Delayed Antibody Response in the Acute Phase of Infection Is Associated with a Lower Mental Component of Quality of Life in Survivors of Severe and Critical COVID-19.

Background: The long-term sequelae of coronavirus disease 2019 (COVID-19) significantly affects quality of life (QoL) in disease survivors. Delayed development of the adaptive immune response is associated with more severe disease and a worse prognosis in COVID-19. The effects of delayed immune response on COVID-19 sequelae and QoL are unknown. Methods: We conducted a prospective study to assess the relationship between the delayed antibody response in the acute phase of infection in naïve unvaccinated patients suffering from severe or critical COVID-19 and their QoL 12 months after hospital discharge. The 12-item Short Form Survey (SF-12) questionnaire was used for assessment of QoL. The SF-12 evaluates both mental and physical components of QoL, incorporating a mental component score (MCS-12) and a physical component score (PCS-12). A delayed antibody response was defined as testing negative for anti-spike SARS-CoV-2 antibodies at the time of hospital admission. Results: The study included 274 patients (154 men and 120 women). Of the enrolled patients, 144 had a delayed immune response. These patients had a significantly lower MCS-12 (p = 0.002), but PCS-12 (p = 0.397) was not significantly different at the 12-month follow-up compared to patients with positive anti-spike SARS-CoV-2 antibodies. The MCS-12 at the time of follow-up was negatively associated with delayed antibody response irrespective of possible confounders (p = 0.006; B = 3.609; ηp2 = 0.035; 95% CI = 1.069-6.150). An MSC-12 below 50 points at the time of follow-up was positively associated with delayed antibody response (p = 0.001; B = 1.092; OR = 2.979; 95% CI = 1.554-5.711). Conclusions: This study confirmed that, in patients with severe and critical COVID-19, a negative result for anti-spike SARS-CoV-2 antibodies at the time of hospital admission is associated with a lower mental component of QoL in unvaccinated patients naïve to COVID-19 one year after hospital discharge.

Case Report: Stroke-like migraine attacks after radiation therapy syndrome: a rare complication 26 years after cranial radiotherapy.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare delayed complication of cranial radiotherapy, that may present decades after brain irradiation. Here we present a case of 41-year old patient with a history of grade 3 oligodendroglioma, epilepsy and migraine, 26 years after brain radiation therapy, who was admitted with right hemicranial headache, nausea, left homonymous hemianopsia, weakness of the left arm and left-sided hemihypesthesia. After considering alternate diagnoses, we ultimately diagnosed SMART syndrome. Despite its rare occurrence and unknown pathophysiology, there are more case reports of SMART syndrome reported due to advancements in oncology treatment and increasing patients' survival rates. Therefore, diagnosis of SMART syndrome should always be considered in patients with a history of cranial radiation presenting with focal neurologic deficits and migraine, especially with a change in pattern of their usual migraine attack.

Acute endurance exercise modulates growth differentiation factor 11 in cerebrospinal fluid of healthy young adults.

Objective: Strong evidence supports the benefits of exercise for healthy ageing, including reduced risk of neurodegenerative diseases. Recent studies suggested interorgan crosstalk as a key element of systemic adaptive response, however, the role of specific molecules in mediating exercise effects on the human brain are not fully understood. In the present study, we explored the exercise-related regulation of Growth Differentiation Factor 11 (GDF11) in cerebrospinal fluid (CSF) and blood. Methods: The samples of serum, plasma and CSF were obtained before and 60min after acute exercise (90min run) from twenty healthy young individuals. Additional serum and plasma samples were collected immediately after run. GDF11 protein content (immunoblotting), body composition (bioelectrical impedance), physical fitness (VO2max, cycle spiroergometry) and cognitive functions (standardized computerized tests, Cogstate) were evaluated. Results: Running decreased GDF11 protein content in CSF (-20.6%. p=0.046), while GDF11 in plasma and serum were not regulated. Two GDF11-specific antibodies of different origin were used to corroborate this result. Individuals with higher physical fitness displayed greater exercise-induced decrease of GDF11 in CSF than those with lower physical fitness (p=0.025). VO2max correlated positively with GDF11 in serum (r=0.63, p=0.020) as well as with the exercise-induced change in GDF11 levels in CSF (r=0.59, p=0.042). Indirect measure of blood-brain barrier permeability (i.e. CSF/serum albumin ratio) tended to positively correlate with CSF/serum GDF11 ratio (p=0.060). CSF levels of GDF11 correlated positively with cognitive functions, including working memory, both before and after run (p<0.05). Conclusion: Running-induced down-regulation of the GDF11 protein in the cerebrospinal fluid of healthy young individuals indicates the potential role of GDF11 in the exercise-induced cross-talk between periphery and the brain.

Idiopathic Normal Pressure Hydrocephalus and Progressive Supranuclear Palsy: Two Single Entities or Neurodegenerative Overlap Syndrome? A Case Report.

The differential diagnosis of idiopathic normal pressure hydrocephalus (iNPH) and progressive supranuclear palsy (PSP) is difficult. The importance of proper diagnosis is particularly important for iNPH, which can be effectively treated with a ventriculoperitoneal (VP) shunt. In our case report, we present a unique case of a patient with overlapping symptoms and radiological findings of iNPH and PSP. Our patient underwent the VP shunt after a differential diagnostic evaluation which resulted in significant improvement in their clinical condition and quality of life, albeit for a short time.

Impairment of endothelial function in Parkinson's disease.

OBJECTIVE: There are conflicting data regarding the relationship between Parkinson's disease (PD) and the atherosclerotic process. This study aimed to compare endothelial function in patients with PD and matched controls. In PD subjects, we searched for factors contributing to endothelial dysfunction as well. Traditional vascular risk factors, PD characteristics, and PD medication were considered. RESULTS: We prospectively enrolled 41 patients with PD and 41 controls matched for age, sex, body mass index, and vascular risk factors. Endothelial function (EF) was assessed using peripheral arterial tonometry (EndoPAT 2000 device) and expressed as reperfusion hyperemia index (RHI). Clinical characteristics including PD medication were recorded. RHI was non-significantly lower in the PD group than in controls (1.8 ± 0.5 vs. 1.9 ± 0.5, p = 0.478). In PD patients, in linear regression analysis, smoking (beta = -0.453, p = 0.008) and use of dopamine agonists (beta = -0.365, p = 0.030) were significant contributors in a model predicting RHI. Despite non-significant differences in endothelial dysfunction between PD patients and controls, our results suggest an association between smoking, dopamine agonists, and impaired EF in PD patients. The small sample size, as well as the absence of an extended search for traditional and non-traditional vascular risk factors, are the most important factors limiting the interpretation of the current results.

Cerebrospinal fluid and plasma metabolomics of acute endurance exercise.

Metabolomics has emerged as a powerful new tool in precision medicine. No studies have yet been published on the metabolomic changes in cerebrospinal fluid (CSF) produced by acute endurance exercise. CSF and plasma were collected from 19 young active adults (13 males and 6 females) before and 60 min after a 90-min monitored outdoor run. The median age, BMI, and VO2 max of subjects was 25 years (IQR 22-31), 23.2 kg/m2 (IQR 21.7-24.5), and 47 ml/kg/min (IQR 38-51), respectively. Targeted, broad-spectrum metabolomics was performed by liquid chromatography, tandem mass spectrometry (LC-MS/MS). In the CSF, purines and pyrimidines accounted for 32% of the metabolic impact after acute endurance exercise. Branch chain amino acids, amino acid neurotransmitters, fatty acid oxidation, phospholipids, and Krebs cycle metabolites traceable to mitochondrial function accounted for another 52% of the changes. A narrow but important channel of metabolic communication was identified between the brain and body by correlation network analysis. By comparing these results to previous work in experimental animal models, we found that over 80% of the changes in the CSF correlated with a cascade of mitochondrial and metabolic changes produced by ATP signaling. ATP is released as a co-neurotransmitter and neuromodulator at every synapse studied to date. By regulating brain mitochondrial function, ATP release was identified as an early step in the kinetic cascade of layered benefits produced by endurance exercise.

Levodopa-Carbidopa Intestinal Gel Improves Symptoms of Orthostatic Hypotension in Patients with Parkinson's Disease-Prospective Pilot Interventional Study.

Parkinson's disease (PD) is currently considered progressive neurodegeneration of both the central and peripheral nervous systems. Widespread neuropathological changes lead to a complex clinical presentation with typical motor (hypokinesia, tremor, and rigidity) and various nonmotor symptoms. Orthostatic hypotension is one of the most disabling nonmotor features contributing to increased morbidity and mortality and decreased quality of life (QoL). Our study aimed to disclose the effect of a continuous infusion of levodopa-carbidopa intestinal gel (LCIG) on symptoms of orthostatic hypotension. Nine patients indicated for LCIG and eight matched patients on optimized medical treatment (OMT) were examined with scales for orthostatic symptoms (SCOPA-AUT), nonmotor symptoms and motor fluctuations (MDS-UPDRS), and QoL (PDQ39) at both baseline and after six months. The scores of "light-headedness after standing" and "fainting" decreased in the LCIG group compared to the OMT group. Treatment with LCIG was associated with a significantly higher decrease in the score of "light-headedness after standing". Change in the PDQ39 correlated positively with fluctuation improvement and with change in the scores of both "light-headedness" and "fainting". LCIG treatment improved symptoms of orthostatic hypotension in patients with PD mainly by a reduction in motor complications. Decreased severity in both motor and nonmotor fluctuations was connected also with improved QoL. Continuous treatment with LCIG should be considered not only in the case of severe motor fluctuation but also in patients with nonmotor fluctuations responsive to dopaminergic treatment.

Effect of Pillbox Organizers with Alarms on Adherence to Pharmacotherapy in Parkinson Disease Patients Taking Three and More Daily Doses of Dopaminergic Medications.

Improvement of adherence to pharmacotherapy in patients with Parkinson's disease (PD) is a challenge in routine clinical practice. Our study was aimed at the effect of pillbox organizers with alarms improving adherence to pharmacotherapy and its impact on clinical outcomes. Forty nonadherent patients with PD being treated with ≥ 3 daily doses of levodopa and/or dopamine agonists were pseudorandomized and consecutively ranked to groups A (early-start intervention) and B (delayed-start intervention). We used the following validated diagnostic instruments: MMAS-8 (adherence), PDQ-8 (quality of life, QoL), GDS (depression), NMSS (non-motor symptoms), MDS-UPDRS III (motor involvement), MDS-UPDRS IV, and WOQ-9 (motor and non-motor fluctuations and dyskinesias). We proved a significantly improved rate of adherence with the use of pillbox organizers with alarms. Moreover, after only four weeks of using the pillbox organizer, we detected an improvement in QoL scores, motor involvement, motor-, and non-motor fluctuations. Our study showed that pillbox organizers with alarms are efficient in improving adherence to pharmacotherapy in PD. It also could contribute to better motor states, less severe fluctuations, and improved QoL.

Gait Disorders Questionnaire-Promising Tool for Virtual Reality Designing in Patients With Parkinson's Disease.

Background: Gait disorders (GD) are frequent and disabling symptoms in patients with Parkinson's disease, mostly because they significantly limit mobility and often lead to fear of falls or actual falls. Nowadays, rehabilitation is considered to be the most effective nonpharmacological approach to reduce risk of falls. Using paradigms in virtual reality (VR) is a promising tool in neurorehabilitation because of the potential improvement in motor learning and improvement in daily functioning by replicating everyday real-life scenarios. Objective: To identify the most prevalent everyday situations which impair gait in PD that could be simulated in virtual reality (VR) environment. Methods: A newly developed self-report questionnaire consisting of 15 binary response items (YES/NO) encompassing everyday walking situations was administered to 62 patients diagnosed with idiopathic PD according to MDS Clinical Diagnostic Criteria. We included patients able to walk unassisted for at least 10 min and without significant cognitive impairment. Mokken Scale Analysis was used to evaluate psychometric properties of the scale. Results: Questionnaires from 58 patients were analyzed (31 men, age = 63 ± 9.9 y, disease duration = 7.02 ± 4.03 y, LEDD = 1115 ± 549.4 mg, H&Y = 2.4 ± 0.6). Only 10 items (out of 15) were identified as scalable and these were included in Gait Disorders Questionnaire (GDQ). The most prevalent trigger of gait disorders was walking under time pressure, followed by gait in crowded places and walking while dual-tasking. The total score of GDQ significantly correlated with the disease duration (r s = 0.347, p = 0.008) and modified H&Y staging (r s = 0.288, p = 0.028). Conclusion: With the use of GDQ we identified the most prevalent everyday transition activities that provoke gait disorders in patients with PD. The results may be useful for further development and systematic application of VR paradigms for physiotherapy of PD patients.

Adherence to Pharmacotherapy in Patients With Parkinson's Disease Taking Three and More Daily Doses of Medication.

Background: Once-daily treatment formulation is associated with better adherence in comparison to more complex medication regimens. The study aimed to detect the extent of adherence to pharmacotherapy in Parkinson disease (PD) patients who take a minimum of three daily doses of drugs, and to identify factors associated with lower levels of adherence. Methods: The cohort was selected from non-demented PD patients. The 8-Item Morisky Medication Adherence Scale (MMAS-8), 8-Item Parkinson's Disease Questionnaire (PDQ-8), Geriatric Depression Scale (GDS), Non-Motor Symptom Assessment Scale (NMSS), 9-Item Wearing-off Questionnaire (WOQ-9), MDS-UPDRS III (motor examination), and IV (motor complications) scales were used in this study. Results: From a total of 124 subjects, 33.9% reported a high level of adherence, 29.8% reported a medium level of adherence, and 36.3% reported a low level of adherence to their pharmacotherapy. The level of non-adherence correlated with gender, longer disease duration, higher scores of PDQ-8, NMSS, WOQ-9, and MDS-UPDRS IV. Detailed analysis of NMSS demonstrated a correlation between the level of adherence and domains sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, and urinary symptoms. Independent risk factors for non-adherence were excessive daytime sleepiness, anhedonia, and forgetfulness. Conclusion: Non-adherence to more complicated medication regimens is frequent in PD patients and is associated with gender, longer PD duration, poorer quality of life, frequency and severity of non-motor symptoms, and more severe motor and non-motor fluctuations. Non-adherence was predicted by non-motor symptoms including fatigue, mood disturbances, and subjective cognitive complaints.

Clinical aspects of adherence to pharmacotherapy in Parkinson disease: A PRISMA-compliant systematic review.

BACKGROUND: Parkinson disease (PD) is the second most common neurodegenerative disease with various motor and nonmotor symptoms. Progressive course of PD requires frequent medication adjustments. Various combinations of drugs and dose regimens could be used to control symptoms. Thus, not surprisingly, adherence to pharmacotherapy is frequently suboptimal in these patients having negative effect on motor control and patient's quality of life. METHODS: In this article, we offer up-to-date review of adherence in PD compared with other chronic conditions. In addition, we summarize factors influencing level of adherence, ways of measuring, and methods of adherence optimization. For the review of adherence in PD, a literature search was undertaken using PubMed database and relevant search terms. Articles were screened for suitability and data relevance. RESULTS: PubMed and Scopus databases were systematically searched in 2016 and data extraction was a multistep process based on the PRISMA Guidelines. CONCLUSION: According to the recent data, sufficient control of motor symptoms and adequate quality of life are primary goals in the treatment of PD. Adherence to pharmacotherapy play a key role in this process, thus the medication should be tailored for each patient. In order to improve level of suboptimal adherence, these patients should have got recommended various dosing devices or alarms. Good communication with the patients and their relatives or caregivers is also essential.

Aerobic-Strength Exercise Improves Metabolism and Clinical State in Parkinson's Disease Patients.

Regular exercise ameliorates motor symptoms in Parkinson's disease (PD). Here, we aimed to provide evidence that exercise brings additional benefits to the whole-body metabolism and skeletal muscle molecular and functional characteristics, which might help to explain exercise-induced improvements in the clinical state. 3-months supervised endurance/strength training was performed in early/mid-stage PD patients and age/gender-matched individuals (n = 11/11). The effects of exercise on resting energy expenditure (REE), glucose metabolism, adiposity, and muscle energy metabolism (31P-MRS) were evaluated and compared to non-exercising PD patients. Two muscle biopsies were taken to determine intervention-induced changes in fiber type, mitochondrial content, and expression of genes related to muscle energy metabolism, as well as proliferative and regenerative capacity. Exercise improved the clinical disability score (MDS-UPDRS), bradykinesia, balance, walking speed, REE, and glucose metabolism and increased muscle expression of energy sensors (AMPK). However, the exercise-induced increase in muscle mass/strength, mitochondrial content, type II fiber size, and postexercise phosphocreatine (PCr) recovery (31P-MRS) were found only in controls. Nevertheless, MDS-UPDRS was associated with muscle AMPK and mechano-growth factor (MGF) expression. Improvements in fasting glycemia were positively associated with muscle function and the expression of Sirt1 and Cox7a1, and the parameters of fitness/strength were positively associated with the expression of MyHC2, MyHC7, and MGF. Moreover, reduced bradykinesia was associated with better muscle metabolism (maximal oxidative capacity and postexercise PCr recovery; 31P-MRS). Exercise training improved the clinical state in early/mid-stage Parkinson's disease patients, including motor functions and whole-body metabolism. Although the adaptive response to exercise in PD was different from that of controls, exercise-induced improvements in the PD clinical state were associated with specific adaptive changes in muscle functional, metabolic, and molecular characteristics. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT02253732.