% men, who had PD on average for 5 years. The cumulative incidence of cognitive impairment was 8.5% at year 1, increasing to 47.4% by year 6. All incident MCI cases had progressed to dementia by year 5. In a multivariate analysis, predictors of future decline were male sex (p = 0.02), higher Unified Parkinson's Disease Rating Scale motor score (p ≤ 0.001), and worse global cognitive score (p < 0.001). CONCLUSIONS: Approximately half of patients with PD with normal cognition at baseline develop cognitive impairment within 6 years and all new MCI cases progress to dementia within 5 years. Our results show that the transition from normal cognition to cognitive impairment, including dementia, occurs frequently and quickly. Certain clinical and cognitive variables may be useful in predicting progression to cognitive impairment in PD.

New concepts in the early and preclinical detection of Parkinson's disease: therapeutic implications.

Parkinson's disease is a chronic neurodegenerative disorder leading to progressive motor impairment for which there is no cure. Currently, the diagnosis is made by the presence of cardinal motor features and several associated non-motor symptoms. However, at this point, the underlying neuropathological changes are already underway, and efforts in basic and clinical research have converged to suggest that Parkinson's disease actually begins well before symptom onset. As a result, the identification and development of disease-modifying therapies is difficult. In this review, we begin by summarizing what is known of disease pathogenesis in the context of early symptomatology. We then discuss the Parkinson's at-risk syndrome and highlight how this conceptual framework can be a useful for studies of early disease biomarkers and putative disease-modifying neurotherapeutics. With this framework, we discuss several clinical assessments, radiological studies and molecular assays that may be useful in early disease detection.