Coenzyme Q(10) (CoQ(10)) is an essential component of the mitochondrial electron transport chain. It is also an antioxidant in cellular membranes and lipoproteins. All cells produce CoQ(10) by a specialized cytoplasmatic-mitochondrial pathway. CoQ(10) deficiency can result from genetic failure or ageing. Some drugs including statins, widely used by inter alia elderly, may inhibit endogenous CoQ(10) synthesis. There are also chronic diseases with lower levels of CoQ(10) in tissues and organs. High doses of CoQ(10) may increase both circulating and intracellular levels, but there are conflicting results regarding bioavailability. Here, we review the current knowledge of CoQ(10) biosynthesis and primary and acquired CoQ(10) deficiency, and results from clinical trials based on CoQ(10) supplementation. There are indications that supplementation positively affects mitochondrial deficiency syndrome and some of the symptoms of ageing. Cardiovascular disease and inflammation appear to be alleviated by the antioxidant effect of CoQ(10). There is a need for further studies and well-designed clinical trials, with CoQ(10) in a formulation of proven bioavailability, involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ(10) treatment in neurodegenerative disorders, as well as in metabolic syndrome and its complications.

During domestication animals have undergone changes in size of brain and other vital organs. We hypothesize that this could be a correlated effect to increased tameness. Red Junglefowl (ancestors of domestic chickens) were selected for divergent levels of fear of humans for five generations. The parental (P0) and the fifth selected generation (S5) were culled when 48–54 weeks old and the brains were weighed before being divided into telencephalon, cerebellum, mid brain and optic lobes. Each single brain part as well as the liver, spleen, heart and testicles were also weighed. Brains of S5 birds with high fear scores (S5 high) were heavier both in absolute terms and when corrected for body weight. The relative weight of telencephalon (% of brain weight) was significantly higher in S5 high and relative weight of cerebellum was lower. Heart, liver, testes and spleen were all relatively heavier (% of body weight) in S5 high. Hence, selection for tameness has changed the size of the brain and other vital organs in this population and may have driven the domesticated phenotype as a correlated response.

The objective of this exploratory study is to investigate if lane departures are associated with local sleep, measured via source-localized electroencephalography (EEG) theta power in the 5-9 Hz frequency range. Thirty participants drove in an advanced driving simulator, resulting in 135 lane departures at high levels of self-reported sleepiness. These lane departures were compared to matching non-departures at the same sleepiness level within the same individual. There was no correspondence between lane departures and global theta activity. However, at the local level an increased risk for lane departures was associated with increased theta content in brain regions related to motor function.

OBJECTIVE: To study associations of clinical characteristics and treatment choice with functional outcome, mortality, and time to death in a national sample of aneu METHODS: Data were extracted from a prospective grade, 1-year mortality, and survival probability were assessed at one year after ictus. Logistic univariate, multivariate, and Cox regression analyses were used to study the variables' associations with the outcomes. grades 1-4) was observed in 35.4% of patients. Microsurgery was preferred for middle cerebral artery aneurysms and Fisher grade 4. Treatment modality was not associated with any outcome measure. Dichotomized World Federation of Neurosurgical Societies (dWFNS), age, and delayed ischemic neurological deficit (DIND) showed significant correlations with dGOSE and 1-year mortality in multivariate regression analyses. Pupil dilatation was associated with a 1-year mortality outcome. Cox regression analysis howed lower survival probability for pupil dilatation (hazard ratio [HR]: 3.546), poor dWFNS (HR: 3.688), higher age (HR: 1.051), and DIND occurrence (HR: 2.214). CONCLUSIONS: The patient selection in Sweden after aneurysmal subarachnoidal hemorrhage showed similar values for dGOSE, 1-year mortality, and survival probability between patients treated with microsurgery or endovascular technique. Poor dWFNS, higher age, and DIND were significantly associated with unfavorable dGOSE, mortality, and survival probability. Pupil dilatation was significantly associated with mortality and survival probability

Inflammation is one of the fundamental processes in numerous diseases. Cluster of differentiation (CD) 93, a glycoprotein, has been reported to be associated with a number of these diseases. There are reports indicating that a high plasma level of CD93 is associated with adverse events in ischaemic heart disease. Additionally, there are reports indicating different cardiovascular risks between different single nucleotide polymorphisms (SNPs) of CD93. Therefore, the present study aimed to determine whether the plasma concentration of CD93 and polymorphism of rs2749812 in CD93 were associated with clinical conditions and mortality in an elderly population. In 470 healthy elderly community-living individuals a novel clinical examination involving echocardiography and blood sampling was performed. The population was followed for 6.7 years. Plasma levels of CD93 and SNP analyses of rs2749812 of CD93 using PCR methodology were used. During the follow-up period, 106 (22.6%) all-cause and 61 (13.0%) cardiovascular deaths were registered. Those with the highest plasma concentration had markedly higher all-cause mortality. Evaluating the A/A, A/G and G/G genotypes, the G/G group exhibited significantly higher cardiovascular mortality (P=0.026), and an almost two-fold increased risk in a multivariate Cox regression model compared with the A/G genotype. Evaluation of subgroups with respect to sex, diabetes and hypertension revealed markedly increased cardiovascular risk in the G/G genotype in all subgroups. All results persisted in the multiple models used. In the present study, the glycoprotein CD93 was demonstrated to have prognostic cardiovascular information, with increased risk for those with a high plasma concentration. Furthermore, the G/G genotype of rs2749812 of CD93 has a significantly higher cardiovascular risk, as demonstrated here, and could therefore be regarded as a possible cardiovascular risk biomarker that might in the future be used to offer optimised cardiovascular patient handling. However, this was a small study, and more research is required.

Sammanfattning 

Bakgrund: Neurologisk rehabilitering innefattar ofta livslånga kontinuerliga insatser. För att få ett önskvärt resultat av rehabilitering krävs en god följsamhet från patienten. Forskning har visat att god följsamhet kräver att patienten får information om sin behandling samt känner sig delaktig. Det saknas dock forskning om vilken information och vilken typ av informationsform patienten efterfrågar inom neurologisk rehabilitering. 

Syfte: Syftet med studien var att beskriva patientens perspektiv på behovet av information vid rehabilitering av neurologiska funktionsnedsättningar, och vad de upplever betydelsefullt för att uppnå följsamhet och delaktighet.

Metod: En kvalitativ intervjustudie med semistrukturerade frågor (Januari 2022). Data analyserades genom kvalitativ innehållsanalys med induktiv ansats. Inklusive pilotintervju genomfördes 10 intervjuer med patienter som deltagit i neurologisk rehabilitering.

Resultat: Analys av materialet resulterade i 4 kategorier, Erhållen information, Önskad information, Delaktighet, Fysioterapeuten bemötande och Kommunikation. Varje kategori kompletterades även med underrubriker. 

Konklusion:  I resultatet framkom det att patienter har behov av en mångsidig information både avseende informationens innehåll och förmedling. Det framkom även att fysioterapeutens bemötande och en god kommunikation var viktiga faktorer för informationsförmedlingen och därmed betydelsefullt för att uppnå delaktighet och följsamhet. 

Alzheimers disease (AD) is an incurable, progressive and devastating neurodegenerative disease. Pathogenesis of AD is associated with the aggregation and accumulation of amyloid beta (A & beta;), a major neurotoxic mediator that triggers neuroinflammation and memory impairment. Recently, we found that cellulose ether compounds (CEs) have beneficial effects against prion diseases by inhibiting protein misfolding and replication of prions, which share their replication mechanism with A & beta;. CEs are FDA-approved safe additives in foods and pharmaceuticals. Herein, for the first time we determined the therapeutic effects of the representative CE (TC-5RW) in AD using in vitro and in vivo models. Our in vitro studies showed that TC-5RW inhibits A & beta; aggregation, as well as neurotoxicity and immunoreactivity in A & beta;-exposed human and murine neuroblastoma cells. In in vivo studies, for the first time we observed that single and weekly TC-5RW administration, respectively, improved memory functions of transgenic 5XFAD mouse model of AD. We further demonstrate that TC-5RW treatment of 5XFAD mice significantly inhibited A & beta; oligomer and plaque burden and its associated neuroinflammation via regulating astrogliosis, microgliosis and proinflammatory mediator glial maturation factor beta (GMF & beta;). Additionally, we determined that TC-5RW reduced lipopolysaccharide-induced activated gliosis and GMF & beta; in vitro. In conclusion, our results demonstrate that CEs have therapeutic effects against A & beta; pathologies and cognitive impairments, and direct, potent anti-inflammatory activity to rescue neuroinflammation. Therefore, these FDA-approved compounds are effective candidates for developing therapeutics for AD and related neurodegenerative diseases associated with protein misfolding.

The effects of cognitive behavioral therapy for insomnia (CBT-I) have consistently been shown to improve insomnia symptoms and other health-related outcomes, but the effects on QoL have been inconsistent. Many factors including the type CBT-I delivery and type of instrument used to assess QoL make the topic complex. The present systematic review and meta-analysis synthesized the evidence of CBT-I efficacy on QoL outcomes across different populations, delivery modes, and methodological aspects. Following the guidelines on preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), a literature search was conducted through PubMed, Web of Science, Scopus, and PsycINFO using keywords from relevant MeSH terms based on PICOS (Participants, Intervention, Comparison, Outcome and Study) criteria. Clinical trials investigating the effect of CBT-I as an intervention on QoL with any kind of control group were eligible if they reported mean scores and variation of QoL. Meta-analysis using a random-effect model was conducted to calculate the standardized mean differences (SMDs) in a set including all identified studies, as well as in three sub-sets: face-to-face CBT-I using randomized controlled trials (RCTs), online CBT-I using RCTs, and one-group pre- and post-treatment design. A total of 24 studies comprising 1977 participants (808 in an intervention group) from 12 countries were eligible for meta-analysis. The overall pooled estimate of SMD of QoL when all 24 studies were included was 0.47 (95% CI: 0.22; 0.72; I-2 = 84.5%; tau(2) = 0.31; p < 0.001). The overall pooled estimate of SMD of QoL was 0.46 (95% CI: 0.01-0.90; I-2 = 87.5%; tau(2) = 0.48, p < 0.001) for intervention groups with face-to-face CBT-I compared to controls; 0.47 (95% CI: 0.02-0.92; I-2 = 88.3%; tau(2) = 0.36; p = 0.04) for intervention groups with digital CBT-I compared to controls, and 0.46 (95% CI: 0.12-0.80; I-2 = 52.9%; tau(2) = 0.07; p = 0.08) for one-group pre- and post-comparison using CBT-I intervention compared to baseline. Moreover, effects of CBT-I on QoL were different across populations (pooled SMD = 0.59 for patients with insomnia; 0.29 for patients with insomnia comorbid with another major disorder; and 0.48 for other conditions) and types of QoL instruments (pooled SMD = 0.36 for disease-specific QoL instrument not on insomnia, 0.43 for generic QoL instrument, and 0.67 for a single-QoL-item instrument). The probability of publication bias was ruled out in overall and design specific sub-group analysis based on funnel plot and Eggers test. In conclusion, this meta-analysis confirmed a moderate, overall effect of CBT-I in improving QoL. However, due to small power and heterogeneity, future studies are needed to better explore the impact of moderating factors such as mode of delivery and type of QoL measure for assessment used.

The pathological use of the internet - conceptualized as internet addiction - might be crucial in initiating and increasing sleep disturbances in the community. While inconsistent evidence is reported regarding the association of internet addiction and sleep disturbances, the severity of this association remains unclear. This systematic review and meta-analysis were conducted to increase our understanding of the relationship between internet addiction and sleep disturbances. A systematic review was conducted through Scopus, PubMed Central, ProQuest, ISI Web of Knowledge, and EMBASE using keywords related to internet addiction and sleep problems. Observational studies (cohort, case-control or cross-sectional studies) focusing on association between internet addiction and sleep disturbances including sleep problems and sleep duration were selected. A meta-analysis using random-effect model was conducted to calculate the odds ratio (OR) for experiencing sleep problems and standardized mean differences (SMDs) for sleep duration. Eligible studies (N = 23) included 35,684 participants. The overall pooled OR of having sleep problems if addicted to the internet was 2.20 (95% CI: 1.77-2.74). Additionally, the overall pooled SMDs for sleep duration for the IA group compared to normal internet users was -0.24 (95% CI: -0.38, -0.10). Results of the meta-analysis revealed a significant OR for sleep problems and a significant reduced sleep duration among individuals addicted to the internet. (C) 2019 Elsevier Ltd. All rights reserved.

Patient MRI from DBS implantations in the subthalamic nucleus (STN) were reviewed and it was found that around 10% had Virchow-Robin spaces (VRS). Patient-specific models were developed to evaluate changes in the electric field (EF) around DBS leads. The patients (n = 7) were implanted bilaterally either with the standard voltage-controlled lead 3389 or with the directional current-controlled lead 6180. The EF distribution was evaluated by comparing simulations using patient-specific models with homogeneous models without VRS. The EF, depicted with an isocontour of 0.2 V/mm, showed a deformation in the presence of the VRS around the DBS lead. For patient-specific models, the radial extension of the EF isocontours was enlarged regardless of the operating mode or the DBS lead used. The location of the VRS in relation to the active contact and the stimulation amplitude, determined the changes in the shape and extension of the EF. It is concluded that it is important to take the patients? brain anatomy into account as the high conductivity in VRS will alter the electric field if close to the DBS lead. This can be a cause of unexpected side effects.

Objective: The objective of this study was to evaluate the diagnostic yield and clinical utility of an automated AI video-based seizure detection device, Nelli (R), (SDD) in pharmacoresistant epilepsy patients. The SDD captures and automatically classifies nocturnal motor behavior suggestive of epileptic seizures or non-epileptic motor behavior of potential clinical value. Methods: Patients with focal epilepsy and pharmacoresistance referred for inpatient long-term video-EEG monitoring were prospectively recruited. Participants were monitored in their home at night with the SDD for a median of 15.5 nights. Captured video recordings were analyzed by clinical experts and each SDD-registration session was classified as diagnostic or not. Clinical utility for each participant was assessed from pre-specified utility measures. The outcome measures were compared between major focal motor and subtle focal motor seizures. Results: One SDD-registration session in each of the 20 participants was performed and analyzed. Video recordings were captured in 18 sessions. Diagnostic yield was found in 11 registration sessions (55.0 %) and clinical utility in 8 registration sessions (40.0 %). No significant difference was found between the AI-algorithm classification and clinical experts' consensus assessment of captured video recordings as epileptic or not. Positive predictive value was 81.8 % for registration sessions containing video recordings classified as epileptic seizures. The diagnostic yield and clinical utility were significantly higher among major focal motor seizures (81.8 % and 63.6 %) compared to subtle focal motor seizures. Significance: The SDD is useful to evaluate patients with pharmacoresistant epilepsy and major focal motor seizures (hyperkinetic, tonic, clonic, focal to bilateral tonic-clonic seizures); it may facilitate the diagnostic process in patients referred for long-term inpatient video-EEG evaluation and beneficially change anti-seizure treatments. The SDD provided accurate classification of major focal motor seizures as epileptic, or non- epileptic, and may serve as a useful diagnostic tool to distinguish epileptic and non-epileptic episodic events with a prominent motor component.

IntroductionInternet-based psychological treatments for depression have been around for more than 20 years. There has been a continuous line of research with new research questions being asked and studies conducted.Areas coveredIn this paper, the author reviews studies with a focus on papers published from 2020 and onwards based on a Medline and Scopus search. Internet-based cognitive behavior therapy (ICBT) programs have been developed and tested for adolescents, older adults, immigrant groups and to handle a societal crisis (e.g. COVID-19). ICBT works in regular clinical settings and long-term effects can be obtained. Studies on different treatment orientations and approaches such as acceptance commitment therapy, unified protocol, and tailored treatments have been conducted. Effects on quality-of-life measures, knowledge acquisition and ecological momentary assessment as a research tool have been reported. Factorial design trials and individual patient data meta-analysis are increasingly used in association with internet intervention research. Finally, prediction studies and recent advances in artificial intelligence are mentioned.Expert opinionInternet-delivered treatments are effective, in particular if therapist guidance is provided. More target groups have been covered but there are many remaining challenges including how new tools like artificial intelligence will be used when treating depression.

Introduction: Internet-supported and therapist-guided cognitive behaviour therapy (ICBT) is effective for a range of problems in the short run, but less is known about the long-term effects with follow-ups of two years or longer.Areas covered: This paper reviews studies in which the long-term effects of guided ICBT were investigated. Following literature searches in PubMed and other sources meta-analytic statistics were calculated for 14 studies involving a total of 902 participants, and an average follow-up period of three years. Studies were from Sweden (n=11) or the Netherlands (n=3). Long-term outcome studies were found for panic disorder, social anxiety disorder, generalized anxiety disorder, depression, mixed anxiety and depression, obsessive-compulsive disorder, pathological gambling, stress and chronic fatigue. The duration of the treatments was usually short (8-15weeks). The pre-to follow-up effect size was Hedges g=1.52, but with a significant heterogeneity. The average symptom improvement across studies was 50%. Treatment seeking in the follow-up period was not documented and few studies mentioned negative effects.Expert commentary: While effects may be overestimated, it is likely that therapist-supported ICBT can have enduring effects. Long-term follow-up data should be collected for more conditions and new technologies like smartphone-delivered treatments.

Small fiber neuropathy (SFN) has been suggested as a trigger of restless legs syndrome (RLS). An increased prevalence of peripheral neuropathy has been demonstrated in Parkinsons disease (PD). We aimed to investigate, in a cross-sectional manner, whether SFN is overrepresented in PD patients with concurrent RLS relative to PD patients without RLS, using in vivo corneal confocal microscopy (IVCCM) and quantitative sensory testing (QST) as part of small fiber assessment. Study participants comprised of age- and sex-matched PD patients with (n = 21) and without RLS (n = 21), and controls (n = 13). Diagnosis of RLS was consolidated with the sensory suggested immobilization test. Assessments included nerve conduction studies (NCS), Utah Early Neuropathy Scale (UENS), QST, and IVCCM, with automated determination of corneal nerve fiber length (CNFL) and branch density (CNBD) from wide-area mosaics of the subbasal nerve plexus. Plasma neurofilament light (p-NfL) was determined as a measure of axonal degeneration. No significant differences were found between groups when comparing CNFL (p = 0.81), CNBD (p = 0.92), NCS (p = 0.82), and QST (minimum p = 0.54). UENS scores, however, differed significantly (p = 0.001), with post-hoc pairwise testing revealing higher scores in both PD groups relative to controls (p = 0.018 and p = 0.001). Analysis of all PD patients (n = 42) revealed a correlation between the duration of l-dopa therapy and CNBD (rho = -0.36, p = 0.022), and p-NfL correlated with UENS (rho = 0.35, p = 0.026) and NCS (rho = -0.51, p = 0.001). Small and large fiber neuropathy do not appear to be associated with RLS in PD. Whether peripheral small and/or large fiber pathology associates with central neurodegeneration in PD merits further longitudinal studies.

ObjectiveTo determine the utility of symptoms, signs, comorbidities and background variables for the prediction of outcome of treatment in iNPH. MethodsA prospective observational study of consecutively included iNPH patients, who underwent neurological, physiotherapeutic and neuropsychological assessments before and after shunt surgery. The primary outcome measure was the total change on the iNPH scale, and patients were defined as improved postoperatively if they had improved by at least five points on that scale. Results143 iNPH patients were included, and 73% of those were improved after surgery. None of the examined symptoms or signs could predict which patients would improve after shunt surgery. A dominant subjective complaint of memory problems at baseline was predictive of non-improvement. The reported comorbidities, duration of symptoms and BMI were the same in improved and non-improved patients. Each of the symptom domains (gait, neuropsychology, balance, and continence) as well as the total iNPH scale score improved significantly (from median 53 to 69, p < 0.001). The proportions of patients with shuffling gait, broad-based gait, paratonic rigidity and retropulsion all decreased significantly. DiscussionThis study confirms that the recorded clinical signs, symptoms, and impairments in the adopted clinical tests are characteristic findings in iNPH, based on that most of them improved after shunt surgery. However, our clinical data did not enable predictions of whether patients would respond to shunt surgery, indicating that the phenotype is unrelated to the reversibility of the iNPH state and should mainly support diagnosis. Absence of specific signs should not be used to exclude patients from treatment.

Background: There is little knowledge about the factors influencing the long-term outcome after surgery for idiopathic normal pressure hydrocephalus (iNPH).

Objective: To evaluate the effects of reoperation due to complications and of vascular comorbidity (hypertension, diabetes, stroke and heart disease) on the outcome in iNPH patients, 2–6 years after shunt surgery.

Methods: We included 979 patients from the Swedish Hydrocephalus Quality Registry (SHQR), operated on for iNPH during 2004–2011. The patients were followed yearly by mailed questionnaires, including a self-assessed modified Rankin Scale (smRS) and a subjective comparison between their present and their preoperative health condition. The replies were grouped according to the length of follow-up after surgery. Data on clinical evaluations, vascular comorbidity, and reoperations were extracted from the SHQR.

Results: On the smRS, 40% (38–41) of the patients were improved 2–6 years after surgery and around 60% reported their general health condition to be better than preoperatively. Reoperation did not influence the outcome after 2–6 years. The presence of vascular comorbidity had no negative impact on the outcome after 2–6 years, assessed as improvement on the smRS or subjective improvement of the health condition, except after 6 years when patients with hypertension and a history of stroke showed a less favorable development on the smRS.

Conclusion: This registry-based study shows no negative impact of complications and only minor effects of vascular comorbidity on the long-term outcome in iNPH.

Objective: To describe survival and causes of death in 979 treated iNPH patients from the Swedish Hydrocephalus Quality Registry (SHQR), and to examine the influence of comorbidities, symptom severity and postoperative outcome.

Methods: All 979 patients operated for iNPH 2004–2011 and registered in the SHQR were included. A matched control group of 4890 persons from the general population was selected by Statistics Sweden. Data from the Swedish Cause of Death Registry was obtained for patients and controls.

Results: At a median 5.9 (IQR 4.2–8.1) year follow-up, 37% of the iNPH patients and 23% of the controls had died. Mortality was increased in iNPH patients by a hazard ratio of 1.81, 95% CI 1.61–2.04, p < 0.001. More pronounced symptoms in the preoperative ordinal gait scale and the Mini-mental State Examination were the most important independent predictors of mortality along with the prevalence of heart disease. Patients who improved in both the gait scale and in the modified Rankin Scale postoperatively (n = 144) had a similar survival as the general population (p = 0.391). Deaths due to cerebrovascular disease or dementia were more common in iNPH patients, while more controls died because of neoplasms or disorders of the circulatory system.

Conclusions: Mortality in operated iNPH patients is 1.8 times increased compared to the general population, a lower figure than previously reported. The survival of iNPH patients who improve in gait and functional independence is similar to that of the general population, indicating that shunt surgery for iNPH, besides improving symptoms and signs, can normalize survival.

Background: Monocytes form an important part of the human innate immune system by taking part in inflammatory reactions. With time, monocytes have gained interest in the role they may play during the event of myocardial infarction (MI). The current paradigm suggests that monocytes consist of three subdivisions which differ in phenotypic and dynamic patterns after an MI. In the inflammation that ensues, the different subsets have been shown to have an impact on reparative processes and patient recovery. Methods results: We searched Medline and Embase until April 5, 2016, for observational studies or clinical trials regarding monocyte functions and dynamics in MI. Apart from studies in humans, extensive work has been done in mice in an effort to understand the complex nature of monocyte dynamics. Animal models might add useful information on mapping these processes. Conclusion: The question still remains whether animal data can, to a certain degree, be extrapolated to monocyte functions during human MI. This review aims to summarize current available evidence on both mice and men with particular focus on the understanding of monocyte subsets dynamics and effects in human MI. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Objective: To rapidly exclude severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using artificial intelligence applied to the electrocardiogram (ECG). Methods: A global, volunteer consortium from 4 continents identified patients with ECGs obtained around the time of polymerase chain reaction-confirmed COVID-19 diagnosis and age- and sex-matched controls from the same sites. Clinical characteristics, polymerase chain reaction results, and raw electrocardiographic data were collected. A convolutional neural network was trained using 26,153 ECGs (33.2% COVID positive), validated with 3826 ECGs (33.3% positive), and tested on 7870 ECGs not included in other sets (32.7% positive). Performance under different prevalence values was tested by adding control ECGs from a single high-volume site. Results: The area under the curve for detection of acute COVID-19 infection in the test group was 0.767 (95% CI, 0.756 to 0.778; sensitivity, 98%; specificity, 10%; positive predictive value, 37%; negative predictive value, 91%). To more accurately reflect a real-world population, 50,905 normal controls were added to adjust the COVID prevalence to approximately 5% (2657/58,555), resulting in an area under the curve of 0.780 (95% CI, 0.771 to 0.790) with a specificity of 12.1% and a negative predictive value of 99.2%. Conclusion: Infection with SARS-CoV-2 results in electrocardiographic changes that permit the artificial intelligence-enhanced ECG to be used as a rapid screening test with a high negative predictive value (99.2%). This may permit the development of electrocardiography-based tools to rapidly screen individuals for pandemic control. (C) 2021 Mayo Foundation Medical Education and Research

STUDY DESIGN:: Register study enhanced and verified by medical records and personal interviews and examinations. SETTINGS:: Sweden. OBJECTIVES:: To define a method of identifying a study population of rare events. To point out the relative importance of every step, an example is given of identifying persons who sustained traumatic spinal cord injury (SCI) in childhood. METHODS:: Cases were identified in seven steps that all needed to be fulfilled, from definition of selection criteria through combination of several data sources, to the use of several verification methods. RESULTS:: Initial screening by registers identified 384 possible cases, which however were found by subsequent analysis to include a large number of incorrect cases. At completion of all analytic steps, 35 living cases could be fully verified and 14 deceased cases could be partially verified. CONCLUSIONS:: Registers offer a practical initial source for study population identification. The screening of International Classification of Diseases codes defining SCI only included less than 30% of true SCIs. Subsequently, further refinement and quality control is necessary in order to ensure validity. Such further verification is time-consuming, but nevertheless necessary in order to verify a true cohort.Spinal Cord (2003) 41, 337-346. doi:andlt;highlightandgt;10.1038andlt;/highlightandgt;/andlt;highlightandgt;sj.scandlt;/highlightandgt;.andlt;highlightandgt;3101456andlt;/highlightandgt; [ABSTRACT FROM AUTHOR]

[No abstract available]

BACKGROUND/OBJECTIVE: Spinal cord injury (SCI) occurring during adolescence poses additional challenges because of the concurrent age

Objective: Neurophysiological investigation has shown that patients with clinically complete spinal cord injury can have residual motor sparing ("motor discomplete"). In the current study somatosensory conduction was assessed in a patient with clinically complete spinal cord injury and a novel methodology for assessing such preservation is described, in this case indicating "sensory discomplete" spinal cord injury.andlt;br /andgt;Methods: Blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) was used to examine the somatosensory system in a healthy subject and in a subject with a clinically complete cervical spinal cord injury, by applying tactile stimulation above and below the level of spinal cord injury, with and without visual feedback.andlt;br /andgt;Results: In the participant with spinal cord injury, somatosensory stimulation below the neurological level of the lesion gave rise to BOLD signal changes in the corresponding areas of the somatosensory cortex. Visual feedback of the stimulation strongly modulated the somatosensory BOLD signal, implying that cortico-cortical rather than spino-cortical connections can drive activity in the somatosensory cortex. Critically, BOLD signal change was also evident when the visual feedback of the stimulation was removed, thus demonstrating sensory discomplete spinal cord injury.andlt;br /andgt;Conclusion: Given the existence of sensory discomplete spinal cord injury, preserved but hitherto undetected somatosensory conduction might contribute to the unexplained variability related to, for example, the propensity to develop decubitus ulcers and neuropathic pain among patients with clinically complete spinal cord injury.

Myofascial temporomandibular disorders (TMD) are the most common cause of chronic pain in the orofacial region. Microdialysis has been used to study metabolic changes in the human masseter muscle. The insertion of the microdialysis probe causes acute tissue trauma that could affect the metabolic milieu and thereby influence the results when comparing healthy subjects to those with TMD. This study aimed to investigate the levels of serotonin and glutamate during the acute tissue trauma period in healthy subjects and in patients with TMD. Microdialysis was carried out in 15 patients with TMD and 15 controls, and samples were collected every 20 min during a period of 140 min. No significant alterations of serotonin or glutamate were observed over the 2 h period for the healthy subjects. For the TMD group, a significant decrease in serotonin was observed over time (p amp;lt; 0.001), followed by a significant increase between 120 and 140 min (p amp;lt; 0.001). For glutamate, a significant reduction was observed at 40 min compared to baseline. The results showed that there was a spontaneous increase of serotonin 2 h after the insertion of the catheter in patients with TMD. In conclusion, the results showed that there are differences in the masseter muscle levels of serotonin and glutamate during acute nociception in patients with myofascial TMD compared to healthy subjects.

Objectives To estimate productivity loss and associated indirect costs in high-risk patients treated for hyperlipidemia who experience cardiovascular (CV) events. Methods Retrospective population-based cohort study conducted using Swedish medical records linked to national registers. Patients were included based on prescriptions of lipid-lowering therapy between 1 January 2006 and 31 December 2011 and followed until 31 December 2012 for identification of CV events and estimation of work productivity loss (sick leave and disability pension) and indirect costs. Patients were stratified into two cohorts based on CV risk level: history of major cardiovascular disease (CVD) and coronary heart disease (CHD) risk equivalent. Propensity score matching was applied to compare patients with new events (cases) to patients without new events (controls). The incremental effect of CV events was estimated using a difference-in-differences design, comparing productivity loss among cases and controls during the year before and the year after the cases event. Results The incremental effect on indirect costs was largest in the CHD risk equivalent cohort (n = 2946) at (sic)3119 (P value amp;lt;0.01). The corresponding figure in the major CVD history cohort (n = 4508) was (sic)2210 (P value amp;lt;0.01). There was substantial variation in productivity loss depending on the type of event. Transient ischemic attack and revascularization had no significant effect on indirect costs. Myocardial infarction ((sic)), unstable angina ((sic)) and, most notably, ischemic stroke ((sic)) yielded substantial incremental cost estimates (P values amp;lt;0.01). Conclusions Indirect costs related to work productivity losses of CV events are substantial in Swedish high-risk patients treated for hyperlipidemia and vary considerably by type of event.

BackgroundThe training of impaired attention after acquired brain injury is central for successful reintegration in daily living, social, and working life. Using statistical process control, we found different improvement trajectories following attention training in a group of relatively homogeneous patients early after acquired brain injury (ABI). ObjectiveTo examine the contribution of pre-injury factors and clinical characteristics to differences in outcome after early attention training. Materials and MethodsData collected in a clinical trial comparing systematic attention training (APT) with activity-based attention training (ABAT) early after brain injury were reanalyzed. ResultsStroke patients (p = 0.004) with unifocal (p = 0.002) and right hemisphere lesions (p = 0.045), and those with higher mental flexibility (TMT 4) (p = 0.048) benefitted most from APT training. Cognitive reserve (p = 0.030) was associated with CHANGE and APT as the sole pre-injury factor. For TBI patients, there was no statistical difference between the two treatments. ConclusionOur study identifies indiscernible factors predicting improvement after early attention training. APT is beneficial for patients with right-hemispheric stroke in an early recovery phase. Knowledge of prognostic factors, including the level of attention deficit, diagnosis, and injury characteristics, is vital to maximizing the efficiency of resource allocation and the effectiveness of rehabilitative interventions to enhance outcomes following stroke and TBI.

Irritable bowel syndrome (IBS) is a chronic visceral pain disorder with female predominance, characterized by recurrent abdominal pain and disturbed bowel habits in the absence of an identifiable organic cause. This prevalent and debilitating disease, which accounts for a substantial economic and individual burden, lacks exact diagnostic tools and effective treatment, since its pathophysiology remains uncertain. The bidirectional and multilayered brain-gut axis is a well-established disease model, however, the interactions between central and peripheral mechanisms along the brain-gut axis remain incompletely understood. One of the welldescribed triggering factors, yet accounting for only a fraction of IBS prevalence, is bacterial gastroenteritis that affects mucosal barrier function. Altered gut microbiota composition as well as disturbed intestinal mucosal barrier function and its neuroimmune regulation have been reported in IBS, however, the impact of live bacteria, neither commensal nor pathogenic, on intestinal barrier has not been studied yet. Furthermore, abnormal central processing of visceral sensations and psychological factors such as maladaptive coping have previously been suggested as centrally-mediated pathophysiological mechanisms of importance in IBS. Brain imaging studies have demonstrated an imbalance in descending pain modulatory networks and alterations in brain regions associated with interoceptive awareness and pain processing and modulation, particularly in anterior insula (aINS), although biochemical changes putatively underlying these central alterations remain poorly understood. Most importantly, however, possible associations between these documented changes on central and peripheral levels, which may as complex interactions contribute to disease onset and chronification of symptoms, are widely unknown.

This thesis aimed to investigate the peripheral and central mechanisms in women with IBS compared to female healthy controls (HC) and to explore possible mutual associations between these mechanisms.

In Paper I, we studied paracellular permeability and passage of live bacteria, both commensal and pathogenic through colonic biopsies mounted in Ussing chambers. We explored the regulation of the mucosal barrier function by mast cells and the neuropeptide vasoactive intestinal polypeptide (VIP) as well as a correlation between mucosal permeability and gastrointestinal and psychological symptoms. We observed increased paracellular permeability and the passage of commensal and pathogenic live bacteria in patients with IBS compared with HC, which was diminished by blocking the VIP receptors as well as after stabilizing mast cells in both groups. Moreover, higher paracellular permeability was associated with less somatic and psychological symptoms in patients.

In Paper II, we aimed to determine the association between colonic mucosa paracellular permeability and structural and resting state functional brain connectivity. We demonstrated different patterns of associations between mucosa permeability and functional and structural brain connectivity in IBS patients compared to HC. Specifically, lower paracellular permeability in IBS, similar to the levels detected in HC, was associated with more severe IBS symptoms and increased functional and structural connectivity between intrinsic brain resting state network and descending pain modulation brain regions. Our findings further suggested that this association between mucosa permeability and functional brain connectivity was mainly mediated by coping strategies.

In Paper III, we investigated putative alterations in excitatory and inhibitory neurotransmission of aINS, as the brain’s key node of the salience network crucially involved in cognitive control, in IBS patients relative to HC and addressed possible connections with both symptoms and psychological factors. We found decreased concentrations of the excitatory neurotransmitter Glx in bilateral aINS in IBS patients compared to HC, while inhibitory neurotransmitter GABA+ levels were comparable. Further, we demonstrated hemisphere-specific associations between abdominal pain, coping and aINS excitatory neurotransmitter concentration.

In conclusion, this thesis broadens the knowledge on peripheral and central mechanisms in IBS and presents novel findings that bring together the ends of brain-gut axis. Our results depict association between mucosal permeability, IBS symptoms and functional and structural connectivity engaging brain regions involved in emotion and pain modulation as well as underlying neurotransmitter alterations.

Adequate bowel cleansing is essential for high-quality colonoscopy. Recently, a new very low-volume 1 litre (1L) polyethylene glycol (PEG) plus ascorbate solution (ASC) has been introduced. Our aims were to assess the effectiveness and tolerability of this product compared to low-volume 2L PEG-ASC and high-volume 4L PEG solutions, in a real-life setting. In six endoscopy units in Sweden, outpatients undergoing colonoscopy were either prescribed solutions according to local routines, or the very low-volume solution in split dose regimen. Bowel cleansing effectiveness and patient experience was assessed using the Boston Bowel preparation scale (BBPS) and a patient questionnaire. A total of 1098 patients (mean age 58 years, 52% women) were included. All subsegment and the total BBPS scores were significantly greater for 1L PEG-ASC in comparison to other solutions (p < 0.05 for 1L PEG-ASC and 4L PEG for transverse and left colon, otherwise p < 0.001). Nausea was more frequent with 1L PEG-ASC compared to 2L PEG-ASC (p < 0.001) and vomiting were more often reported compared to both other solutions (p < 0.01 and p < 0.05 for 2L PEG-ASC and 4L PEG, respectively). Smell, taste, and total experience was better for 1L PEG-ASC compared to 4L PEG (p < 0.001), and similar compared to the 2L PEG-ASC. In conclusion, 1L PEG-ASC leads to better bowel cleansing compared to 2L PEG-ASC or 4L PEG products, with similar or greater patient satisfaction.

OBJECTIVE The Computerized General Neuropsychological INPH Test (CoGNIT) provides the clinician and the researcher with standardized and accessible cognitive assessments in patients with idiopathic normal pressure hydrocephalus (INPH). CoGNIT includes tests of memory, executive functions, attention, manual dexterity, and psychomotor speed. Investigations of the validity and reliability of CoGNIT have been published previously. The aim of this study was to evaluate CoGNITs sensitivity to cognitive change after shunt surgery in patients with INPH. METHODS Forty-one patients with INPH (median Mini-Mental State Examination score 26) were given CoGNIT preoperatively and at a postoperative follow-up 4 months after shunt surgery. Scores were compared to those of 44 healthy elderly control volunteers. CoGNIT was administered by either a nurse or an occupational therapist. RESULTS Improvement after shunt surgery was seen in all cognitive domains: memory (10-word list test, p amp;lt; 0.01); executive functions (Stroop incongruent color and word test, p amp;lt; 0.01); attention (2-choice reaction test, p amp;lt; 0.01); psychomotor speed (Stroop congruent color and word test, p amp;lt; 0.01); and manual dexterity (4-finger tapping, p amp;lt; 0.01). No improvement was seen in the Mini-Mental State Examination score. Preoperative INPH test scores were significantly impaired compared to healthy control subjects (p amp;lt; 0.001 for all tests). CONCLUSIONS In this study the feasibility for CoGNIT to detect a preoperative impairment and postoperative improvement in INPH was demonstrated. CoGNIT has the potential to become a valuable tool in clinical and research work.

Purpose: Preferences for patient-centeredness is an important indicator in healthcare service delivery. However, it remains largely unexplored in the field of communication science and disorders. This study investigated speech-language pathologists (SLPs) preferences for patient-centeredness Method: The study involved a cross-sectional survey design. SLPs (n = 102) fully completed the modified Patient-Practitioner Orientation Scale (PPOS; Krupat et al, 2000) and also provided demographic details. Data were analyzed using descriptive statistics, correlation, and linear regression methods. Results: Mean PPOS scores indicated that SLPs value patient-centeredness. There was a strong positive correlation among sharing and caring subscales with the full-scale. Results from the linear regression modeling suggested no relationship between demographic factors and preferences for patient-centeredness. Conclusions: SLPs value patient-centeredness, although there may be regional and cultural variations. Qualitative investigations may help uncover dimensions of patient-centeredness that were not captured in the PPOS scale. In addition, further research should explore congruence in preferences for patient-centeredness among SLPs and patients.

Background and Objectives Intestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson disease. The primary objective of this trial was to investigate whether continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady-state plasma concentrations of levodopa that are equivalent in magnitude, and noninferior in variability, to those obtained with LCIG in patients with advanced Parkinson disease. Methods A concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved LCIG in a randomized, 3-period crossover, open-label, multicenter trial. Formulations were infused for 16 hours to patients with Parkinson disease who were using LCIG as their regular treatment. Patients were recruited from several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and noninferior variability of DIZ101 and DIZ102 vs LCIG with respect to levodopa plasma concentrations. Results With dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits compared with LCIG in the 18 participants who received all treatments. Although the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Owing to poor uptake of LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n = 20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient. Discussion It is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa-containing solution.

Parkinsons disease is the second most common neurodegenerative disease. Lewy bodies with alpha-synuclein as the major component and loss of dopaminergic nerve cells in substantia nigra are neuropathological features. The diagnosis of Parkinsons disease is based on the occurrence of bradykinesia, rigidity and resting tremor. The disease is also associated with several non-motor symptoms. The therapy is mainly based on pharmacological treatment to increase dopamine signaling and neurosurgical deep brain stimulation. The symptoms and signs of the progressive disease change over time, requiring treatment adjustments. Patients should be followed by a physician, nurse and a multidisciplinary team with expertise in Parkinsons disease.

ObjectivesOff-label use of rituximab to treat MS patients in Sweden is high, and the need for long-term safety data may not be met. Our objectives were to assess the rate of rituximab prescription in patients with multiple sclerosis in Sweden and, in addition, to evaluate the safety of rituximab in a single centre for patients with multiple sclerosis. Material and MethodsReview of the Swedish MS register was performed to study the number of MS patients treated with rituximab during the last 6years. Investigation also included a retrospective review of medical files in search for possible side effects/adverse events in all adult patients with MS treated with rituximab at Uppsala University Hospital. ResultsPresently, in Sweden the rate of rituximab prescriptions in relation to other annually started of disease- modifying drugs in MS is 53.5%. ConclusionsThe share of MS patients in Sweden who are treated with rituximab is very high, and also rapidly increasing. Taken into account the off-label use, cases with adverse medical conditions that could possibly be related to rituximab use should be reported thoroughly.

Background: Intrathecal baclofen (ITB) treatment is considered a powerful tool in the management of severe spasticity in neurological conditions such as multiple sclerosis, cerebral palsy, and traumatic spinal cord and brain injury. 

Objectives: The objective of this study was to assess the effectiveness of the ITB in patients with inherited ataxia suffering from severe painful spasms and/or spasticity. 

Method: A total of 5 patients with spinocerebellar ataxia 3 or 7 or Friedreich’s ataxia were included in this observational multicenter study. The patients were interviewed and completed outcome measures assessing pain (The Brief Pain Inventory), fatigue (Fatigue Severity Scale), and life satisfaction (LiSAT-9) before and 1 year after the treatment. Spasticity (Modified Ashworth Scale) and spasm frequency (SPFS) were measured objectively for each patient. 

Results: The mean treatment time was 1.9 years. Evaluation of established standard forms revealed symptomatic relief from spasticity, spasms, pain, and fatigue in addition to improved body posture, sleep, and life satisfaction after ITB treatment. 

Conclusions: We report the potential beneficial effects of ITB treatment in patients with inherited ataxia who also suffer from spasticity/spasms. ITB treatment indication in neurological disorders allows for extension to the treatment of spasticity/ spasms in patients with hereditary ataxia.

PAX6 gene mutations cause a variety of eye and central nervous system (CNS) abnormalities. Aniridia is often accompanied by CNS abnormalities such as pineal gland atrophy or hypoplasia, leading to disturbed circadian rhythm and sleep disorders. Less is known on the coincidence of narcolepsy in this patient group. We aimed to find out whether the circadian rhythm or sleep-wake structure was affected in patients with aniridia. Four members of a family segregating with congenital aniridia in two generations were included in the study. The patients were subjected to genetic testing for a PAX6 mutation, multiple sleep latency test, whole-brain magnetic resonance imaging (MRI), hypocretin-1 in cerebrospinal fluid, and Human Leukocyte Antigen DQ beta1*06:02. All four members were heterozygous for the pathogenic c.959-1Gamp;gt;A mutation in the PAX6 gene. Sleep disturbance was observed in all family members. The index patient was diagnosed with narcolepsy. MRI showed a hypoplastic pineal gland in all members. We describe the first case of a patient with PAX6 haploinsufficiency, aniridia and pineal gland hypoplasia diagnosed with narcolepsy type-1, suggesting a complex sleep disorder pathogenesis.

Background: The role of environmental factors in neurological disorders constitutes a topic of increasing importance. Teaching in European universities should expand and update this field gaining future health professionals including adjacent disciplines. Aim: To describe recent efforts to create courses that cover crucial interdisciplinary content that we believe should be included in modern education, and to adapt modern pedagogic strategies. Methods: In collaboration with RISE (Rencontres Internationales Sante&lt;acute accent&gt; Environnement), elective courses focused on Environmental Health and Medicine (EHM) were developed, in France, Sweden, and Turkey. The courses combined classic teaching methods and new pedagogic and digital solutions to create environment-related health awareness and facilitate future interprofessional collaboration in this field. Results: UPRISE is an innovative elective course introduced in 2020 in Sweden's Uppsala University with the participation of lecturers from several countries and aim to recruit students from different universities. A total of 45, mainly female students (68%), participated in the course. In Strasbourg, France, a novel course on environmental medicine was held in 2019-2023 and examined 90 students, of which more than half were female. Nine graduate nurse students in Turkey attended ten seminar series focused on EHM. Overall, students expressed satisfaction with the courses. Conclusions: This European project for courses in higher education arising from RISE was met with appreciation and challenges from academic institutions. However, due to considerable efforts to introduce the EHM concept, a unique compulsory course for all medical students in the second year of training started in 2023 in all French medical faculties. In 2023, UPRISE was integrated into ENLIGHT, the European University Network to promote equitable quality of Life, sustainability, and Global engagement through Higher education Transformation.

Objectives: To determine drug utilization pathways from the incident healthcare visit due to epilepsy and three years onward. Material and methods: Anti-epileptic drug utilization was calculated using individual information on inpatient- and outpatient care utilization and drug sales. Throughout, we used national register information pertaining to pharmaceutical sales linked to diagnosis-related healthcare utilization. Information on pharmaceutical sales was collected for the 2007-2013 period. Results: For the entire studied period, a majority of new patients with epilepsy were initiated on anti-epileptic drug treatment with a monotherapy (98%); most of these patients remained on that first treatment (64%). The three most frequently prescribed drugs accounted for 72% of the initiated AED treatments. Patients with epilepsy (ICD-10: G40/41) were most commonly prescribed carbamazepine, lamotrigine and valproate. The most common second-line monotherapy was levetiracetam. About 12% of new patients with epilepsy who were initiated on AED treatment during the period eventually switched to an add-on therapy. The proportion of patients who were initiated on treatment with carbamazepine or valproate decreased, and the proportion of patients who remained on their initial monotherapy increased between 2007 and 2013. Conclusions: A limited number of anti-epileptic drugs accounted for the treatment of a majority of new patients with epilepsy (carbamazepine, lamotrigine and valproate accounted for more than 70%). Add-on therapies showed the same pattern, as the most frequently prescribed add-on regimens were the same ones that accounted for most of the monotherapies. There was a tendency towards fewer patients being initiated on AED treatment with either carbamazepine or valproate.

ObjectivesTo estimate the prevalence of epilepsy, costs associated with in- and outpatient care, drug utilization and productivity losses due to epilepsy in Sweden for the years 2005 and 2011. MethodsCost components were calculated using registry data on inpatient- and outpatient-care utilization, drug sales and early pensions granted due to permanent disability and mortality. Moreover, by cross-identification of information in healthcare and pharmaceutical registries, we were able to distinguish between pharmaceuticals prescribed for epilepsy and non-epilepsy indications. ResultsThe prevalence of epilepsy was estimated at 0.62% in 2005 and 0.88% in 2011. The total cost of epilepsy increased during the same period, while the per-patient cost decreased from Euro2929 to Euro1729. Direct medical costs accounted for about 36% of the estimated total cost in 2005 and 60% in 2011. The estimated healthcare cost due to epilepsy as a share of total healthcare costs for all illnesses was about the same in 2005 as in 2011 (0.2%), while the corresponding pharmaceutical cost increased from about 0.5% in 2005 to almost 1% in 2011. ConclusionsThe per-patient cost of epilepsy is substantial, implying a significant aggregated cost incurred on society (despite a prevalenceless than1%). Our results suggest that the per-patient pharmaceutical utilization increased, while the per-patient physician visits and hospitalizations decreased, between 2005 and 2011. Moreover, we demonstrate that the 2005 prevalence measure was underestimated the true prevalence in 2005.

The pre-symptomatic stage of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) occurs several decades before the clinical onset. Changes in the lysosomal network, i.e. the autophagosomal, endosomal and lysosomal vesicular system, are among the first alterations observed. There are currently no treatments to slow or cure neurodegenerative diseases, and there is a great need for discovery of treatment targets in cellular pathways where pathology pre-dates the neuronal death. It is also crucial to be able to diagnose neurodegenerative diseases earlier, both to enable early intervention treatment and aid in selecting clinical trial populations before the patient has widespread pathology.

This thesis aims at investigating the potential of lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease.

A targeted search for lysosomal network proteins was performed in cerebrospinal fluid (CSF) from AD patients, and seven proteins: early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), lysozyme, microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were elevated. The levels of EEA1, LAMP-1, LAMP-2, LC3, lysozyme and Rab3 were also measured in CSF from parkinsonian syndrome patients: PD, clinically diagnosed 4-repeat tauopathy, pathologically confirmed corticobasal degeneration (CBD) and pathologically confirmed progressive supranuclear palsy (PSP) patients. LAMP-1 and LAMP-2 were decreased in PD. LC3 and lysozyme levels were increased in 4-repeat tauopathy patients. EEA1 was decreased and lysozyme increased in PSP, and LAMP-1, LAMP-2, LC3 and lysozyme were increased in CBD. The lysosomal network proteins had different CSF protein profiles in all the parkinsonian syndromes, as well as in AD. It should be emphasized that only a select few of the lysosomal network proteins were observed to be changed, rather than a general change in lysosomal network proteins, which implicates the involvement of these seven proteins in specific pathological processes. The most interesting candidates, LAMP-2 and lysozyme, were selected for further study for their involvement in the pathology of AD.

Lysozyme was found to co-localise with Aβ plaques in AD patients and overexpression prolonged survival and improved the activity in a Drosophila model of AD. Lysozyme was found to alter the aggregation pathway of Aβ_1-42, to counteract the formation of toxic Aβ species and to protect from Aβ_1-42 induced cell toxicity. Aβ_1-42 in turn was found to increase the expression of lysozyme in both neuronal and glial cells. These data suggest that lysozyme levels rise in AD as a compensatory response which is protective against Aβ associated toxicity.

LAMP-2 mRNA and protein were found increased in brain areas relevant for AD pathology and various cellular models showed complex involvement of LAMP-2 in Aβ related pathology, with extensive crosstalk between LAMP-2 and Aβ. Exposure to oligomeric Aβ_1-42 caused an upregulation of LAMP-2 and in turn, overexpression of LAMP-2 caused a reduction in secreted levels of Aβ_1-42, as well as changing the generation pattern of Aβ and affecting clearance and secretion of Aβ_1-42. These data indicate that the increased levels of LAMP-2 in AD could be an attempt to regulate Aβ generation and secretion.

In summary, this thesis reports that utilising lysosomal network proteins as biomarkers and novel therapeutic targets for neurodegenerative diseases holds great promise.

Stroke och slaganfall är två alternativa namn på en akut inträdande funktionsnedsättning i hjärnan. Stroke uppkommer genom störningar i blodflödet till hjärnan, vilka i sin tur ger upphov till mer eller mindre omfattande vävnadsskador. Det finns två stora undergrupper av stroke: hjärninfarkter och hjärnblödningar. Infarkter är sådana vävnadsskador som uppstår till följd av att blodflödet i ett kärl stoppas. Vid hjärnblödningar uppstår vävnadsskadan till följd av att ett blodkärl brister.

Background Optical coherence tomography (OCT) could be complementary to magnetic resonance imaging (MRI) of the brain in monitoring course of multiple sclerosis (MS) and clinically isolated syndrome (CIS). Thinning of neurons in ganglion cell-inner plexiform layer (GCIPL) measured by OCT is assumed to be associated with brain atrophy. Objectives To evaluate association of GCIPL with brain parameters detected by quantitative MRI (qMRI) and MR-spectroscopy (MRS) in early MS and CIS. Methods Seventeen newly diagnosed MS and 18 CIS patients were prospectively included. The patients were assessed at baseline as well as at 1 year follow-up by OCT, qMRI and MRS. Brain parenchymal and myelin volumes (BPV, MYV respectively) and the corresponding fractions (BPF, MYF) were measured with qMRI. Metabolites including myo-inositol (myo-Ins) were measured in the normal-appearing white matter (NAWM) using MRS. T-tests and ANOVA were used to analyze group differences, and linear regression models to evaluate association of GCIPL with BPV, MYV and myo-Ins after correlation analysis. Results Disease activity reflected by lesions on MRI and presence of CSF oligoclonal IgG bands were more prominent in MS compared to CIS. GCIPL, BPV, MYV, BPF and MYF were reduced, while concentration of myo-Ins was increased in MS compared to CIS. Follow-up showed consistency of thinner GCIPL in MS compared to CIS. GCIPL thinning correlated with reduced BPV and MYV (P &lt; .05 for both), but with increased myo-Ins (P &lt; .01). Conclusions Significant GCIPL thinning occurs in early MS and is associated with enhanced brain inflammation and atrophy.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) has a high sensitivity for detecting cognitive dysfunction. Swedish normative data does not exist and international norms are often derived from populations where cognitive impairment has not been screened for and not been thoroughly assessed to exclude subjects with dementia or mild cognitive impairment.

OBJECTIVE: To establish norms for MoCA and develop a regression-based norm calculator based on a large, well-examined cohort.

METHODS: MoCA was administered on 860 randomly selected elderly people from a population-based cohort from the EPIC study. Cognitive dysfunction was screened for and further assessed at a memory clinic. After excluding cognitively impaired participants, normative data was derived from 758 people, aged 65-85.

RESULTS: MoCA cut-offs (-1 to -2 standard deviations) for cognitive impairment ranged from <25 to <21 for the lowest educated and <26 to <24 for the highest educated, depending on age group. Significant predictors for MoCA score were age, sex and level of education.

CONCLUSION: We present detailed normative MoCA data and cut-offs according to the DSM-5 criteria for cognitive impairment based on a large population-based cohort of elderly individuals, screened and thoroughly investigated to rule out cognitive impairment. Level of education, sex, and age should be taken in account when evaluating MoCA score, which is facilitated by our online regression-based calculator that provide percentile and z-score for a subject's MoCA score.

In several international studies, an increasing women-to-men (w/m) ratio in patients with multiple sclerosis (MS) has been reported. Such sex ratios have been analysed by year of onset or by year of birth. In a Swedish study, data from the Swedish MS register (SMSreg) were used to analyse the w/m ratio in Sweden. The sex ratio was analysed both by year of birth (8834 patients) and by year of onset (9098 patients). No increased w/m ratio was seen in this study. The age-specific sex ratio did not demonstrate any significant changes. However, a new investigation of the sex ratio in Sweden, based on data from all available data sources (19,510 patients), showed a significantly increased w/m ratio of MS in Sweden from 1.70 to 2.67. Environmental factors such as cigarette smoking, hormonal factors and nutrition are of interest in this context, but the cause of the increasing w/m ratio in MS is yet not possible to explain.

Objective: The primary aim was to estimate the pooled mean score of quality of life (QoL) (total, mental and physical health components) among patients with Restless Legs Syndrome (RLS). Secondary aims were to assess: (I) QoL differences for RLS vs. control groups, (II) heterogeneity and possible sources; and (III) moderating variables. Methods: Studies identified in PubMed, Scopus, Web of Science, and ProQuest between January 2000 and December 2022 were included. Methodological quality was assessed with Newcastle Ottawa Scale. The protocol was pre -registered (PROSPERO, CRD42023387318). Results: Twenty-seven studies (20121 participants, 12 countries) were included. The corrected pooled estimated mean score of QoL was 47.92 (27 studies, CI 95 %: 43.11 to 52.72, range 0 -100, i.e., low -high QoL) and was marginally affected by publication year (increased 0.89 by each year, p = 0.12). The corrected pooled estimated mean score of the mental health component was 47.32 (17 studies, 95 % CI: 43.12 to 51.51, range 0 -100) and influenced by RLS instrument (decreased with recent versions, p = 0.05). The corrected pooled estimated mean score of the physical health component was 39.08 (17 studies, 95 % CI: 33.05 to 45.10, range 0 -100), with no statistically significant moderator. The pooled estimated QoL scores were statistically significantly lower in RLS patients compared to control groups with standardized mean difference (SMD) of -0.78, -0.57 and -0.50 respectively for overall QoL (24 studies), physical and mental health components (14 studies). Total QoL SMD was affected by proportion of women. Conclusion: Low QoL was revealed among RLS patients, which was statistically significantly reduced compared to control groups.

Long-term adherence to continuous positive airway pressure (CPAP) is low among patients with obstructive sleep apnea (OSA). The potential role of "habit" in sustaining adherence to CPAP use has not been studied. This study aimed to establish the relevance of habit to CPAP adherence, via validation of an adaptation of the Self-Report Habit Index (the CPAP Habit Index-5; CHI-5). Analyses focused on the homogeneity, reliability, and factor structure of the CHI-5 and, in line with theoretical predictions, its utility as a predictor of long-term CPAP adherence in middle-aged patients with OSA. A prospective longitudinal design was used. 117 patients with objectively verified OSA intended for CPAP treatment were recruited. Data was collected via clinical examinations, respiratory recordings, questionnaires, and CPAP devices at baseline, 2 weeks, 6 months, and 12 months. The CHI-5 showed satisfactory homogeneity interitem correlations (0.42-0.93), item-total correlations (0.58-0.91), and reliability ( α = 0.92). CHI-5 data at 6 months showed a one-factor solution and predicted 63% of variance in total CPAP use hours after 12 months. Based on the satisfactory measurement properties and the high amount of CPAP use variance it explained, the CHI-5 can be seen as a useful tool in clinical practice.

BACKGROUND: Continuous positive airway treatment (CPAP) is the recommended treatment for patients with obstructive sleep apnea (OSA). Outcome measures often focus on clinical and/or self-rated variables related to the medical condition. However, a brief validated instrument focusing on the whole life situation (i.e., ethos) suitable for clinical practice is missing. The aim of this study was to investigate factorial structure, categorical functioning of the response scale, and differential item functioning across sub-populations of the Ethos Brief Index (EBI) among patients with obstructive sleep apnea (OSA) before and after initiation of continuous positive airway pressure (CPAP).

METHODS: A prospective design, including 193 patients with OSA (68% men, 59.66 years, SD 11.51) from two CPAP clinics, was used. Clinical assessment and overnight respiratory polygraphy were used to diagnose patients. Questionnaires administered before and after 6 months of CPAP treatment included EBI, Epworth Sleepiness Scale (ESS), Hospital Anxiety and Depression Scale, and global perceived health (initial item in SF-36). The validity and reliability of the EBI were investigated using Rasch and confirmatory factor analysis models. Measurement invariance, unidimensionality, and differential item functioning across gender groups, Apnea-Hypopnea Index, and ESS groups were assessed.

RESULTS: The reliability of the EBI was confirmed using composite reliability and Cronbach's alpha. The results supported unidimensionality of the EBI in confirmatory factor analysis and the Rasch model. No differential item functioning was found. A latent profile analysis yielded two profiles of patients with low (n = 42) and high (n = 151) ethos. Patients in the low ethos group were younger and had higher depression scores, lower perceived health, and higher body mass index.

CONCLUSIONS: The EBI is a valid tool with robust psychometric properties suitable for use among patients with OSA before and after treatment with CPAP is initiated. Future studies should focus on its predictive validity.

Adherence to continuous positive airway pressure (CPAP) treatment tends to be low. Brief validated instruments focusing on shared decision making have not been used in a CPAP context. The aim was to investigate factorial structure, categorical functioning of the response scale and differential item functioning across sub-populations of the CollaboRATE and Sure questionnaires among patients with obstructive sleep apnea (OSA) before CPAP treatment is initiated. A prospective design, including 193 objectively diagnosed (polygraphy) OSA patients (68% men, 59.7 years, SD 11.5) from two CPAP clinics was used. Data were collected with the following questionnaires; Sure, CollaboRATE, Attitudes to CPAP Inventory, Epworth sleepiness scale, minimal insomnia symptoms scale, and hospital anxiety and depression scale. Objective CPAP use was collected after 6 months; 49% demonstrated decisional conflict on SURE and 51% scored low levels of shared decision making on CollaboRATE. Unidimensionality was found for both CollaboRATE (one factor explaining 57.4%) and SURE (one factor explaining 53.7%), as well as local independence. Differential item functioning showed both to be invariant across both male and female patients. Internal consistency (Cronbach's alpha 0.83) and composite reliability (0.89) were good. Latent class analyses showed that patients with low decisional conflict and high shared decision making were more adherent to CPAP treatment. CollaboRATE and SURE provided good validity and reliability scores to measure shared decision making and decisional conflict in relation to CPAP treatment. The questionnaires can be used by healthcare personnel as a tool to simplify the assessment of shared decision making.

Background Glioblastoma is the most common malignant brain tumor in adults. Non-invasive clinical parameters could play a crucial role in treatment planning and serve as predictors of patient survival. Our register-based real-life study aimed to investigate the prognostic value of presenting symptoms. Methods Data on presenting symptoms and survival, as well as known prognostic factors, were retrieved for all glioblastoma patients in Sweden registered in the Swedish Brain Tumor Registry between 2018 and 2021. The prognostic impact of different presenting symptoms was calculated using the Cox proportional hazard model. Results Data from 1458 adults with pathologically verified IDH wild-type glioblastoma were analyzed. Median survival time was 345 days. The 2-year survival rate was 21.5%. Registered presenting symptoms were focal neurological deficits, cognitive dysfunction, headache, epilepsy, signs of raised intracranial pressure, and cranial nerve symptoms, with some patients having multiple symptoms. Patients with initial cognitive dysfunction had significantly shorter survival than patients without; 265 days (245-285) vs. 409 days (365-453; P &lt; .001). The reduced survival remained after Cox regression adjusting for known prognostic factors. Patients presenting with seizures and patients with headaches had significantly longer overall survival compared to patients without these symptoms, but the difference was not retained in multivariate analysis. Patients with cognitive deficits were less likely to have radical surgery and to receive extensive anti-neoplastic nonsurgical treatment. Conclusions This extensive real-life study reveals that initial cognitive impairment acts as an independent negative predictive factor for treatment decisions and adversely affects survival outcomes in glioblastoma patients.

Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-D-aspartate receptor agonist, are increased. The enzyme amino-beta-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Asberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (Pamp;lt;0.001) and blood (P=0.001 and Pamp;lt;0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.