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Abstract Background Favorable movement behavior patterns, comprising more physical activity, less sedentary behavior, and sufficient sleep, may promote the maintenance of good quality of life (QoL) with advancing age. The aim of the present study was to investigate whether movement behaviors predict future changes in QoL among community-dwelling older adults over a four-year follow-up. Methods Participants were 75-, 80- and 85-year-old community-dwelling older adults (n = 203) followed up for 4 years. Participants wore thigh- and trunk-mounted accelerometers for 3–7 days at baseline. Proportion of time-use in physical activity, standing and sedentary behavior were assessed based on body posture and movement intensity. Time in bed was determined using an automated algorithm. QoL was assessed during a home interview using the short Older People’s Quality of Life Questionnaire at baseline and follow-up (range 13–65, higher scores indicate higher QoL). Compositional linear regression analysis was used to study whether baseline time-use composition predicts changes in QoL. Results Over the 4-year follow-up, QoL scores decreased by 5% on average. Higher physical activity in relation to the other movement behaviors was associated with increase in QoL over time (βilr 0.94, p = 0.013), but this association attenuated after adding baseline physical function into the model. Sedentary behavior, standing, and time in bed were not associated with changes in QoL. Theoretical reallocation of 30 min of physical activity into sedentary behavior, standing or time in bed was estimated to decrease QoL by 0.5 (CI 95% -0.6 to -0.4), 0.6 (-0.7 to -0.5) and 0.4 (-0.5 to -0.3) points, respectively. Conclusions Theoretical reallocation of physical activity into sedentary behavior, standing, and time in bed was found to be associated with prospective decline in QoL among older adults. Engaging more in physical activity and less in more passive activities may promote better QoL with advancing age.

Abstract Background Successful ageing is the term often used for depicting exceptional ageing and can be measured with multidimensional models including physical, psychological and social wellbeing. The aim of this study was to test multidimensional successful ageing models to investigate whether these models can predict successful ageing, and which individual subcomponents included in the models are most significantly associated with successful ageing. Methods Successful ageing was defined as the ability to live at home without daily care at the age of 84 years or over. Data on the participants’ physical, psychological and social wellbeing were gathered at baseline and the follow-up period was 20 years. Four successful ageing models were constructed. Backward stepwise logistic regression analysis was used to identify the individual subcomponents of the models which best predicted successful ageing. Results All successful ageing models were able to predict ageing successfully after the 20-year follow-up period. After the backward stepwise logistic regression analysis, three individual subcomponents of four models remained statistically significant and were included in the new model: having no heart disease, having good self-rated health and feeling useful. As a model, using only these three subcomponents, the association with successful ageing was similar to using the full models. Conclusions Multidimensional successful ageing models were able to predict successful ageing after a 20-year follow-up period. However, according to the backward stepwise logistic regression analysis, the three subcomponents (absence of heart disease, good self-rated health and feeling useful) significantly associated with successful ageing performed as well as the multidimensional successful ageing models in predicting ageing successfully.

Constituents of air pollution, the ultrafine particles (UFP) with a diameter of ≤0.1 μm, are considerably related to traffic emissions. Several studies link air pollution to Alzheimer's disease (AD), yet the exact relationship between the two remains poorly understood. Mitochondria are known targets of environmental toxicants, and their dysfunction is associated with neurodegenerative diseases. The olfactory mucosa (OM), located at the rooftop of the nasal cavity, is directly exposed to the environment and in contact with the brain. Mounting evidence suggests that the UFPs can impact the brain directly through the olfactory tract. By using primary human OM cultures established from nasal biopsies of cognitively healthy controls and individuals diagnosed with AD, we aimed to decipher the effects of traffic-related UFPs on mitochondria. The UFP samples were collected from the exhausts of a modern heavy-duty diesel engine (HDE) without aftertreatment systems, run with renewable diesel (A0) and petroleum diesel (A20), and from an engine of a 2019 model diesel passenger car (DI-E6d) equipped with state-of-the-art aftertreatment devices and run with renewable diesel (Euro6). OM cells were exposed to three different UFPs for 24-h and 72-h, after which cellular processes were assessed on the functional and transcriptomic levels. Our results show that UFPs impair mitochondrial functions in primary human OM cells by hampering oxidative phosphorylation (OXPHOS) and redox balance, and the responses of AD cells differ from cognitively healthy controls. RNA-Seq and IPA® revealed inhibition of OXPHOS and mitochondrial dysfunction in response to UFPs A0 and A20. Functional validation confirmed that A0 and A20 impair cellular respiration, decrease ATP levels, and disturb redox balance by altering NAD and glutathione metabolism, leading to increased ROS and oxidative stress. RNA-Seq and functional assessment revealed the presence of AD-related alterations in human OM cells and that different fuels and engine technologies elicit differential effects.

We identified data-driven multidimensional physical activity (PA) profiles using several novel accelerometer-derived metrics. Participants aged 75, 80, and 85 (n = 441) wore triaxial accelerometers for 3–7 days. PA profiles were formed with k-means cluster analysis based on PA minutes, intensity, fragmentation, sit-to-stand transitions, and gait bouts for men and women. Associations with physical capacity and life-space mobility were examined using age-adjusted general linear models. Three profiles emerged: "Exercisers" and "actives" accumulated relatively high PA minutes, with actives engaging in lighter intensity PA. "Inactives" had the highest activity fragmentation and lowest PA volume, intensity, and gait bouts. Inactives showed lower scores in physical capacity and life-space mobility compared with exercisers and actives. Exercisers and actives had similar physical capacity and life-space mobility, except female exercisers had higher walking speed in the 6-min walk test. Our findings demonstrate the importance of assessing PA as multidimensional behavior rather than focusing on a single metric. [ABSTRACT FROM AUTHOR]

Purpose: This prospective longitudinal study aimed to explore (a) the development of social-pragmatic understanding of children with bilateral hearing aids (BiHAs), bilateral cochlear implants (BiCIs), and typical hearing (TH) between the ages of 4 and 6 years and (b) group differences between children with BiHAs, BiCIs, and TH. Method: The Pragma test was used for a comprehensive assessment of social-pragmatic understanding of a total of 86 children: 19 children with BiHAs, 22 children with BiCIs, and 45 children with TH. The Pragma test requires answering socially and contextually demanding questions and explaining the right answers. The explanation tasks are targeted at studying the participant's own awareness of the inferencing process. The children in this study were assessed yearly at the ages of 4, 5, and 6 years. Results: The participants with BiHAs, BiCIs, and TH showed significant development in their social-pragmatic understanding between the ages of 4 and 6 years, but most children with hearing loss (HL) still did not meet age expectations at the age of 6 years. Children with BiHAs and BiCIs both showed large-scale inferential difficulties, including utilizing theory of mind, utilizing verbal and visual information, and understanding conversational norms and emotions in context. Conclusions: Children with BiHAs and BiCIs are at risk of delays in social-pragmatic understanding despite early detection of HL, early amplification, and cochlear implantation. Therefore, the social-pragmatic abilities of children with HL should be assessed regularly, and the children with HL should have early access to social-pragmatic interventions where utilizing contextual information is practiced comprehensively.

Abstract Background The neurological effects of the coronavirus disease of 2019 (COVID-19) raise concerns about potential long-term consequences, such as an increased risk of Alzheimer's disease (AD). Neuroinflammation and other AD-associated pathologies are also suggested to increase the risk of serious SARS-CoV-2 infection. Anosmia is a common neurological symptom reported in COVID-19 and in early AD. The olfactory mucosa (OM) is important for the perception of smell and a proposed site of viral entry to the brain. However, little is known about SARS-CoV-2 infection at the OM of individuals with AD. Methods To address this gap, we established a 3D in vitro model of the OM from primary cells derived from cognitively healthy and AD individuals. We cultured the cells at the air–liquid interface (ALI) to study SARS-CoV-2 infection under controlled experimental conditions. Primary OM cells in ALI expressed angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), and several other known SARS-CoV-2 receptor and were highly vulnerable to infection. Infection was determined by secreted viral RNA content and confirmed with SARS-CoV-2 nucleocapsid protein (NP) in the infected cells by immunocytochemistry. Differential responses of healthy and AD individuals-derived OM cells to SARS-CoV-2 were determined by RNA sequencing. Results Results indicate that cells derived from cognitively healthy donors and individuals with AD do not differ in susceptibility to infection with the wild-type SARS-CoV-2 virus. However, transcriptomic signatures in cells from individuals with AD are highly distinct. Specifically, the cells from AD patients that were infected with the virus showed increased levels of oxidative stress, desensitized inflammation and immune responses, and alterations to genes associated with olfaction. These results imply that individuals with AD may be at a greater risk of experiencing severe outcomes from the infection, potentially driven by pre-existing neuroinflammation. Conclusions The study sheds light on the interplay between AD pathology and SARS-CoV-2 infection. Altered transcriptomic signatures in AD cells may contribute to unique symptoms and a more severe disease course, with a notable involvement of neuroinflammation. Furthermore, the research emphasizes the need for targeted interventions to enhance outcomes for AD patients with viral infection. The study is crucial to better comprehend the relationship between AD, COVID-19, and anosmia. It highlights the importance of ongoing research to develop more effective treatments for those at high risk of severe SARS-CoV-2 infection. Graphical Abstract

Introduction: We examined whether autonomic nervous system (ANS) and postural control regulation during orthostatic test reflect physical resilience by studying their associations with maximal walking speed and mortality. Methods: The participants were community-dwelling Finnish men (n = 303) and women (n = 386) aged 75, 80, and 85 years at baseline. Systolic and diastolic blood pressure (BP), heart rate, heart rate variability (HRV), respiratory rate, and postural sway were obtained using a digital sphygmomanometer, a single-channel ECG, and thigh- and chest-worn accelerometers. Linear and Cox regression models were used to estimate the associations of the physiological indices with maximal 10-m walking speed and 5-year mortality separately for sexes. Results: Better maintenance of BP under orthostatic stress was associated with faster walking speed in women and lower mortality hazard in men. Greater HRV in terms of low frequency power and lower respiration rate in supine position and smaller orthostatic changes in these were associated with faster walking speed especially in women. Less postural sway after standing up was associated with faster walking speed in women (−0.057, SE 0.022, p = 0.011) and more postural sway with increased mortality hazard in men (HR 1.71, 95 % CI 1.20–2.43) even after controlling for BP responses. Conclusions: In addition to ANS regulation at rest and under stress, adaptation of postural control system to orthostasis may be used in quantifying older adults' physical resilience. Wearable sensors capturing stimulus-response patterns and natural fluctuations of body functions may provide opportunities to monitor and incorporate different subsystems' resilience also in free-living conditions.

Abstract Background Successful ageing is the term often used for depicting exceptional ageing but a uniform definition is lacking. The aim was to re-examine and describe the successful agers living at home at the age of 84 years or over after a 20-year follow-up. The purpose was also to identify possible factors leading to their successful ageing. Methods Successful ageing was defined as the ability to live at home without daily care. Data on the participants’ functional ability, objective health, self-rated health and satisfaction with life were gathered at baseline and after a 20-year follow-up period. A measurement of personal biological age (PBA) was established and the difference between the PBA and the chronological age (CA) was counted. Results The participants’ mean age was 87.6 years (Standard deviation 2.5, range 84–96). All analyzed variables depicted poorer physical ability and subjective health at re-examination than at baseline. Still, 99% of the participants were at least moderately satisfied with their lives. The PBA at baseline was 6.5 years younger than CA, and at re-examination, the difference was even more pronounced at 10.5 years. Discussion Even though the participants were chronologically older, had poorer physical ability and subjective health, they were still satisfied with their lives indicating possible psychological resilience. The difference between the PBA and CA was greater at re-examination than at baseline indicating that they were also biologically successful agers. Conclusions Successful agers were satisfied with life despite hardships and had a lower biological than chronological age. Further research is needed to evaluate causality.

Abstract Background Various indexes have been developed to estimate the risk for mortality, institutionalization, and other adverse outcomes for older people. Most indexes are based on a large number of clinical or laboratory parameters. An index based on only a few parameters would be more practical to use in every-day clinical practice. Our aim was to create an index to predict the risk for mortality and institutionalization with as few parameters as possible without compromising their predictive ability. Methods A prospective study with a 10-year follow-up period. Thirty-six clinical and fourteen laboratory parameters were combined to form an index. Cox regression model was used to analyze the association of the index with institutionalization and mortality. A backward statistical method was used to reduce the number of parameters to form an easy-to-use index for predicting institutionalization and mortality. Results The mean age of the participants (n = 1172) was 73.1 (SD 6.6, range 64‒97) years. Altogether, 149 (14%) subjects were institutionalized, and 413 (35%) subjects deceased during the follow-up. Institutionalization and mortality rates increased as index scores increased both for the large 50-parameter combined index and for the reduced indexes. After a backward variable selection in the Cox regression model, three clinical parameters remained in the index to predict institutionalization and six clinical and three laboratory parameters in the index to predict mortality. The reduced indexes showed a slightly better predictive value for both institutionalization and mortality compared to the full index. Conclusions A large index with fifty parameters included many unimportant parameters that did not increase its predictive value, and therefore could be replaced with a reduced index with only a few carefully chosen parameters, that were individually associated with institutionalization or death.

IntroductionThere is limited understanding of how older adults can reach kinematic goals in rehabilitation while performing exergames and conventional exercises, and how similar or different the kinematics during exergaming are when compared with conventional therapeutic exercise with similar movement. The aim of this study was to describe the movement characteristics performed during exercise in custom-designed exergames and conventional therapeutic exercises among patients who have undergone unilateral total knee replacement (TKR). In addition, the secondary aim was to assess the relation of these exercise methods, and to assess participants' perceived exertion and knee pain during exergaming and exercising.Materials and methodsPatients up to 4 months after the TKR surgery were invited in a single-visit exercise laboratory session. A 2D motion analysis and force plates were employed to evaluate movement characteristics as the volume, range, and intensity of movement performed during custom-designed knee extension-flexion and weight shifting exergames and conventional therapeutic exercises post TKR. The perceived exertion and knee pain were assessed using the Borg Rating of Perceived Exertion and Visual Analog Scale, respectively.ResultsEvaluation of seven patients with TKR [age median (IQR), 65 (10) years] revealed that the volume and intensity of movement were mostly higher during exergames. Individual goniometer-measured knee range of motion were achieved either with exergames and conventional therapeutic exercises, especially in knee extension exercises. The perceived exertion and knee pain were similar after exergames and conventional therapeutic exercises.ConclusionsDuring custom-designed exergaming the patients with TKR achieve the movement characteristics appropriate for post-TKR rehabilitation without increasing the stress and pain experienced even though the movement characteristics might be partly different from conventional therapeutic exercises by the volume and intensity of movement. Physical therapists could consider implementing such exergames in rehabilitation practice for patients with TKR once effectiveness have been approved and they are widely available.

Abstract Background Objective health measures, such as registered illnesses or frailty, predict mortality and institutionalization in older adults. Also, self-reported assessment of health by simple self-rated health (SRH) has been shown to predict mortality and institutionalization. The aim of this study was to assess the association of objective and subjective health with mortality and institutionalization in Finnish community-dwelling older adults. Methods In this prospective study with 10- and 18-year follow-ups, objective health was measured by registered illnesses and subjective health was evaluated by simple SRH, self-reported walking ability (400 m) and self-reported satisfaction in life. The participants were categorized into four groups according to their objective and subjective health: 1. subjectively and objectively healthy, 2. subjectively healthy and objectively unhealthy, 3. subjectively unhealthy and objectively healthy and 4. subjectively and objectively unhealthy. Cox regression model was used in the analyses. Death was used as a competing factor in the institutionalization analyses. Results The mean age of the participants (n = 1259) was 73.5 years (range 64.0–100.0). During the 10- and 18-year follow-ups, 466 (37%) and 877 (70%) died, respectively. In the institutionalization analyses (n = 1106), 162 (15%) and 328 (30%) participants were institutionalized during the 10- and 18-year follow-ups, respectively. In both follow-ups, being subjectively and objectively unhealthy, compared to being subjectively and objectively healthy, was significantly associated with a higher risk of institutionalization in unadjusted models and with death both in unadjusted and adjusted models. Conclusions The categorization of objective and subjective health into four health groups was good at predicting the risk of death during 10- and 18-year follow-ups, and seemed to also predict the risk of institutionalization in the unadjusted models during both follow-ups. Poor subjective health had an additive effect on poor objective health in predicting mortality and could therefore be used as part of an older individual’s health evaluation when screening for future adverse outcomes.

Clozapine (CZP) is the only effective drug in schizophrenia resistant to typical antipsychotics. However, existing dosage forms (oral or orodispersible tablets, suspensions or intramuscular injection) show challenging limitations. After oral administration, CZP has low bioavailability due to a large first-pass effect, while the i.m. route is often painful, with low patient compliance and requiring specialised personnel. Moreover, CZP has a very low aqueous solubility. This study proposes the intranasal route as an alternative route of administration for CZP, through its encapsulation in polymeric nanoparticles (NPs) based on Eudragit® RS100 and RL100 copolymers. Slow-release polymeric NPs with dimensions around 400–500 nm were formulated to reside and release CZP in the nasal cavity, where it can be absorbed through the nasal mucosa and reach the systemic circulation. CZP-EUD-NPs showed a controlled release of CZP for up to 8 h. Furthermore, to reduce mucociliary clearance and increase the residence time of NPs in the nasal cavity to improve drug bioavailability, mucoadhesive NPs were formulated. This study shows that the NPs already exhibited strong electrostatic interactions with mucin at time zero due to the presence of the positive charge of the used copolymers. Furthermore, to improve the solubility, diffusion and adsorption of CZPs and the storage stability of the formulation, it was lyophilised using 5% (w/v) HP-β-CD as a cryoprotectant. It ensured the preservation of the NPs’ size, PDI and charge upon reconstitution. Moreover, physicochemical characterisation studies of solid-state NPs were performed. Finally, toxicity studies were performed in vitro on MDCKII cells and primary human olfactory mucosa cells and in vivo on the nasal mucosa of CD-1 mice. The latter showed non-toxicity of B-EUD-NPs and mild CZP-EUD-NP-induced tissue abnormalities.

Purpose: Habitual strength and power-demanding activities of daily life may support the maintenance of adequate lower extremity functioning with aging, but this has been sparingly explored. Hence, we examined whether the characteristics of free-living sit-to-stand (STS) transitions predict a decline in lower extremity functioning over a 4-yr follow-up. Methods: A total of 340 community-dwelling older adults (60% women; age 75, 80, or 85 yr) participated in this prospective cohort study. At baseline, a thigh-worn accelerometer was used continuously (3-7 d) to monitor the number and intensity of free-living STS transitions. A decline in lower extremity functioning was defined as a drop of ≥2 points in the Short Physical Performance Battery (SPPB) from baseline to follow-up. Maximal isometric knee extension strength was measured in the laboratory. Results: Eighty-five participants (75%women) declined in SPPB over 4 yr. After adjusting for age, sex, and baseline SPPB points, higher free-living peak STS angular velocity (odds ratio (OR), 0.70; 95% confidence interval (CI), 0.52-0.92, per 20°⋅s-1 increase) protected against a future decline. When adjusting the model for maximal isometric knee extension strength, the statistical significance was attenuated (OR = 0.72; 95% CI = 0.54-0.96, per 20°⋅s-1 increase). Conclusions: Performing STS transitions at higher velocities in the free-living environment can prevent a future decline in lower extremity function. This indicates that changes in daily STS behavior may be useful in the early identification of functional loss. Free-living peak STS angular velocity may be a factor underlying the longitudinal association of lower extremity strength and performance. [ABSTRACT FROM AUTHOR]

Abstract Background Previously, several indexes based on a large number of clinical and laboratory tests to predict mortality and frailty have been produced. However, there is still a need for an easily applicable screening tool for every-day clinical practice. Methods A prospective study with 10- and 18-year follow-ups. Fourteen common laboratory tests were combined to an index. Cox regression model was used to analyse the association of the laboratory index with institutionalization and mortality. Results The mean age of the participants (n = 1153) was 73.6 (SD 6.8, range 64.0–100.0) years. Altogether, 151 (14.8%) and 305 (29.9%) subjects were institutionalized and 422 (36.6%) and 806 (69.9%) subjects deceased during the 10- and 18-year follow-ups, respectively. Higher LI (laboratory index) scores predicted increased mortality. Mortality rates increased as LI scores increased both in unadjusted and in age- and gender-adjusted models during both follow-ups. The LI did not significantly predict institutionalization either during the 10- or 18-year follow-ups. Conclusions A practical index based on routine laboratory tests can be used to predict mortality among older people. An LI could be automatically counted from routine laboratory results and thus an easily applicable screening instrument in clinical settings.

An early symptom of Alzheimer’s disease (AD) is an impaired sense of smell, for which the molecular basis remains elusive. Here, we generated human olfactory neurosphere-derived (ONS) cells from people with AD and mild cognitive impairment (MCI), and performed global RNA sequencing to determine gene expression changes. ONS cells expressed markers of neuroglial differentiation, providing a unique cellular model to explore changes of early AD-associated pathways. Our transcriptomics data from ONS cells revealed differentially expressed genes (DEGs) associated with cognitive processes in AD cells compared to MCI, or matched healthy controls (HC). A-Kinase Anchoring Protein 6 (AKAP6) was the most significantly altered gene in AD compared to both MCI and HC, and has been linked to cognitive function. The greatest change in gene expression of all DEGs occurred between AD and MCI. Gene pathway analysis revealed defects in multiple cellular processes with aging, intellectual deficiency and alternative splicing being the most significantly dysregulated in AD ONS cells. Our results demonstrate that ONS cells can provide a cellular model for AD that recapitulates disease-associated differences. We have revealed potential novel genes, including AKAP6 that may have a role in AD, particularly MCI to AD transition, and should be further examined.

Abstract Background and aims Children with extremely low‐birth weight (ELBW) have a high risk for cognitive, motor, and attention impairments and learning disabilities. Longitudinal follow‐up studies to a later age are needed in order to increase understanding of the changes in neurodevelopmental trajectories in targeting timely intervention. The aims of this study were to investigate cognitive and motor outcomes, attention‐deficit hyperactivity (ADHD) behaviour, school performance, and overall outcomes in a national cohort of ELBW children at preadolescence, and minor neuromotor impairments in a subpopulation of these children and to compare the results with those of full‐term controls. The additional aim was to report the overall outcome in all ELBW infants born at 22 to 26 gestational weeks. Methods This longitudinal prospective national cohort study included all surviving ELBW (birth weight

Olfaction is orchestrated by olfactory mucosal cells located in the upper nasal cavity. Olfactory dysfunction manifests early in several neurodegenerative disorders including Alzheimer’s disease, however, disease-related alterations to the olfactory mucosal cells remain poorly described. The aim of this study was to evaluate the olfactory mucosa differences between cognitively healthy individuals and Alzheimer’s disease patients. We report increased amyloid-beta secretion in Alzheimer’s disease olfactory mucosal cells and detail cell-type-specific gene expression patterns, unveiling 240 differentially expressed disease-associated genes compared to the cognitively healthy controls, and five distinct cell populations. Overall, alterations of RNA and protein metabolism, inflammatory processes, and signal transduction were observed in multiple cell populations, suggesting their role in Alzheimer’s disease-related olfactory mucosa pathophysiology. Furthermore, the single-cell RNA-sequencing proposed alterations in gene expression of mitochondrially located genes in AD OM cells, which were verified by functional assays, demonstrating altered mitochondrial respiration and a reduction of ATP production. Our results reveal disease-related changes of olfactory mucosal cells in Alzheimer’s disease and demonstrate the utility of single-cell RNA sequencing data for investigating molecular and cellular mechanisms associated with the disease.