Moderate Stages Of Disease Research Articles

Moderate aortic stenosis: Navigating the uncharted.

Aortic stenosis (AS) stands as the most common valvular heart disease in developed countries and is characterized by progressive narrowing of the aortic valve orifice resulting in elevated transvalvular flow resistance, left ventricular hypertrophy, and progressive increased risk of heart failure and sudden death. This narrative review explores clinical challenges and evolving perspectives in moderate AS, where discrepancies between aortic valve area and pressure gradient measurements may pose diagnostic and therapeutic quandaries. Transthoracic echocardiography is the first-line imaging modality for AS evaluation, yet cases of discordance may require the application of ancillary noninvasive diagnostic modalities. This review underscores the importance of accurate grading of AS severity, especially in low-gradient phenotypes, emphasizing the need for vigilant follow-up. Current clinical guidelines primarily recommend aortic valve replacement for severe AS, potentially overlooking latent risks in moderate disease stages. The noninvasive multimodality imaging approach-including echocardiography, cardiac magnetic resonance, computed tomography, and nuclear techniques-provides unique insights into adaptive and maladaptive cardiac remodeling in AS and offers a promising avenue to deliver precise indications and exact timing for intervention in moderate AS phenotypes and asymptomatic patients, potentially improving long-term outcomes. Nevertheless, what we may have gleaned from a large amount of observational data is still insufficient to build a robust framework for clinical decision-making in moderate AS. Future research will prioritize randomized clinical trials designed to weigh the benefits and risks of preemptive aortic valve replacement in the management of moderate AS, as directed by specific imaging and nonimaging biomarkers.

INDEX ASSESSMENT OF PERIODONTAL TISSUES AND DETERMINATION OF TREATMENT NEEDS IN PATIENTS WITH CHRONIC RHEUMATIC HEART DISEASE

This study addresses the pressing scientific and practical issue in modern dentistry: enhancing dental care effectiveness for patients with chronic rheumatic heart disease. The purpose of this research is to comprehensively assess the condition of tooth-supporting tissues and quantify inflammatory phenomena in periodontal tissues among patients with chronic rheumatic heart disease, as well as to determine the necessary extent of periodontal care based on periodontal indices. Participants and methods. The periodontal tissues of 719 patients with chronic rheumatic heart disease from the Rheumatology Department of Lviv Regional Clinical Hospital, along with 290 clinically healthy individuals in the comparison group, were examined. To evaluate the clinical course of dystrophic-inflammatory periodontal diseases in patients with chronic rheumatic heart disease, we examined 267 individuals in the main group who had generalized periodontitis, categorized as follows: 42 patients with initial stage (I degree), 115 with moderate (II degree), and 110 with severe (III degree) periodontitis. The comparison group comprised 70 patients diagnosed with generalized periodontitis, among them, 21 had initial-stage disease, 29 had moderate-stage disease, and 20 had severe-stage disease. During the analysis, the oral hygiene was assessed by applying hygienic indices by J.C. Green and J.R. Vermillion (OHI-S, 1964) and Fedorov-Volodkina. The Muhlemann and Son index was used to objectively measure gingival papillary bleeding (RVI); the papillary-marginal-alveolar index (PMA) in the Parma modification, in combination with the Schiller-Pysarev test (1989), was employed to evaluate gingival inflammation. The periodontal index (PI) by A.L. Russel (1956) was used to assess the state of periodontal tissues, and pathological changes were recorded using the periodontal screening PSR test. Results were scored, and based on established criteria and scores, the need for treatment and its extent were determined. Results and discussion. According to the results of dental examinations in patients with chronic rheumatic heart disease, a high prevalence of periodontal diseases was found, reaching 92.49%. This was 13.18% higher compared to the prevalence in the control group. Dystrophic-inflammatory conditions with advanced severity levels were predominant, as evidenced by the index indicators. In chronic rheumatic heart disease patients, the average periodontal index was 6.11±0.10, compared to 4.14±0.19 in clinically healthy individuals (p < 0.05). Moreover, a higher lesion of periodontal tissues was observed in younger age groups. As the duration of rheumatic disease increased, the frequency of detecting generalized periodontitis also increased, with this condition being diagnosed in all subjects with a 10-year history of rheumatic disease. Conclusion. The Analysis of the research data on the condition of periodontal tissues, along with objective index assessments, reveals the following: periodontal diseases are more prevalent in individuals with chronic rheumatic heart disease, particularly affecting younger age groups. The severity and progression of these diseases are influenced by the course of the underlying condition. This underscores the presence of pathogenetic conditions that contribute to the rapid progression of the dystrophic-inflammatory process in periodontal tissues. It also emphasizes the importance of providing specialized periodontal care to patients with chronic rheumatic heart disease, with the level of care directly linked to the course and duration of the systemic disease.

Stimulation of PSTPIP1 to trigger proinflammatory responses in asymptomatic SARS-CoV-2 infections

BackgroundA hyperinflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection gravely worsens the clinical progression of coronavirus disease 2019 (COVID-19). Although the undesirable effects of inflammasome activation have been correlated to the severity of COVID-19, the mechanisms of this process in the asymptomatic infection and disease progression have not yet been clearly elucidated. MethodsWe performed strand-specific RNA sequencing in 39 peripheral blood mononuclear cell (PBMC) samples from asymptomatic individuals（n = 10）, symptomatic patients（n = 16） and healthy donors（n = 13）. ResultsDysregulation of pyrin inflammasomes along with the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene was identified in SARS-COV-2 infection. Notably, the PSTPIP1 expression level showed a significant negative correlation with an adjacent long-noncoding RNA (lncRNA) RP11-797A18.6 in the asymptomatic individuals compared with the healthy controls. In addition, a decline in the nuclear factor kappa B subunit 1 (NFKB1) gene expression was observed in asymptomatic infection, followed by a rise in the mild and moderate disease stages, suggesting that altered NFKB1 expression and associated proinflammatory signals may trigger a disease progression. ConclusionsOverall, our results indicate that PSTPIP1-dependent pyrin inflammasomes-mediated pyroptosis and NF-κB activation might be potential preventive targets for COVID-19 disease development and progression.

ELBOW OSTEOARTHRITIS: PATHOGENESIS, CLINICAL PRESENTATION, WORK-UP

ABSTRACT Degenerative joint disease of the elbow, although much rarer than in lower limbs, affecting about 2% of population, may be the result of primary and secondary etiologies and may significantly affect the quality of life, leading to pain, loss of motion and functional disability. A detailed medical history combined with physical examination and imaging modalities can help to locate the source of symptoms and choose the appropriate treatment. Nonoperative management is the initial therapy for elbow arthritis and is limited to relief of pain by rest, activity modification, analgesics and nonsteroid anti-inflammatory medications. When conservative management fails, surgical treatment should be used according to the patient’s expectations, age, severity and etiology of elbow arthritis. Patients with posttraumatic and primary elbow osteoarthritis in mild and moderate stage of disease may be treated by arthroscopic osteocapsular arthroplasty which consist of soft tissue and bony debridement, osteophytes and loose bodies removal, synovectomy, capsular release and bony contouring of humerus and ulnae. Total elbow arthroplasty is dedicated to low-demand, elderly patients with rheumatoid, inflammatory, posttraumatic or primary elbow osteoarthritis in severe stage. For younger, high-demand patients with severe osteoarthritis of the elbow which affects the majority of the ulnohumeral articular surface a good option for surgical treatment is interposition arthroplasty with/using auto or allografts.

Experience of the United Arab Emirates in the use of monoclonal antibody drug sotrovimab in high-risk vaccinated and unvaccinated patients with COVID-19: an observational cohort study

ObjectivesMonoclonal antibodies can slow COVID-19 progression. This study describes the experience of using sotrovimab in patients with COVID-19 at high risk for disease progression and hospitalisation within the United Arab...

Preliminary report of Iranian Registry of Alzheimer's disease in Tehran province: A cross-sectional study in Iran.

Alzheimer's disease (AD) is the main cause of dementia and over the 55 million people live with dementia worldwide. We aimed to establish the first database called the Iranian Alzheimer's Disease Registry to create a powerful source for future research in the country. In this report, the design and early results of the Iranian Alzheimer's Disease Registry will be described. We performed this multicenter investigation and patients' data including age, sex, educational level, disease status, Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS) from 2018 to 2021 were collected, registered, and analyzed by GraphPad Prism software. Totally 200 AD patients were registered in our database. 107 (54%) were women and age of 147 (74%) were over 65. The mean age for men and women was 76.20 ± 8.29 and 76.40 ± 8.83 years, respectively. 132 (66%) were married and 64 (32%) were illiterate. Also, 94 (47%) were in the moderate stage of disease, and 150 (75%) lived at home together with their families. The most frequent neurological comorbidity was psychosis (n = 72, 36%), while hypertension was the most common non-neurological comorbidity (n = 104, 52%). The GDS score of women in the mild stage (5.23 ± 2.9 vs. 6.9 ± 2.6, p = 0.005) and moderate stage (5.36 ± 2.4 vs. 8.21 ± 2.06, p = <0.001) of the disease was significantly greater than men. In univariate analysis, MMSC score was remarkably associated with stroke (β = -2.25, p = 0.03), psychosis (β = -2.18, p = 0.009), diabetes (β = 3.6, p = <0.001), and hypercholesteremia (β = 1.67, p = 0.05). Also, the MMSE score showed a notable relationship with stroke (β = -2.13, p = 0.05) and diabetes (β = 3.26, p = <0.001) in multivariate analysis. Iranian Alzheimer's Disease Registry can provide epidemiological and clinical data to use for purposes such as enhancing the current AD management in clinical centers, filling the gaps in preventative care, and establishing effective monitoring and cure for the disease.

Live longer and better without aortic valve stenosis

Live longer and better without aortic valve stenosis

Living With Frontotemporal Degeneration: Diagnostic Journey, Symptom Experiences, and Disease Impact.

Frontotemporal degeneration (FTD) is an umbrella term encompassing a range of rare neurodegenerative disorders that cause progressive declines in cognition, behavior, and personality. Hearing directly from individuals living with FTD and their care partners is critical in optimizing care, identifying meaningful clinical trial endpoints, and improving research recruitment and retention. The current paper presents a subset of data from the FTD Insights Survey, chronicling the diagnostic journey, symptoms, and the impact of FTD on distress, quality of life, and independence, in the mild to moderate stages of the disease. Survey respondents included 219 individuals diagnosed with FTD and 437 current care partners, representing a range of FTD diagnoses. Around half of survey respondents reported seeing three or more doctors before an FTD diagnosis was given, and a range of prior diagnoses were noted. Most frequently endorsed symptoms tended to be consistent with clinical characteristics of the specific diagnosis, though there was significant variability in symptoms reported within diagnostic categories as well as considerable overlap in symptoms between diagnostic categories. Cognitive and language symptoms of FTD were generally most distressing to the person diagnosed, and a loss of independence was endorsed as affecting quality of life. The distinct perspectives of diagnosed persons and care partners regarding disease impact differed notably for bvFTD/Pick's disease. Participating independently in a range of activities, within the home, outside the home, and with other people, were reported as challenging for people living with FTD, underscoring the degree to which the lives of these individuals are affected even at the mild and moderate stages of disease. Overall, by heeding the perspectives of those living with FTD, we can begin to design more meaningful research studies, provide better care, and develop therapies that improve quality of life.

Harmonic ratio is the most responsive trunk-acceleration derived gait index to rehabilitation in people with Parkinson’s disease at moderate disease stages

BackgroundHarmonic ratios (HRs), recurrence quantification analysis in the antero-posterior direction (RQAdetAP), and stride length coefficient of variation (CV) have recently been shown to characterize gait abnormalities and fall risk in people with Parkinson's disease (pwPD) at moderate disease stages. Research questionThis study aimed to i) assess the internal and external responsiveness to rehabilitation of HR, RQAdetAP, and CV, ii) identify the baseline predictors of normalization of the gait stability indexes, and iii) investigate the correlations between the gait indexes modifications (∆) and clinical and kinematic ∆s in pwPD at Hoehn and Yahr disease staging classification 3. MethodsThe trunk acceleration patterns of 21 pwPD and 21 age- and speed-matched healthy subjects (HSmatched) were acquired during gait using an inertial measurement unit at baseline (T0). pwPD were also assessed after a 4-week rehabilitation period (T1).Each participant's HR in the antero-posterior (HRAP), medio-lateral (HRML), and vertical directions, RQAdetAP, CV, spatio-temporal, and kinematic variables were calculated. ResultsAt T1, HRAP and HRML improved to normative values and showed high internal and external responsiveness. Lower HRs and higher pelvic rotation values at baseline were predictors of ∆HRs. A minimal clinically important difference (MCID) ≥ 21.5 % is required to normalize HRAP with 95 % probability. MCID ≥ 36.9 % is required to normalize HRML with 92 % probability. ∆HRAP correlated with ∆HRML and both correlated with ∆stride length and ∆pelvic rotation, regardless of ∆gait speed. RQAdetAP and step length CV were not responsive to rehabilitation. SignificanceWhen using inertial measurement units, HRAP and HRML can be considered as responsive outcome measures for assessing the effectiveness of rehabilitation on trunk smoothness during walking in pwPD at moderate disease stages.

Paving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective.

Paving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective.

No Higher Risk-Seeking Tendencies or Altered Self-Estimation in a Social Decision-Making Task in Patients with Parkinson's Disease.

Parkinson's disease (PD) has been associated with a tendency towards more risky decisions. However, the commonly used paradigms typically neglect the social context. Here, we investigated social decision-making and self-estimation in a competitive experimental task. A computerized experimental setting was used in which 86 PD patients (age = 66.5 [50-79], 62.8% male, H&Y = 2 [1.5-3]) and 44 healthy controls (HC; age = 67 [54-79], 54.4% male) in groups of four performed mathematical addition tasks in which they were asked to calculate as many sums as possible in five minutes. Participants had to choose their preferred compensation scheme ("piece rate" versus "tournament") and retrospectively rank their performance in comparison to the suspected performance of the others. A comprehensive neuropsychological test battery was also conducted. No significant difference was found in overall social decision-making and self-estimation between PD patients and HC. However, for those individuals who made inadequate decisions, PD patients engaged in significantly more risk-averse and HC in more risky decisions. Concerning those inadequate decisions, the PD patients made more extreme decisions (severity of social decision-making) in both directions (risk-averse, risk-seeking). Our data indicate that social decision-making behavior and self-estimation are largely intact in PD patients with mild to moderate disease stages and intact global cognition, executive functions, and social cognition. Future studies with more heterogeneous PD samples regarding their neuropsychological profile will have to examine at which state social decision-making may be affected and by which factors this behavior might be influenced.

Infographic: Four training modalities to improve functional mobility in people with Parkinson’s disease

Impairment of functional mobility is one of the most disabling symptoms in people with Parkinson’s disease (PwPD). Limitations in mobility lead to sedentarism, which may decrease the quality of life in PwPD. Several studies demonstrated that the combination of exercise with the traditional pharmacological treatment (i.e., levodopa) is effective to improve mobility in PwPD 1-5. Although the effects of traditional modalities (e.g., walking overground and cycling) are well documented, other stimuli may also induce positive responses on mobility in PwPD. However, such studies demonstrated trivial results or effectiveness in terms of functional mobility, indicating that the exercise – mainly using non-traditional stimuli – should be carefully prescribed. To avoid practical mistakes and ensure a high probability of success in mobility rehabilitation in PwPD, rehabilitation professionals must apply up-to-date and high-quality knowledge about mobility. Also, they must recognize the effects of different exercise modalities to improve functional mobility and the motivators and barriers to exercise in PwPD 1. This infographic aims to present (1) the motiving factors and barriers of training in PwPD, (2) the main effects of four exercise modalities on functional mobility (considering its underlining mechanisms), and (3) demonstrate the training evidence to improve the functional mobility. The exercise modalities were selected from the four recent meta-analyses (searched on PUBMED) that tested the exercise effects on functional mobility and presented data related to exercise prescription for PwPD. The encouragement of other persons is the most motivating factor for PwPD during exercise. The lacking of encouragement, fatigue and depression are related to exercise barriers in PwPD 1. Suárez-Iglesias et al. 2 demonstrated that Pilates was effective to improve functional mobility, improving Timed Up and Go (TUG) performances. Interventions using hydrotherapy, with or without land-based therapy, also showed positive effects on TUG values 3. Dance modality, associated with auditory cues, promoted positive effects on gait velocity, TUG, and freezing of gait 4. Finally, Robinson et al. 5 observed that treadmill training, when compared to no-exercise ones, improved the gait velocity and step length in PwPD regardless of use or not body weight support. Overall these results were observed in patients with early to moderate stages of disease (Hoehn and Yahr &lt; 3). These main effects and the mechanism related to the positive responses were presented in the infographic. Despite the noteworthy positive effects of exercise using these modalities in PwPD, recommendations for training prescriptions are still debatable. The characteristics of the modalities were poorly described in most of the studies. For example, even with the availability of acceptable and practical tools, the exercise intensity or its increment throughout the training was not properly reported. Therefore, it is difficult to determine a specific guideline to improve functional mobility in PwPD. The discussion about prescriptions (hydrotherapy) and the program with the highest weight in the meta-analysis (dance, pilates and treadmill) were presented in the infographic. Future studies should detail, as many as, possible training characteristics, increasing the reproducibility and applicability of the results.

Epidemiology of Pandemic COVID-19 and Its Association with Some Chronic Diseases in Sulaimani City, Iraq

The study aims to provide the epidemiological characteristics of the COVID-19 patients who admitted to Shahid Dr Hemin Teaching Hospital in Sulaimani city, Iraq. It is a cross-sectional study, the data were collected by a convenience sampling method in the hospital, which started from 2nd October to 31th of December 2020. The current study included all the patients who admitted to the hospital, which involved 371 patients. The data were collected from patient’s medical record and a direct interview method was used for filling in the questionnaire form. The collected data were analysed by the SPSS program to produce descriptive statistics such as frequency, percentage, mean and standard deviation while Chi-square test used to find out the association between variables with considering a p-value ? 0.05 as a significant interpretation. The results show that the age of hospitalized COVID-19 patients ranges from 19-95 years old with mean of (63.69±12.73). The age of majority of patients 159 (42.9%) was between 65-79 years old followed by 50-64 years old 124 (33.4%). Male to female ratio was 2:1. Most of the patients were retired 119 (32.1%) in comparison to other occupations and illiterate patients 151(40.7%) were dominance over other patient’s education levels. In addition, majority of patients had hypertension 278(74.9%), diabetes 132 (35.6%) and cardiovascular disease (CVD) 130 (35.0%) and 230 (62.0%) and 141(38.0%) of them were in severe and moderate stage of disease respectively. Also, there was a significant association between the patient’s age group and patients’ outcome while for gender, occupation, and education level, stage of the disease, there were non-significant. The presence of CVD, hypertension and diabetes increase the mortality rate among the patients. In conclusion, age of COVID-19 patient has a great impact on increasing mortality rate and the presence of comorbidities among the patients significantly raise the mortality rate of COVID-19.

Safety and efficacy of riluzole in spinocerebellar ataxia type 2 in France (ATRIL): a multicentre, randomised, double-blind, placebo-controlled trial

Riluzole has been reported to be beneficial in patients with cerebellar ataxia; however, effectiveness in individual subtypes of disease is unclear due to heterogeneity in participants' causes and stages of disease. Our aim was to test riluzole in a single genetic disease, spinocerebellar ataxia type 2. We did a randomised, double-blind, placebo-controlled, multicentre trial (the ATRIL study) at eight national reference centres for rare diseases in France that were part of the Neurogene National Reference Centre for Rare Diseases. Participants were patients with spinocerebellar ataxia type 2 with an age at disease onset of up to 50 years and a scale for the assessment and rating of ataxia (SARA) score of at least 5 and up to 26. Patients were randomly assigned centrally (1:1) to receive either riluzole 50 mg orally or placebo twice per day for 12 months. Two visits, at baseline and at 12 months, included clinical measures and 3T brain MRI. The primary endpoint was the proportion of patients whose SARA score improved by at least 1 point. Analyses were done in the intention-to-treat population (all participants who were randomly assigned) and were done with only the observed data (complete case analysis). This trial is registered at ClinicalTrials.gov (NCT03347344) and has been completed. Between Jan 18, 2018, and June 14, 2019, we enrolled 45 patients. 22 patients were randomly assigned to receive riluzole and 23 to receive placebo. Median age was 42 years (IQR 36-57) in the riluzole group and 49 years (40-56) in the placebo group and 23 (51%) participants were women. All participants presented with moderate-stage disease, characterised by a median SARA score of 13·5 (IQR 9·5-16·5). The primary endpoint, SARA score improvement of at least 1 point after 12 months, was observed in seven patients (32%) in the treated group versus nine patients (39%) in the placebo group, with a mean difference of -10·3% (95% CI -37·4% to 19·2%; p=0·75). SARA score showed a median increase (ie, worsening) of 0·5 points (IQR -1·5 to 1·5) in the riluzole group versus 0·3 points (-1·0 to 2·5) in the placebo group (p=0·70). No serious adverse event was reported in the riluzole-treated group whereas four patients in placebo group had a serious adverse event (hepatic enzyme increase, fracture of external malleolus, rectorrhagia, and depression). The number of patients with adverse events was similar in both groups (riluzole 16 [73%] patients vs placebo 19 [83%] patients; p=0·49). We were able to recruit 45 patients moderately affected by spinocerebellar ataxia type 2 for this trial. Riluzole did not improve clinical or radiological outcomes in these patients. However, our findings provide data on progression of spinocerebellar ataxia type 2 that might prove to be valuable for the design of other clinical trials. French Ministry of Health.

529. Systematic Review and Meta-Analysis of Ivermectin Safety Profile in COVID-19 Trials

BackgroundThere is a continued and pressing need for safe and effective treatment of COVID-19. Significant survival benefits have been shown by dexamethasone, tocilizumab and sarilumab, however they are only recommended in hospitalised COVID-19 patients. Ivermectin is a well-established and readily available antiparasitic drug which may be suitable for treatment in mild and moderate disease stages. It recently demonstrated anti-viral properties in vitro and now over 80 clinical trials have been registered worldwide to test its effectiveness in COVID-19 patients. This meta-analysis aims to collect data on adverse events reported in new COVID-19 treatment trials for the use of ivermectin as a repurposed medication.MethodsData was extracted from randomised trials of COVID-19 treatment trials identified through systematic searches of PUBMED, EMBASE, MedRxiv and trial registries. The primary outcome of this meta-analysis is the frequency of adverse events. Key safety events included serious, gastrointestinal, neurological, cardiovascular and dermatological adverse events.ResultsOverall, 18 trials investigating ivermectin for COVID-19 in a total of 2496 participants reported safety data and were included. There was no significant difference in the proportion of all adverse events between ivermectin and the comparator. There were 371/1261 (29%) adverse events recorded in the ivermectin containing arms and 376/1284 (29%) in the control arms (RR 1.02 [95% CI 0.77 - 1.34]; p = 0.91). There was no significant difference in the rate of serious adverse events across treatment arms (RR 1.95 [95% CI 0.75 - 5.11]; p = 0.18). No significant differences between ivermectin and the control were seen across different subcategories of adverse events. Figure 1 shows a summary of the results for all adverse events. Forest plot comparing ivermectin and the control for all adverse events in COVID-19 trials, subdivided into single-day dosing trials and multi-day dosing trials.ConclusionThe results of recent COVID-19 trials show that overall, ivermectin is safe and well-tolerated. No significant difference in adverse event reporting was found across all subgroups in single and multi-day treatment regimens for the studies analysed. Safety reporting methodologies often varied across trials. Future and ongoing trials should be encouraged to collect and monitor safety data systematically.Disclosures All Authors: No reported disclosures

Cytokine Profile in Plasma Extracellular Vesicles of Parkinson's Disease and the Association with Cognitive Function.

Plasma extracellular vesicles (EVs) containing various molecules, including cytokines, can reflect the intracellular condition and participate in cell-to-cell signaling, thus emerging as biomarkers for Parkinson’s disease (PD). Inflammation may be a crucial risk factor for PD development and progression. The present study investigated the role of plasma EV cytokines as the biomarkers of PD. This cross-sectional study recruited 113 patients with PD, with mild to moderate stage disease, and 48 controls. Plasma EVs were isolated, and the levels of cytokines, including pro-interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1, were evaluated. Patients with PD had significantly increased plasma EV pro-IL-1β and TNF-α levels compared with controls after adjustment for age and sex. Despite the lack of a significant association between plasma EV cytokines and motor symptom severity in patients with PD, cognitive dysfunction severity, assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment, was significantly associated with plasma EV pro-IL-1β, IL-6, IL-10, and TNF-α levels. This association was PD specific and not found in controls. Furthermore, patients with PD cognitive deficit (MMSE < 26) exhibited a distinguished EV cytokine profile compared to those without cognitive deficit. The findings support the concept of inflammatory pathogenesis in the development and progression of PD and indicate that plasma EV cytokines may serve as PD biomarkers in future.

Genetic knockdown of Klk8 has sex-specific multi-targeted therapeutic effects on Alzheimer's pathology in mice.

Previous work in our lab has identified the protease kallikrein-8 (KLK8) as a potential upstream mover in the pathogenesis of Alzheimer's disease (AD). We showed pathologically elevated levels of KLK8 in the cerebrospinal fluid and blood of patients with mild cognitive impairment or dementia due to AD, and in brains of patients and transgenic CRND8 (TgCRND8) mice in incipient stages of the disease. Furthermore, short-term antibody-mediated KLK8 inhibition in moderate stage disease alleviated AD pathology in female mice. However, it remains to be shown whether long-term reversal of KLK8 overexpression can also counteract AD. Therefore, the effects of genetic Klk8-knockdown were determined in TgCRND8 mice. The effects of heterozygous ablation of murine Klk8 (mKlk8) gene on AD pathology of both sexes were examined by crossbreeding TgCRND8 [hAPP+/-] with mKlk8-knockdown [mKlk8+/-] mice resulting in animals with or without AD pathology which revealed pathologically elevated or normal KLK8 levels. mKlk8-knockdown had negligible effects on wildtype animals but led to significant decline of amyloid beta (Aβ) and tau pathology as well as an improvement of structural neuroplasticity in a sex-specific manner in transgenics. These changes were mediated by a shift to non-amyloidogenic cleavage of the human amyloid precursor protein (APP), recovery of the neurovascular unit and maintaining microglial metabolic fitness. Mechanistically, Klk8-knockdown improved Aβ phagocytosis in primary glia and Aβ resistance in primary neurons. Most importantly, transgenic mice revealed less anxiety and a better memory performance. These results reinforce the potential of KLK8 as a therapeutic target in AD.

Patterns and predictors of referrals to allied health services for individuals with Parkinson's disease: A Parkinson's foundation (PF) QII study

IntroductionRehabilitation therapies are critical for optimizing quality-of-life and daily functions for individuals living with Parkinson's disease (PD). Thus, understanding the patterns of and under what conditions physicians make rehabilitation referrals is important for optimizing care. MethodWe analyzed data from 5020 participants (4 countries) collected from 1/3/2016 to 4/20/2018 as part of the Parkinson's Foundation Quality Improvement Initiative (PF QII). Data were analyzed for single discipline and multidiscipline referrals to speech language pathology (SLP), physical therapy (PT), and occupational therapy (OT). Group comparisons (referred vs. not-referred) and regression procedures were implemented to determine demographic and clinical variables that were associated with an increased likelihood of rehabilitation referral. Results35.3% of participants were referred to rehabilitation services. Of these, 25.1% received a multidiscipline referral. There was a statistically significant effect of disease stage on both single discipline (χ2(2) = 45.1, p < 0.0001) and multidiscipline (χ2(2) = 74.2, p < 0.0001) referrals, with higher rates in later stages. Referred vs. not-referred participants differed significantly on a number of variables; however, only falls in the 6-months prior, advanced- and moderate-stage disease, older age, hospital admissions, and higher caregiver burden were associated with an increased likelihood of rehabilitation referral (adjusted odds ratios ≥ 1, Range = 1.08 to 1.62). ConclusionsDespite evidence supporting multidiscipline and proactive rehabilitation in PD, the majority of referrals were made to a single service and may be reactions to falls or advancing disease. Data suggest there may be missed opportunities for optimizing care through proactive rehabilitation interventions.

Awareness of Functional Status: People with Alzheimer's Disease Abilities to Self-Report Impairment in Activities of Daily Living.

Background:Awareness of functional status may underlie specific profiles and differences related to stage severity in individuals with Alzheimer’s disease (AD).Objective:This study aimed to assess self-reported experiences of awareness of functional activity in people with mild and moderate AD.Methods:This is a mixed methods approach. The qualitative part was conducted through semi-structured interviews concerning the experiences and awareness of deficits in 38 older adults with mild or moderate AD. The quantitative approach included a comparison between groups with regard to concerns of awareness and clinic and demographic data.Results:Impairment on awareness of disease and awareness of functional deficits was observed even in the mild stages of AD. There was also a noticeable progression of impairments of both kinds of awareness from mild to moderate stage of disease. The majority of participants with mild and moderate AD were partially aware of their functional deficits. Both groups of participants reported some negative impact; however, they were not able to entirely describe their functional status. Also, deficits to recognize the need for help with hygiene and general tasks were observed. Significant differences were found in awareness of need for help with general tasks and awareness of need for help with hygiene tasks.Conclusion:People with mild and moderate AD may describe their aware of the disease better than specific functional deficits, and most of them can provide some reports concerning to the impact of the disease.

Automated Analysis of Diffusion-Weighted Magnetic Resonance Imaging for the Differential Diagnosis of Multiple System Atrophy from Parkinson's Disease.

ABSTRACTBackgroundManual region‐of‐interest analysis of putaminal and middle cerebellar peduncle diffusivity distinguishes patients with multiple system atrophy (MSA) and Parkinson's disease (PD) with high diagnostic accuracy. However, a recent meta‐analysis found substantial between‐study heterogeneity of diagnostic accuracy due to the lack of harmonized imaging protocols and standardized analyses pipelines.ObjectiveEvaluation of diagnostic accuracy of observer‐independent analysis of microstructural integrity as measured by diffusion‐tensor imaging in patients with MSA and PD.MethodsA total of 29 patients with MSA and 19 patients with PD (matched for age, gender, and disease duration) with 3 years of follow‐up were investigated with diffusion‐tensor imaging and T1‐weighted magnetic resonance imaging. Automated localization of relevant brain regions was obtained, and mean diffusivity and fractional anisotropy values were averaged within the regions of interest. The classification was performed using a C5.0 hierachical decision tree algorithm.ResultsMean diffusivity of the middle cerebellar peduncle and cerebellar gray and white matter compartment as well as the putamen were significantly increased in patients with MSA and showed superior effect sizes compared to the volumetric analysis of these regions. A classifier model identified mean diffusivity of the middle cerebellar peduncle and putamen as the most predictive parameters. Cross‐validation of the classification model yields a Cohen's κ and overall diagnostic accuracy of 0.823 and 0.914, respectively.ConclusionAnalysis of microstructural integrity within the middle cerebellar peduncle and putamen yielded a superior effect size compared to the volumetric measures, resulting in excellent diagnostic accuracy to discriminate patients with MSA from PD in the early to moderate disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society