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Purpose To investigate in vivo viscoelastic parameters related to early histopathological changes in the hippocampus and the cortex in early, preclinical Alzheimer's disease (AD) stages. Materials and Methods Magnetic resonance elastography (MRE) was applied to female APP23 mice, an established transgenic mouse model of AD, at three different stages early in disease progression. To investigate the potential therapeutic effects of physical, cognitive, and social stimulation on brain viscoelasticity and histopathological characteristics, MRE was also applied after exposing young APP23 mice to environmentally enriched cage conditions (ENR), for 1, 12, or 24 weeks, which corresponds to adolescent, young-adult, and adult age at the time of analysis. Results Viscosity in the hippocampus of APP23 mice is lower than in controls (CTR) (P = 0.005) and does not increase with age, as in CTR mice (adolescent vs. young-adult: P = 1.000, vs. adult: P = 0.493, young-adult vs. adult: P = 1.000). Hippocampal cell numbers decrease with disease progression in APP23 mice (P < 0.001). Elasticity in the hippocampus is also reduced in APP23 mice (P = 0.024) but increases (P = 0.027) with disease progression. ENR in APP23 mice transiently increased hippocampal cell numbers (P = 0.002) but not viscosity (P = 0.838). Conclusion MRE detects alterations in viscoelasticity in the hippocampus related to early histopathological changes in the APP23 mouse model of AD. Level of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:105–114.

Background Surgical site infection (SSI) affects up to 20% of people with a primary closed wound after surgery. Wound dressings may reduce SSI. Objective To assess the feasibility of a multicentre randomised controlled trial (RCT) to evaluate the effectiveness and cost-effectiveness of dressing types or no dressing to reduce SSI in primary surgical wounds. Design Phase A – semistructured interviews, outcome measure development, practice survey, literature reviews and value-of-information analysis. Phase B – pilot RCT with qualitative research and questionnaire validation. Patients and the public were involved. Setting Usual NHS care. Participants Patients undergoing elective/non-elective abdominal surgery, including caesarean section. Interventions Phase A – none. Phase B – simple dressing, glue-as-a-dressing (tissue adhesive) or ‘no dressing’. Main outcome measures Phase A – pilot RCT design; SSI, patient experience and wound management questionnaires; dressing practices; and value-of-information of a RCT. Phase B – participants screened, proportions consented/randomised; acceptability of interventions; adherence; retention; validity and reliability of SSI measure; and cost drivers. Data sources Phase A – interviews with patients and health-care professionals (HCPs), narrative data from published RCTs and data about dressing practices. Phase B – participants and HCPs in five hospitals. Results Phase A – we interviewed 102 participants. HCPs interpreted ‘dressing’ variably and reported using available products. HCPs suggested practical/clinical reasons for dressing use, acknowledged the weak evidence base and felt that a RCT including a ‘no dressing’ group was acceptable. A survey showed that 68% of 1769 wounds (727 participants) had simple dressings and 27% had glue-as-a-dressing. Dressings were used similarly in elective and non-elective surgery. The SSI questionnaire was developed from a content analysis of existing SSI tools and interviews, yielding 19 domains and 16 items. A main RCT would be valuable to the NHS at a willingness to pay of £20,000 per quality-adjusted life-year. Phase B – from 4 March 2016 to 30 November 2016, we approached 862 patients for the pilot RCT; 81.1% were eligible, 59.4% consented and 394 were randomised (simple, n = 133; glue, n = 129; no dressing, n = 132); non-adherence was 3 out of 133, 8 out of 129 and 20 out of 132, respectively. SSI occurred in 51 out of 281 participants. We interviewed 55 participants. All dressing strategies were acceptable to stakeholders, with no indication that adherence was problematic. Adherence aids and patients’ understanding of their allocated dressing appeared to be key. The SSI questionnaire response rate overall was 67.2%. Items in the SSI questionnaire fitted a single scale, which had good reliability (test–retest and Cronbach’s alpha of > 0.7) and diagnostic accuracy (c-statistic = 0.906). The key cost drivers were hospital appointments, dressings and redressings, use of new medicines and primary care appointments. Limitations Multiple activities, often in parallel, were challenging to co-ordinate. An amendment took 4 months, restricting recruitment to the pilot RCT. Only 67% of participants completed the SSI questionnaire. We could not implement photography in theatres. Conclusions A main RCT of dressing strategies is feasible and would be valuable to the NHS. The SSI questionnaire is sufficiently accurate to be used as the primary outcome. A main trial with three groups (as in the pilot) would be valuable to the NHS, using a primary outcome of SSI at discharge and patient-reported SSI symptoms at 4–8 weeks. Trial registration Phase A – Current Controlled Trials ISRCTN06792113; Phase B – Current Controlled Trials ISRCTN49328913. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 39. See the NIHR Journals Library website for further project information. Funding was also provided by the Medical Research Council ConDuCT-II Hub (reference number MR/K025643/1).

In the course of CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a dysregulated adult hippocampal neurogenesis has been suggested as a potential mechanism for early cognitive decline. Previous work has shown that mice overexpressing wild type Notch3 and mice overexpressing Notch3 with a CADASIL mutation display impaired cell proliferation and survival of newly born hippocampal neurons prior to vascular abnormalities. Here, we aimed to elucidate how the long-term survival of these newly generated neurons is regulated by Notch3. Knowing that adult neurogenesis can be robustly stimulated by physical exercise and environmental enrichment, we also investigated the influence of such stimuli as potential therapeutic instruments for a dysregulated hippocampal neurogenesis in the CADASIL mouse model. Therefore, young-adult female mice were housed in standard (STD), environmentally enriched (ENR) or running wheel cages (RUN) for either 28 days or 6 months. Mice overexpressing mutated Notch3 and developing CADASIL (TgN3R169C), and mice overexpressing wild type Notch3 (TgN3WT) were used. We found that neurogenic stimulation by RUN and ENR is apparently impaired in both transgenic lines. The finding suggests that a disturbed neurogenic process due to Notch3-dependent micromilieu changes might be one vascular-independent mechanism contributing to cognitive decline observed in CADASIL.

The biomechanical properties of brain tissue are altered by histopathological changes due to neurodegenerative diseases like Parkinson's disease (PD). Such alterations can be measured by magnetic resonance elastography (MRE) as a non- invasive technique to determine viscoelastic parameters of the brain. Until now, the correlation between histopathological mechanisms and observed alterations in tissue viscoelasticity in neurodegenerative diseases is still not completely understood. Thus, the objective of this study was to evaluate (1) the validity of MRE to detect viscoelastic changes in small and specific brain regions: the substantia nigra (SN), midbrain and hippocampus in a mouse model of PD, and (2) if the induced dopaminergic neurodegeneration and inflammation in the SN is reflected by local changes in viscoelasticity. Therefore, MRE measurements of the SN, midbrain and hippocampus were performed in adult female mice before and at five time points after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin hydrochloride (MPTP) treatment specifically lesioning dopaminergic neurons in the SN. At each time point, additional mice were utilized for histological analysis of the SN. After treatment cessation, we observed opposed viscoelastic changes in the midbrain, hippocampus and SN with the midbrain showing a gradual rise and the hippocampus a distinct transient increase of viscous and elastic parameters, while viscosity and–to a lesser extent—elasticity in the SN decreased over time. The decrease in viscosity and elasticity in the SN was paralleled by a reduced number of neurons due to the MPTP-induced neurodegeneration. In conclusion, MRE is highly sensitive to detect local viscoelastic changes in specific and even small brain regions. Moreover, we confirmed that neuronal cells likely constitute the backbone of the adult brain mainly accounting for its viscoelasticity. Therefore, MRE could be established as a new potential instrument for clinical evaluation and diagnostics of neurodegenerative diseases.