Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease.

Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.

Putaminal dopamine modulates movement motivation in Parkinson's disease.

The relative inability to produce effortful movements is the most specific motor sign of Parkinson's disease, which is primarily characterized by loss of dopaminergic terminals in the putamen. The motor motivation hypothesis suggests that this motor deficit may not reflect a deficiency in motor control per se, but a deficiency in cost-benefit considerations for motor effort. For the first time, we investigated the quantitative effect of dopamine depletion on the motivation of motor effort in Parkinson's disease. A total of 21 early-stage, unmedicated patients with Parkinson's disease and 26 healthy controls were included. An incentivized force task was used to capture the amount of effort participants were willing to invest for different monetary incentive levels and dopamine transporter depletion in the bilateral putamen was assessed. Our results demonstrate that patients with Parkinson's disease applied significantly less grip force than healthy controls, especially for low incentive levels. Congruously, decrease of motor effort with greater loss of putaminal dopaminergic terminals was most pronounced for low incentive levels. This signifies that putaminal dopamine is most critical to motor effort when the trade-off with the benefit is poor. Taken together, we provide direct evidence that the reduction of effortful movements in Parkinson's disease depends on motivation and that this effect is associated with putaminal dopaminergic degeneration.

Mapping of Interventions of Social Protection for Tuberculosis Patients in Africa: A Scoping Review Protocol.

BACKGROUND: Tuberculosis (TB) is a public health problem worldwide, particularly in resource-limited countries. It is considered a social disease with a medical component that persists over time due to several social determinants, most of which are closely linked to poverty and difficult socioeconomic conditions. The objective of this exploratory study is to describe the social protection interventions available for people with TB in Africa. METHODS: Searches will be carried out systematically in MEDLINE (PubMed), Embase (Ovid), Web of Science, Scopus and The Cochrane Library, Africa-Wide Information (EBSCOhost), Google Scholar. Articles will be considered if they describe the social protection, successes and challenges associated with the implementation and delivery of social protection interventions offered to people with TB in African countries. Data from the grey literature will also be considered. PRESENTATION OF RESULTS: We will present a narrative description highlighting the successes and challenges of the social protection interventions identified, and a synthesis accompanied by maps (Africa), figures or tables to summarize the data. CONCLUSION: This exploratory study will map the existing literature on social protection interventions for TB patients and guide future research to inform policy and practice decisions.

CONTEXTE: La tuberculose (TB) est un problème de santé publique dans le monde entier, en particulier dans les pays à ressources limitées. Elle est considérée comme une maladie sociale avec une composante médicale qui persiste dans le temps en raison de plusieurs déterminants sociaux, dont la plupart sont étroitement liés à la pauvreté et à des conditions socio-économiques difficiles. L'objectif de cette étude exploratoire est de décrire les interventions de protection sociale disponibles pour les personnes atteintes de TB dans les pays d'Afrique. METHODE: Des recherches seront effectuées systématiquement dans MEDLINE (PubMed), Embase (Ovid), Web Of Science, Scopus et The Cochrane Library, Africa-Wide Information (EBSCOhost), Google Scholar. Les articles seront pris en considération s'ils décrivent la protection sociale, les succès et les défis associés à la mise en œuvre et à l'exécution des interventions de protection sociale offertes aux personnes atteintes de TB dans les pays d'Afrique. Les données issues de la littérature grise seront également prises en compte. PRESENTATION DES RESULTATS: Nous présenterons une description narrative soulignant les succès et les défis des interventions de protection sociale identifiées, ainsi qu'une synthèse accompagnée de cartes (Afrique), de figures ou de tableaux pour résumer les données. CONCLUSION: Cette étude exploratoire permettra de cartographier la littérature existante sur les interventions de protection sociale pour les patients atteints de tuberculose et d'orienter les recherches futures afin d'éclairer les décisions politiques et pratiques.

Structural underpinnings and long-term effects of resilience in Parkinson's disease.

Resilience in neuroscience generally refers to an individual's capacity to counteract the adverse effects of a neuropathological condition. While resilience mechanisms in Alzheimer's disease are well-investigated, knowledge regarding its quantification, neurobiological underpinnings, network adaptations, and long-term effects in Parkinson's disease is limited. Our study involved 151 Parkinson's patients from the Parkinson's Progression Marker Initiative Database with available Magnetic Resonance Imaging, Dopamine Transporter Single-Photon Emission Computed Tomography scans, and clinical information. We used an improved prediction model linking neuropathology to symptom severity to estimate individual resilience levels. Higher resilience levels were associated with a more active lifestyle, increased grey matter volume in motor-associated regions, a distinct structural connectivity network and maintenance of relative motor functioning for up to a decade. Overall, the results indicate that relative maintenance of motor function in Parkinson's patients may be associated with greater neuronal substrate, allowing higher tolerance against neurodegenerative processes through dynamic network restructuring.

Decentralising DOT for drug-susceptible TB from the health facilities to the community level in Togo.

In Togo, the COVID-19 pandemic paved the way for decentralising directly observed treatment (DOT) to the community level through the evaluation of two innovative community-based DOT approaches-a community health worker-based (CHW-DOT) and family-based (FB-DOT). METHODS We conducted an observational prospective study from April 2021 to January 2022. Sputum conversion at Month 2 and favourable treatment outcomes at Month 6 were assessed and compared between the two groups. Sociodemographic and clinical factors related to these outcomes were identified. RESULTS A total of 182 TB patients were enrolled. The CHW-DOT group had significantly increased odds of sputum conversion (aOR 2.95, 95% CI 1.09-7.98) and lower odds of unsuccessful treatment outcomes (aOR 0.37, 95% CI 0.13-1.1). Non-smokers had 4.85 higher odds of converting than smokers (aOR 4.85, 95% CI 1.76-13.42) and lower odds of an unsuccessful treatment than smokers (aOR 0.11, 95% CI 0.04-0.32). CONCLUSION CHW-DOT is associated with higher sputum smear conversion rates and a more favourable treatment outcome. The use of tobacco, significantly associated with outcomes, also suggests that a smoking cessation component may be a valuable adjunct to a CHW-DOT approach during TB treatment..

Affection of Motor Network Regions by Tau Pathology Across the Alzheimer's Disease Spectrum.

Stereotypical isocortical tau protein pathology along the Braak stages has been described as an instigator of neurodegeneration in Alzheimer's disease (AD). Less is known about tau pathology in motor regions, although higher-order motor deficits such as praxis dysfunction are part of the clinical description. Here, we examined how tau pathology in cytoarchitectonically mapped regions of the primary and higher-order motor network in comparison to primary visual and sensory regions varies across the clinical spectrum of AD. We analyzed tau PET scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort in patients with mild cognitive impairment (MCI; N = 84) and dementia of the Alzheimer's disease type (DAD; N = 25). Additionally, an amyloid-negative sample of healthy older individuals (HC; N = 26) were included. Standard uptake ratio values (SUVRs) were extracted in native space from the left and the right hemispheres. A repeated measurement analysis of variance was conducted to assess the effect of diagnostic disease category on tau pathology in the individual motor regions, controlling for age. We observed that tau pathology varies as a function of diagnostic category in predominantly higher motor regions (i.e., supplementary motor area, superior parietal lobe, angular gyrus, and dorsal premotor cortex) compared to primary visual, sensory and motor regions. Indeed, tau in higher-order motor regions was significantly associated with decline in cognitive function. Together, these results expand our knowledge on the in vivo pattern of tau pathology in AD and suggest that higher motor regions are not spared from tau aggregation in the course of disease, potentially contributing to the symptomatic appearance of the disease.

Impulsive-compulsive behaviour in early Parkinson's disease is determined by apathy and dopamine receptor D3 polymorphism.

Impulsive-compulsive behaviour (ICB) is a frequently observed non-motor symptom in early Parkinson's disease after initiating dopamine replacement therapy. At the opposite end of the motivated behaviour spectrum, apathy occurs in early Parkinson's disease even before dopamine replacement is started. The co-occurrence of these behavioural conditions in Parkinson's disease raises questions about their relationship and underlying pathophysiological determinants. In previous imaging or genetic studies, both conditions have been associated with the limbic dopaminergic system. The risk variant of the Ser9Gly polymorphism of the dopamine receptor D3 (DRD3) is linked to increased dopamine affinity in the limbic striatum. With this in mind, we investigated how ICB expression is explained by apathy and DRD3 polymorphisms and their effects on grey matter volume and dopamine synthesis capacity. Fifty-four patients with early Parkinson's disease took part in anatomical T1-weighted MRI. Forty of them also underwent dynamic PET imaging using [18F]DOPA to measure striatal dopamine synthesis capacity. Further, Ser9Gly (rs6280) gene polymorphism influencing the DRD3 dopamine-binding affinity was determined in all patients. The severity of impulsive-compulsive behaviour and apathy was assessed using the Questionnaire for Impulsive-Compulsive Disorders Rating Scale and the Apathy Evaluation Scale. ICB and the severity of apathy were indeed positively correlated. Apathy and the DRD3 polymorphism were interactive risk factors for ICB severity. Apathy was significantly linked to atrophy of the bilateral putamen. Patients with the DRD3 risk type had reduced dopamine synthesis capacity in the putamen and limbic striatum, apathy was associated with reduced dopamine synthesis capacity in the limbic striatum. The results of [18F]DOPA reached only trend significance. Apathy in drug-naïve PD patients might be a consequence of impaired striatal dopaminergic tone. This may represent a predisposing factor for the development of ICB after the initiation of dopamine replacement therapy. The risk type of DRD3 could further amplify this predisposition due to its higher affinity to dopamine.

Educational level and its association with dopamine transporter loss in patients with Parkinson's disease.

BACKGROUND: According to the cognitive-reserve concept, higher educated dementia patients tolerate more brain pathology than lower educated patients with similar impairment. Here, we examined whether higher education is associated with more severe dopamine terminal loss at the diagnosis of Parkinson's disease (PD). METHODS: Dopamine transporter (DaT) SPECT information of 352 de novo PD patients and 172 healthy controls (HC) were retrieved from PPMI. Correlation analyses were performed between education years and regional DaT signal (i.e., putamen, caudate, striatum), correcting for UPDRS-III, age, sex and MoCA. Second, using a median split on education (Md = 16 yrs), high and low education groups were determined, which were matched for demographic and/or clinical scores and compared based on regional DaT signals. Finally, moderation analyses were conducted in the PD cohort, assessing the effect of education on the relation between putaminal DaT capacity and UPDRS-III. All analyses were performed across the entire cohorts and separately for three age ranges (sixth, seventh and eighth life decade). RESULTS: Only PD patients in their eighth life decade presented a positive association between education and regional dopamine signalling. A significant moderation effect of education on the association between putaminal DaT signal loss and motor symptom severity was observed in this group (B=3.377, t=3.075, p = .003). The remaining analyses did not yield any significant results, neither in the PD nor HC cohort. CONCLUSION: Higher education is not related with greater tolerance against dopamine loss in PD, but may nonetheless assert protective effects at more advanced age.

Randomized Controlled Study in the Use of Aromatherapy for Pain Reduction and to Reduce Opioid Use in the Emergency Department.

INTRODUCTION: This study aimed to evaluate the effects of aromatherapy on emergency department patients' perception of pain and its ability to reduce the use of opioids in an emergency department. METHODS: This randomized, controlled, single-blinded study was conducted in a suburban/rural freestanding emergency department with a therapeutic group, sham group, and control group. RESULTS: A total of 230 patients, 171 females and 59 males, completed the study. Of those who received the therapeutic agent, an average reduction in pain of 1.04 points on the pain scale was reported, whereas the sham group averaged 0.38 and the control group 0.23. There was a statistically significant reduction of pain scores in the therapeutic group. A total of 13 received opioid pain medication during their visit. Of these, the therapeutic group averaged a total of 2.67 morphine milligram equivalents for their visit compared with 3.63 in the sham group and 4.36 in the control group; however, statistical significance was not achieved. DISCUSSION: This study supported what other studies have found, indicating that aromatherapy is effective in reducing pain. A difference between the placebo effect and a true therapeutic effect was seen by using a control group apart from the sham and therapeutic groups. Despite the small effect size (0.3), implementation of aromatherapy into standard practice may be practical considering the anxiolytic effects that have been shown in other studies. Aromatherapy with essential oils should be considered as another tool to use in a multimodal approach in the treatment of pain in the emergency department setting.

A positive neighborhood walkability is associated with a higher magnitude of leisure walking in adults upon COVID-19 restrictions: a longitudinal cohort study.

BACKGROUND: Previous cross-sectional and longitudinal observational studies revealed positive relationships between contextual built environment components and walking behavior. Due to severe restrictions during COVID-19 pandemic lockdowns, physical activity was primarily performed within the immediate living area. Using this unique opportunity, we evaluated whether built environment components were associated with the magnitude of change in walking activity in adults during COVID-19 restrictions. METHODS: Data on self-reported demographic characteristics and walking behaviour were extracted from the prospective longitudinal Lifelines Cohort Study in the Netherlands of participants ≥ 18 years. For our analyses, we made use of the data acquired between 2014-2017 (n = 100,285). A fifth of the participants completed the questionnaires during COVID-19 restrictive policies in July 2021 (n = 20,806). Seven spatial components were calculated for a 500m and 1650m Euclidean buffer per postal code area in GIS: population density, retail and service destination density, land use mix, street connectivity, green space density, sidewalk density, and public transport stops. Additionally, the walkability index (WI) of these seven components was calculated. Using multivariable linear regression analyses, we analyzed the association between the WI (and separate components) and the change in leisure walking minutes/week. Included demographic variables were age, gender, BMI, education, net income, occupation status, household composition and the season in which the questionnaire was filled in. RESULTS: The average leisure walking time strongly increased by 127 min/week upon COVID-19 restrictions. All seven spatial components of the WI were significantly associated with an increase in leisure walking time; a 10% higher score in the individual spatial component was associated with 5 to 8 more minutes of leisure walking/week. Green space density at the 500m Euclidean buffer and side-walk density at the 1650m Euclidean buffer were associated with the highest increase in leisure walking time/week. Subgroup analysis revealed that the built environment showed its strongest impact on leisure walking time in participants not engaging in leisure walking before the COVID-19 pandemic, compared to participants who already engaged in leisure walking before the COVID-19 pandemic. CONCLUSIONS: These results provide strong evidence that the built environment, corrected for individual-level characteristics, directly links to changes observed in leisure walking time during COVID-19 restrictions. Since this relation was strongest in those who did not engage in leisure walking before the COVID-19 pandemic, our results encourage new perspectives in health promotion and urban planning.

Supplementation with Whey Protein, but Not Pea Protein, Reduces Muscle Damage Following Long-Distance Walking in Older Adults.

Background: Adequate animal-based protein intake can attenuate exercise induced-muscle damage (EIMD) in young adults. We examined the effects of 13 days plant-based (pea) protein supplementation compared to whey protein and placebo on EIMD in active older adults. Methods: 47 Physically active older adults (60+ years) were randomly allocated to the following groups: (I) whey protein (25 g/day), (II) pea protein (25 g/day) or (III) iso-caloric placebo. Blood concentrations of creatine kinase (CK) and lactate dehydrogenase (LDH), and skeletal muscle mass, muscle strength and muscle soreness were measured prior to and 24 h, 48 h and 72 h after a long-distance walking bout (20−30 km). Results: Participants walked 20−30 km and 2 dropped out, leaving n = 15 per subgroup. The whey group showed a significant attenuation of the increase in EIMD at 24 h post-exercise compared to the pea and placebo group (CK concentration: 175 ± 90 versus 300 ± 309 versus 330 ± 165, p = p < 0.001). No differences in LDH levels, muscle strength, skeletal muscle mass and muscle soreness were observed across groups (all p-values > 0.05). Conclusions: Thirteen days of pea protein supplementation (25 g/day) does not attenuate EIMD in older adults following a single bout of prolonged walking exercise, whereas the whey protein supplementation group showed significantly lower post-exercise CK concentrations.

Clear-headed into old age: Resilience and resistance against brain aging-A PET imaging perspective.

With the advances in modern medicine and the adaptation towards healthier lifestyles, the average life expectancy has doubled since the 1930s, with individuals born in the millennium years now carrying an estimated life expectancy of around 100 years. And even though many individuals around the globe manage to age successfully, the prevalence of aging-associated neurodegenerative diseases such as sporadic Alzheimer's disease has never been as high as nowadays. The prevalence of Alzheimer's disease is anticipated to triple by 2050, increasing the societal and economic burden tremendously. Despite all efforts, there is still no available treatment defeating the accelerated aging process as seen in this disease. Yet, given the advances in neuroimaging techniques that are discussed in the current Review article, such as in positron emission tomography (PET) or magnetic resonance imaging (MRI), pivotal insights into the heterogenous effects of aging-associated processes and the contribution of distinct lifestyle and risk factors already have and are still being gathered. In particular, the concepts of resilience (i.e. coping with brain pathology) and resistance (i.e. avoiding brain pathology) have more recently been discussed as they relate to mechanisms that are associated with the prolongation and/or even stop of the progressive brain aging process. Better understanding of the underlying mechanisms of resilience and resistance may one day, hopefully, support the identification of defeating mechanism against accelerating aging.

Gray Matter Volume Loss in Proposed Brain-First and Body-First Parkinson's Disease Subtypes.

BACKGROUND: α-Synuclein pathology is associated with neuronal degeneration in Parkinson's disease (PD) and considered to sequentially spread across the brain (Braak stages). According to a new hypothesis of distinct α-synuclein spreading directions based on the initial site of pathology, the "brain-first" spreading subtype would be associated with a more asymmetric cerebral and nigrostriatal pathology than the "body-first" subtype. OBJECTIVE: Here, we tested if proposed markers of brain-first PD (ie, higher dopamine transporter [DaT] asymmetry; absence of rapid eye movement sleep behavior disorder [RBD]) are associated with a greater or more asymmetric reduction in gray matter volume (GMV) in comparison to body-first PD. METHODS: Data of 255 de novo PD patients and 110 healthy controls (HCs) were retrieved from the Parkinson's Progression Markers Initiative. Structural magnetic resonance images were preprocessed, and GMVs and their hemispherical asymmetry were obtained for each of the neuropathologically defined Braak stages. Group and correlation comparisons were performed to assess differences in GMV and GMV asymmetry between PD subtypes. RESULTS: PD patients demonstrated significantly smaller bilateral GMVs compared to HCs, in a pattern denoting stage-dependent disease-related brain atrophy. However, the degree of putaminal DaT asymmetry was not associated with reduced GMV or higher GMV asymmetry. Furthermore, RBD-negative and RBD-positive patients did not demonstrate a significant difference in GMV or GMV asymmetry. CONCLUSIONS: Our findings suggest that putative brain-first and body-first patients do not present diverging brain atrophy patterns. Although certainly not disproving the brain-first/body-first spreading hypothesis, this study fails to provide evidence in support of it. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

WHO target product profiles for TB preventive treatment.

BACKGROUND: The WHO has developed target product profiles (TPPs) describing the most appropriate qualities for future TPT regimens to assist developers in aligning the characteristics of new treatments with programmatic requirements.METHODS: A technical consultation group was convened by the WHO to determine regimen attributes with greatest potential impact for patients (i.e., improved risk/benefit profile) and populations (i.e., reduction in transmission and TB prevalence). The group categorised regimen attributes as 'priority´ or 'desirable´; and defined for each attribute the minimum requirements and optimal targets.RESULTS: Nine priority attributes were defined, including efficacy, treatment duration, safety, drug-drug interactions, barrier to emergence of drug resistance, target population, formulation, dosage, frequency and route of administration, stability and shelf life. Regimens meeting optimal targets were characterised, for example, as having superior efficacy, treatment duration of ≤2 weeks, and improved tolerability and safety profile compared with current regimens. The four desirable attributes included regimen cost, safety in special populations, treatment adherence and need for drug susceptibility testing in the index patient.DISCUSSION: It may be difficult for a single regimen to satisfy all characteristics so regimen developers may have to consider trade-offs. Additional operational aspects may be relevant to the feasibility and public health impact of new TPT regimens.

Impact of Dutch COVID-19 restrictive policy measures on physical activity behavior and identification of correlates of physical activity changes: a cohort study.

BACKGROUND: Identification of characteristics of individuals that are related to decreases in physical activity (PA) levels during lockdown is needed to develop targeted-interventions. This study aims to evaluate changes in domain-specific (i.e. leisure time, transportation, occupational, and household) and total PA due to the Dutch COVID-19 lockdown, which started on March 15 2020. Furthermore, we aim to identify demographic, health-related, and psychological correlates of these changes. METHODS: Individuals who participated in the Nijmegen Exercise Study during 2017-2019 were invited to this study, which was conducted between April 16 and May 12 2020. Participant characteristics (i.e. age, sex, body mass index (BMI), marital status, education, household composition, and occupation status), living environment (i.e. housing type and degree of urbanization), psychological characteristics (i.e. resilience, outcome expectations, vitality, and mental health), and medical history were collected via an online questionnaire. Short Questionnaire to Assess Health-enhancing physical activity was used to assess PA behavior before and during lockdown. Wilcoxon signed-rank test was used to compare PA levels, in metabolic equivalent of task (MET)-minutes per week (min/wk), before and during lockdown. Multivariable linear regression analyses were performed to examine correlates of PA changes. RESULTS: 4033 participants (57% male; 59 ± 13 years) were included. PA decreased significantly during lockdown with mean ± SD changes of 393 ± 2735 MET-min/wk for total, 133 ± 785 MET-min/wk for transportation, 137 ± 1469 MET-min/wk for occupation, and 136 ± 1942 MET-min/wk for leisure time PA. Household PA did not change significantly. Unemployment, COVID-19-related occupational changes, higher BMI, and living in an apartment or semi-detached/terraced house were significantly related to larger decreases in total and domain-specific PA. Higher vitality was related to smaller decreases in total and domain-specific PA. Higher age was significantly associated with a larger decrease in leisure time PA. Lower education was associated with smaller decreases in transportation and occupational PA compared to higher education. CONCLUSION: PA levels significantly reduced during lockdown compared to before lockdown. Declines were observed during transportation and occupation, but were not compensated by an increase in leisure time PA. We identified subgroups that were more susceptible to reductions in domain-specific or total PA levels and should therefore be encouraged to increase their PA levels during lockdown.

Unique regional patterns of amyloid burden predict progression to prodromal and clinical stages of Alzheimer's disease.

Although beta-amyloid (Aß) positivity has shown to be associated with higher risk of progression to Alzheimer's disease (AD) in mild cognitive impairment (MCI), information on the time to conversion to manifest dementia cannot be readily deduced from this binary classification. Here, we assessed if regional patterns of Aß deposition measured with 18F-florbetapir may serve as biomarker for progression risk in Aß-positive cognitively normal (CN) and MCI patients, including clinical follow-up data and cerebrospinal fluid (CSF) biomarkers. Voxel-wise group comparisons between age and sex-matched Aß-positive groups (i.e., CN-stables [n = 38] vs. CN-to-MCI/AD progressors [n = 38], MCI-stables [n = 104] versus MCI-to-AD progressors [n = 104]) revealed higher Aß burden in precuneus, subcortical, and parietal regions in CN-to-MCI/AD progressors and cingulate, temporal, and frontal regions in MCI-to-AD progressors. Importantly, these regional patterns predicted progression to advanced stages on the AD spectrum in the short and the long-term beyond global Aß burden and CSF biomarkers. These results suggest that distinct regional patterns of Aß burden are a valuable biomarker for risk of disease progression in CN and MCI.

Quantitative and individualized assessment of the learning curve in preoperative planning of the acetabular cup size in primary total hip arthroplasty.

INTRODUCTION: The aim of the present study was to investigate the learning curves of 2 trainees with different experience levels to reach proficiency in preoperative planning of the cup size based on learning curve cumulative summation (LC-CUSUM) statistics and a cumulative summation (CUSUM) test. MATERIALS AND METHODS: One-hundred-twenty patients who had undergone primary total hip arthroplasty with a cementless cup were selected. Preoperative planning was performed by an experienced orthopedic surgeon. Trainee 1 (student) and trainee 2 (resident) planned the cup size. The trainees were blinded to the preoperative plan and the definitive cup size. Only after a cup size was chosen, the trainees were unblinded to the preoperative plan of the surgeon. LC-CUSUM was applied to both trainees to determine when proficiency in determining the appropriate cup size was reached. A CUSUM test was applied to ensure retention of proficiency. RESULTS: With reference to the preoperative plan of the surgeon, LC-CUSUM indicated proficiency after 94 planning attempts for trainee 1 and proficiency after 66 attempts for trainee 2, respectively. Trainee 1 and 2 maintained proficiency thereafter. With reference to the definitive cup size, LC-CUSUM did not signal competency within the first 120 planning attempts for trainee 1. Trainee 2 was declared competent after 103 attempts and retained competency thereafter. CONCLUSIONS: LC-CUSUM/CUSUM allow for an individualized, quantitative and continuous assessment of planning quality. Based on LC-CUSUM statistics, the two trainees of this study gain proficiency in planning of the acetabular cup size after 50-100 attempts when an immediate feedback is provided. Previous experience positively influences the performance. The study serves as basis for the medical education of students and residents in joint replacement procedures.

Indication of retrograde tau spreading along Braak stages and functional connectivity pathways.

PURPOSE: Tau pathology progression in Alzheimer's disease (AD) is explained through the network degeneration hypothesis and the neuropathological Braak stages; however, the compatibility of these models remains unclear. METHODS: We utilized [18F]AV-1451 tau-PET scans of 39 subjects with AD and 39 sex-matched amyloid-negative healthy controls (HC) in the ADNI (Alzheimer's Disease Neuroimaging Initiative) dataset. The peak cluster of tau-tracer uptake was identified in each Braak stage of neuropathological tau deposition and used to create a seed-based functional connectivity network (FCN) using 198 HC subjects, to identify healthy networks unaffected by neurodegeneration. RESULTS: Voxel-wise tau deposition was both significantly higher inside relative to outside FCNs and correlated significantly and positively with levels of healthy functional connectivity. Within many isolated Braak stages and regions, the correlation between tau and intrinsic functional connectivity was significantly stronger than it was across the whole brain. In this way, each peak cluster of tau was related to multiple Braak stages traditionally associated with both earlier and later stages of disease. CONCLUSION: We show specificity of healthy FCN topography for AD-pathological tau as well as positive voxel-by-voxel correlations between pathological tau and healthy functional connectivity. We propose a model of "up- and downstream" functional tau progression, suggesting that tau pathology evolves along functional connectivity networks not only "downstream" (i.e., along the expected sequence of the established Braak stages) but also in part "upstream" or "retrograde" (i.e., against the expected sequence of the established Braak stages), with pathology in earlier Braak stages intensified by its functional relationship to later disease stages.