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Background and purpose — Radiostereometric analysis (RSA) is the gold standard to study micromotion of joint replacements. RSA requires the acquisition of additional radiographs increasing the radiation dose of patients included in RSA studies. It is important to keep this dose as low as possible. Effective radiation dose (ED) measurements of RSA radiographs for different joints were done by Teeuwisse et al. some years ago using conventional radiology (CR); for total hip arthroplasty (THA), Teeuwisse et al. reported an ED of 0.150 milliSievert (mSv). With the modern digital radiography (DR) roentgen technique the ED is expected to be less. Material and methods — In this phantom study, simulating a standard patient, the ED for hip RSA radiographs is determined using DR under a variety of different roentgen techniques. The quality of the RSA radiographs was assessed for feasibility in migration analysis using a (semi-)automatic RSA analysis technique in RSA software. Results — A roentgen technique of 90 kV and 12.5 mAs with additional 0.2 copper (Cu) + 1 mm aluminum (Al) external tube filters results in an ED of 0.043 mSv and radiographs suitable for analysis in RSA software. Interpretation — The accumulated ED for a standard patient in a 2-year clinical hip RSA study with 5 follow-up moments and a double acquisition is below the acceptable threshold of 1.0 mSv provided by the EU radiation guideline for studies increasing knowledge for general health. [ABSTRACT FROM AUTHOR]

Immune-mediated platelet refractoriness (PR) remains a significant problem in the setting of platelet transfusion and is predominantly caused by the presence of alloantibodies directed against class I human leukocyte antigens (HLA). Opsonization of donor platelets with these alloantibodies can result in rapid clearance after transfusion via multiple mechanisms, including antibody dependent cellular phagocytosis (ADCP). Interestingly, not all alloimmunized patients develop PR to unmatched platelet transfusions, suggesting variation in HLA-specific IgG responses between patients. Previously, we observed that the glycosylation profile of anti-HLA antibodies was highly variable between PR patients, especially with respect to Fc galactosylation, sialylation and fucosylation. In the current study, we investigated the effect of different Fc glycosylation patterns, with known effects on complement deposition and FcyR binding, on phagocytosis of opsonized platelets by monocyte-derived human macrophages. We found that the phagocytosis of antibody- and complement-opsonized platelets, by monocyte derived M1 macrophages, was unaffected by these qualitative IgG-glycan differences. [ABSTRACT FROM AUTHOR]

Currently available European Alpine Altitude Climate Treatment (AACT) programs combine the physical characteristics of altitude with the avoidance of environmental triggers in the alpine climate and a personalized multidisciplinary pulmonary rehabilitation approach. The reduced barometric pressure, oxygen pressure, and air density, the relatively low temperature and humidity, and the increased UV radiation at moderate altitude induce several physiological and immunological adaptation responses. The environmental characteristics of the alpine climate include reduced aeroallergens such as house dust mites (HDM), pollen, fungi, and less air pollution. These combined factors seem to have immunomodulatory effects controlling pathogenic inflammatory responses and favoring less neuro‐immune stress in patients with different asthma phenotypes. The extensive multidisciplinary treatment program may further contribute to the observed clinical improvement by AACT in asthma control and quality of life, fewer exacerbations and hospitalizations, reduced need for oral corticosteroids (OCS), improved lung function, decreased airway hyperresponsiveness (AHR), improved exercise tolerance, and improved sinonasal outcomes. Based on observational studies and expert opinion, AACT represents a valuable therapy for those patients irrespective of their asthma phenotype, who cannot achieve optimal control of their complex condition despite all the advances in medical science and treatment according to guidelines, and therefore run the risk of falling into a downward spiral of loss of physical and mental health. In the light of the observed rapid decrease in inflammation and immunomodulatory effects, AACT can be considered as a natural treatment that targets biological pathways. [ABSTRACT FROM AUTHOR]

The phase behavior of (A-comb-C)-b-(B-comb-C) diblock copolymer melts is investigated using the strong segregation theory approach. Three different regimes are distinguished. In regime 1 both disordered comb blocks are microphase separated from each other, in regime 2 the side chains C are microphase separated from the disordered A-b-B diblock backbones, and, finally, in regime 3 all species A, B, and C are microphase separated. In the first regime the behavior is similar to that of a simple diblock copolymer melt with a renormalized Flory-Huggins interaction parameter. In regime 2 the region of stability of the different phases is significantly changed compared to simple diblocks due to the comb architecture. The fully microphase separated case, regime 3, is characterized by hierarchical structure formation. We restrict the analysis to systems where selfassembly results in the formation of alternating C layers and internally microphase separated A B layers. The latter consist of alternating A and B layers or disks of the minority component. In the former case, the A and B layers are generally perpendicular to the C layers. The parallel orientation is only possible for small grafting densities. [ABSTRACT FROM AUTHOR]

We report on the crystallization of poly(lactic acid) (PLA) films in the presence of a sorbitol-based nucleating agent; 1,2,3-tridesoxy-4,6:5,7-bis-O-[(4-propylphenyl) methylene]-nonitol (TBPMN). Dispersion of the nucleating agent was performed by solution-mixing and melt-blending. Crystallization behavior was studied by differential scanning calorimetry (DSC). The structure and morphology were characterized by wide-angle X-ray scattering (WAXS), optical imaging, and atomic force microscopy (AFM). A significant impact of the nucleating agent was observed at or above a threshold concentration of 2 wt%, which was assigned to the solubility limit of TBPMN. The degree of crystallinity reached up to 39.6 % with 2 wt% TBPMN. An influence of the dispersion method was observed on the peak temperature of crystallization (T cp). While T cp decreased slightly for solution-mixed films, a sigmoidal trend was noted for melt-blended samples. Under isothermal conditions at 100 °C, the crystallization half-time was lowered from 6.5 min to 1.0 min. Avrami analysis pointed to the formation of 2-dimensional or 3-dimensional crystalline domains; WAXS data revealed α- and α' -crystals, depending on the dispersing method. AFM imaging showed a nanosized fibrillar network of the nucleator within the PLA matrix, demonstrating that TBPMN acted as a soluble self-assembly nucleator. • The crystallization of polylactic acid films in the presence of a sorbitol-based nucleating agent is reported. • Dispersion of the nucleating agent was performed by solution-mixing and melt-blending. • Under isothermal conditions at 100 °C, the crystallization half-time was lowered from 6.5 min to 1.0 min. • AFM imaging showed a nanosized fibrillar network of the nucleator within the PLA matrix. • TBPMN (the sorbitol-based nucleator) acted as a soluble self-assembly nucleator. [ABSTRACT FROM AUTHOR]

Background. As initiators of the adaptive immune response, dendritic cells (DCs) can be used for anti-cancer immunotherapy. On addition of proper maturation stimuli DCs mature and produce pro-inflammatory cytokines that skew T cells in the direction needed for anti-cancer therapy. Further optimization of DC maturation might improve the efficacy of DCs for clinical application. We describe that replating and a subsequent resting period enhance the inflammatory properties of the DCs. Methods. Cultured immature monocyte-derived DCs were harvested and, after replating, were stimulated immediately or after 2 h of rest. Cytokine production was assessed using enzyme-linked immunosorbent assay (ELISA). Dynamics of mitogen-activated protein kinase (MAPK) and nuclear factor kappa b (NFκB) activation in DCs was analyzed using flow cytometry and imaging flow cytometry. Results Resting immature DCs after replating, before addition of Toll-like receptor (TLR) ligands, increased the production of pro-inflammatory but not anti-inflammatory cytokines. In addition, the speed of MAPK phosphorylation and nuclear translocation of NFκB was increased when DCs were allowed to rest before TLR stimulation. The effect was imprinted, transient and did not reflect a temporary loss of responsiveness, indicating that signaling induced by culture adaptation of DCs synergizes with TLR signals to increase cytokine production. DCs rested before TLR stimulation induced more interferon (IFN)-γ production in CD4-positive and CD8-positive T cells. Conclusion Introduction of a resting step in the DC maturation method, which is cheap and easy to implement, will improve the generation of pro-inflammatory DCs for cancer immunotherapy. These DCs enhanced Th1 polarization and IFN-γ production by CD8 T cells, both important hallmarks for the induction of efficient anti-cancer immunity. [ABSTRACT FROM AUTHOR]

Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder resulting from the development of autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). HLA-DRB1*11 provides a risk factor for developing acquired TTP. Pulsing of antigen-presenting cells from HLA-DRB1*11- and HLA-DRB1*03-positive individuals with ADAMTS13 resulted in presentation of peptides derived from the CUB2 domain of ADAMTS13 with core sequences FINVAPHAR or ASYILIRD. Here, we assessed whether FINVAPHAR- or ASYILIRD-reactive CD4+ T cells are present in peripheral blood mononuclear cells from HLA-DRB1*11 and HLA-DRB1*03-positive subjects with acquired TTP. The presence of ADAMTS13-reactive CD4+ T cells was addressed by flow cytometry and the expression of activation marker CD40 ligand by CD4+ T cells. FINVAPHAR-reactive CD4+ T cells were identified in an HLA-DRB1*11-positive patient during the acute phase of the disease whereas ASYILIRD-positive CD4+ T cells were identified in a DRB1*03-positive patient with acquired TTP. Frequencies of CUB2 domain-reactive CD4+ T cells ranged from 3.3% to 4.5%. Control peptides in which the anchor residues were modified did not induce activation of CD4+ T cells. Taken together, our data provide evidence for the involvement of CUB2 domain-reactive CD4+ T cells in the etiology of acquired TTP. [ABSTRACT FROM AUTHOR]

After the resolution of the acute phase of infection, otherwise quiescent antigen-experienced CD8+ T cells confer rapid protection upon reinfection with viral pathogens or, in the case of persistent viruses, help to maintain control of the infection. Depending on the type of virus, antigen-specific CD8+ T cells have distinct traits, ranging from typical memory cell properties in the case of rapidly cleared viruses to immediate effector functions for persistent viruses. We here show that both the differentiation stage, defined by the expression of cell surface markers, such as CD45RA, CCR7, CD28, and CD27, and distinct expression levels of T-bet and eomesodermin (Eomes) predict the functional profile of antigen-experienced CD8+ T cells. Furthermore, virusspecific CD8+ T cells targeting different respiratory syncytial virus-, influenza A virus-, Epstein-Barr virus (EBV)-, human cytomegalovirus (hCMV)-, and HIV-1-specific epitopes adopt distinct T-bet and Eomes expression patterns that appear to be installed early during the primary response. Importantly, the associations between surface phenotype, T-bet/Eomes expression levels, and the expression of markers that predict CD8+ T-cell function change according to viral infection history, particularly against the background of HIV-1 and, to lesser extent, of human cytomegalovirus and/or Epstein-Barr virus infection. Thus, the functionality of human antigen-experienced CD8+ T cells follows at least two dimensions, one outlined by the surface phenotype and another by the T-bet/Eomes expression levels, which are determined by previous or persistent viral challenges. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (hCMV) infection is characterized by a vast expansion of resting effector-type virus-specific T cells in the circulation. In mice, interleukin-7 receptor α (IL-7Rα)-expressing cells contain the precursors for long-lived antigen-experienced CD8+ T cells, but it is unclear if similar mechanisms operate to maintain these pools in humans. Here, we studied whether IL-7Rα-expressing cells obtained from peripheral blood (PB) or lymph nodes (LNs) sustain the circulating effector-type hCMVspecific pool. Using flow cytometry and functional assays, we found that the IL-7Rα+ hCMV-specific T cell population comprises cells that have a memory phenotype and lack effector features. We used next-generation sequencing of the T cell receptor to compare the clonal repertoires of IL-7Rα+ and IL-7Rα- subsets. We observed limited overlap of clones between these subsets during acute infection and after 1 year. When we compared the hCMV-specific repertoire between PB and paired LNs, we found many identical clones but also clones that were exclusively found in either compartment. New clones that were found in PB during antigenic recall were only rarely identical to the unique LN clones. Thus, although PB IL-7Rα-expressing and LN hCMV-specific CD8+ T cells show typical traits of memory-type cells, these populations do not seem to contain the precursors for the novel hCMV-specific CD8+ T cell pool during latency or upon antigen recall. IL-7Rα+ PB and LN hCMV-specific memory cells form separate virus-specific compartments, and precursors for these novel PB hCMV-specific CD8+ effector-type T cells are possibly located in other secondary lymphoid tissues or are being recruited from the naive CD8+ T cell pool. [ABSTRACT FROM AUTHOR]

Background aims. Ex vivo-generated monocyte-derived dendritic cells (DCs) matured with monophosphoryl lipid A (MPLA) and interferon-γ(IFN-γ) can be used as cancer immunotherapy. MPLA/IFN-γDCs induce Thl T cell responses and have migratory capacity. Different culture regimens have been used for generation of immunotherapeutic DCs, with varying results. In the present study, culture conditions for MPLA/IFN-γ-matured type I DCs were optimized for clinical application. Methods. DCs were generated from monocytes in the clinical grade culture media CellGro DC, AIM V or X-VIVO 15 in the absence or presence of 2% human serum (HS) and matured with the use of MPLAIFN-γ. DC yield and DC functionality were assessed. DC functionality was determined by means of analysis of cytokines in culture supernatant, migratory capacity, expression of co-stimulatory molecules, T cell stimulatory capacity of DCs and T helper cell (Th) polarization by the DCs. Results. DCs generated in the presence of 2% HS produced low amounts of pro-inflammatory cytokines and could not migrate irrespective of the medium used. In the absence of HS, MPLAIFN-γDCs generated in X-VIVO did not migrate either. MPLA/IFN-γDCs generated in AIM V have slightly lower capacity to induce Thl cells than do DCs generated in CellGro or X-VIVO. Conclusions. Addition of HS to different GMP culture media is detrimental for pro-inflammatory DC maturation and migration. In the absence of serum, CellGro is the most optimal medium tested for generation of migratory and Thl-inducing MPLA/IFN-γDCs for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Memory formation of activated CD8 T cells is the result of a specific combination of signals that promote long-term survival and inhibit differentiation into effector cells. Much is known about initial cues that drive memory formation, but it is poorly understood which signals are essential during the intermediate stages before terminal differentiation. NKG2D is an activating coreceptor on Ag-experienced CD8 T cells that promotes effector cell functions. Its role in memory formation is currently unknown. In this study, we show that NKG2D controls formation of CD8 memory T cells by promoting survival of precursor cells. We demonstrate that NKG2D enhances IL-15–mediated PI3K signaling of activated CD8 T cells, in a specific phase of memory cell commitment, after activation but before terminal differentiation. This signal is essential for the induction of prosurvival protein Mcl-1 and precursor cell survival. In vivo, NKG2D deficiency results in reduced memory cell formation and impaired protection against reinfection. Our findings show a new role for PI3K and the NKG2D/IL-15 axis in an underappreciated stage of effector to memory cell transition that is essential for the generation of antiviral immunity. Moreover, we provide novel insights how these receptors control both effector and memory T cell differentiation. [ABSTRACT FROM AUTHOR]

Autoantibodies directed against ADAMTS13 prohibit the processing of von Willebrand factor multimers, initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura (TTP). Recently, HLA-DRB1*11 has been identified as a risk factor for the development of acquired TTP. Here, we identified ADAMTS13-denved peptides presented on MHC class II alleles from 17 healthy donors. Dendritic cells from a panel of both HLA-DRB1*11-positive and -negative donors were pulsed with ADAMTS13, and the HLA-DR-presented peptide repertoire was analyzed by mass spectrometry. Interestingly, at low antigen concentrations, HLA-DRB1*11- or DRB1*03-positive donors presented a limited number of CUB2-derived peptides. Pulsing of dendritic cells using higher concentrations of ADAMTS13 resulted in the presentation of larger numbers of ADAMTS13-derived peptides by both HLA-DRB1*11-positive and -negative donors. Although the presented peptides were derived from several ADAMTS13 domains, inspection of the peptide profiles revealed that CUB2 domain- derived peptides were presented with a higher efficiency when compared with other peptides. Remarkably, dendritic cells from DRB1*11 donors pulsed with higher concentrations of ADAMTS13-present derivatives of a single CUB2-derived peptide. We hypothesize that functional presentation of CUB2-derived peptides on HLA-DRB1*11 contributes to the onset of acquired TTP by stimulating low-affinity, self-reactive CD4+ T cells. [ABSTRACT FROM AUTHOR]

Memory T cells form a highly specific defense layer against reinfection with previously encountered pathogens. In addition, memory T cells provide protection against pathogens that are similar, but not identical to the original infectious agent. This is because each T cell response harbors multiple clones with slightly different affinities, thereby creating T cell memory with a certain degree of diversity. Currently, the mechanisms that control size, diversity, and cross-reactivity of the memory T cell pool are incompletely defined. Previously, we established a role for apoptosis, mediated by the BH3-only protein Noxa, in controlling diversity of the effector T cell population. This function might positively or negatively impact T cell memory in terms of function, pool size, and cross-reactivity during recall responses. Therefore, we investigated the role of Noxa in T cell memory during acute and chronic infections. Upon influenza infection, Noxa-/- mice generate a memory compartment of increased size and clonal diversity. Reinfection resulted in an increased recall response, whereas cross-reactive responses were impaired. Chronic infection of Noxa-/- mice with mouse CMV resulted in enhanced memory cell inflation, but no obvious pathology. In contrast, in a model of continuous, high-level T cell activation, reduced apoptosis of activated T cells rapidly led to severe organ pathology and premature death in Noxa-deficient mice. These results establish Noxa as an important regulator of the number of memory cells formed during infection. Chronic immune activation in the absence of Noxa leads to excessive accumulation of primed cells, which may result in severe pathology. [ABSTRACT FROM AUTHOR]

Development of neutralizing Abs to blood coagulation factor VIM (FVIII) provides a major complication in hemophilia care. In this study we explored whether modulation of the uptake of FVIII by APCs can reduce its intrinsic immunogenicity. Endo-cytosis of FVIII by professional APCs is significantly blocked by mAb KM33, directed toward the C1 domain of FVIII. We created a C1 domain variant (FVIII-R2090A/K2092A/F2093A), which showed only minimal binding to KM33 and retained its activity as measured by chromo-genic assay. FVIII-R2090A/K2092A/F2093A displayed a strongly reduced internalization by human monocyte-derived dendritic cells and macrophages, as well as murine BM-derived dendritic cells. We subsequently investigated the ability of this variant to induce an immune response in FVIII-deficient mice. We show that mice treated with FVIII-R2090A/ K2092A/F2093A have significantly lower anti-FVIII Ab titers and FVIII-specific CD4+ T-cell responses compared with mice treated with wild-type FVIII. These data show that alanine substitutions at positions 2090, 2092, and 2093 reduce the immunogenicity of FVIII. According to our findings we hypothesize that FVIII variants displaying a reduced uptake by APCs provide a novel therapeutic approach to reduce inhibitor development in hemophilia A. [ABSTRACT FROM AUTHOR]

Apoptosis plays an essential role in the removal of activated CD8 T cells that are no longer required during or postinfection. The Bim-dependent intrinsic pathway of apoptosis removes effector CD8 T cells upon clearance of viral infection, which is driven by withdrawal of growth factors. Binding of Fas ligand to Fas mediates activation-induced T cell death in vitro and cooperates with Bim to eliminate CD8 T cells during chronic infection in vivo, but it is less clear how this pathway of apoptosis is initiated. In this study, we show that the costimulatory TNFR CD27 provides a dual trigger that can enhance survival of CD8 T cells, but also removal of activated CD8 T cells through Fas-driven apoptosis. Using in vitro stimulation assays of murine T cells with cognate peptide, we show that CD27 increases T cell survival after stimulation with low doses of Ag, whereas CD27 induces Fas-driven T cell apoptosis after stimulation with high doses of Ag. In vivo, the impact of constitutive CD70-driven stimulation on the accumulation of memory and effector CD8 T cells is limited by Fas-driven apoptosis. Furthermore, introduction of CD70 signaling during acute infection with influenza virus induces Fas-dependent elimination of influenza-specific CD8 T cells. These findings suggest that CD27 suppresses its costimulatory effects on T cell survival through activation of Fas-driven T cell apoptosis to maintain T cell homeostasis during infection. [ABSTRACT FROM AUTHOR]

The human lung T cell compartment contains many CD8⁺ T cells specific for respiratory viruses, suggesting that the lung is protected from recurring respiratory infections by a resident T cell pool. The entry site for respiratory viruses is the epithelium, in which a subset of lung CD8⁺ T cells expressing CD103 (αE integrin) resides. Here, we determined the specificity and function of CD103⁺CD8⁺ T cells in protecting human lung against viral infection. Mononuclear cells were isolated from human blood and lung resection samples. Variable numbers of CD103⁺CD8⁺ T cells were retrieved from the lung tissue. Interestingly, expression of CD103 was seen only in lung CD8⁺ T cells specific for influenza but not in those specific for EBV or CMV. CD103⁺ and influenza-reactive cells preferentially expressed NKG2A, an inhibitor of CD8⁺ T cell cytotoxic function. In contrast to CD103⁻CD8⁺ T cells, most CD103⁺CD8⁺ cells did not contain perforin or granzyme B. However, they could quickly upregulate these cytotoxic mediators when exposed to a type I IFN milieu or via contact with their specific antigen. This mechanism may provide a rapid and efficient response to influenza infection, without inducing cytotoxic damage to the delicate epithelial barrier. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of amphiphilic diblock copolypeptides consisting of poly(α-l-glutamic acid) (PLGA) and poly(γ-methyl-l-glutamate-ran-γ-stearyl-l-glutamate) with 30mol % of stearyl substituents (PMLGSLG) and their monolayer behavior at the air–water interface have been studied. PLGA-b-PMLGSLG was synthesized via a diblock copolymer precursor consisting of poly(γ-tert-butyl-l-glutamate) (PtBuLG) and PMLGSLG blocks, with the tert-butyl group as a mild acid-labile protecting group for the carboxylic acid. The polymerization conditions were found to influence the α-helix to β-sheet content ratio and can be tuned to significantly enhance the diblock copolypeptide helicity. Purely α-helical PtBuLG-b-PMLGSLG diblock copolymers were successfully prepared. After removal of the tert-butyl group, the study of the PLGA-b-PMLGSLG amphiphilic diblock copolymers in Langmuir monolayers and Langmuir–Blodgett films demonstrated the formation of a stable α-helical double-brush structure, with the helices tilted away from the substrate surface. These double-brush monolayers combine the unique properties arising from the unidirectionally aligned helix macrodipole and the liquid-like features of the side chain mantle of the PMLGSLG block. Such systems are promising for thin film applications requiring incorporation and orientation of bio- and optical molecules. [Copyright &y& Elsevier]

Abstract: Polypyrrole has been chemically synthesized on thin film nanostructures obtained from comb-shaped supramolecules of polystyrene-block-poly(4-vinyl pyridine) (PS-b-P4VP) hydrogen bonded with pentadecylphenol (PDP). PDP was washed from thin films of cylindrical and lamellar self-assembled comb-copolymer systems, which resulted in removal of the upper layers of microdomains, leaving single cylindrical and lamellar layers covering a substrate, with P4VP segregated at the bottom as well as at the free air interface. This P4VP was complexed with Cu2+ ions, after which chemical oxidation polymerization of pyrrole resulted in a thin polypyrrole layer covering the nanostructured block copolymer. The use of a catalytic amount of bipyrrole greatly improved the quality of the obtained product. The conductivity was measured to be ∼0.7Scm−1. [Copyright &y& Elsevier]

Reports on research which attempted to switch supermolecular polymeric materials with multiple length scales. Use of pentadecylphenol (PDP) and homopolymers such as P4VP; Use of diblock copolymers; Observations made with the use of optical microscopy; Implications of results.

Subtle changes in mobility exist among older adults with mild cognitive impairment (MCI). Life-space mobility defines the frequency and extent of movements in the environment, and lower life-space mobility is associated with adverse health outcomes and MCI. Currently, the underlying mechanism of this association is not well understood. This study examined the functional neural correlates of life-space mobility in community-dwelling older adults with MCI. We first conducted a cross-sectional investigation of the association between resting-state default mode network (DMN) and sensori-motor network (SMN) connectivity and life-space mobility (assessed by the Life-Space Assessment (LSA)) among 60 community-dwelling older adults with MCI using aggregated data from two studies – baseline data from a randomized controlled trial (n = 20) and baseline data from a 12-month prospective study (n = 40). Using data from the 12-month prospective study (n = 35), we then examined whether baseline internetwork connectivity predicts reduced life-space mobility over 12 months. The cross-sectional analysis showed higher DMN-SMN connectivity was associated with lower LSA scores after adjusting for baseline global cognitive function and baseline age (p < 0.01). A significant reduction in LSA scores was observed in the 35 participants of the 12-month prospective study (paired sample t -test mean change = −6.53, p = 0.01). Greater baseline DMN-SMN connectivity was associated with greater reduction in life-space mobility at 12 months (p = 0.04) after adjusting for baseline age, global cognitive function, and LSA score. Our findings suggest that lower and reduced life-space mobility in older adults with MCI may be due to altered functional architecture of the brain such that normal neuro-cognitive motor behaviours may be disrupted. [ABSTRACT FROM AUTHOR]