Chris Frost’s research while affiliated with London School of Hygiene and Tropical Medicine and other places

Introduction: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals. Methods: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. Sample sizes were computed for detecting a reduction of either absolute levels of AD-related pathology (amyloid, tau) or change over time in neurodegeneration (atrophy, hypometabolism, cognitive change). Results: Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 47[95 %CI 25,104], cortical PIB 49[28,99], CSF p-tau181 74[48,125]) for a four-year trial in presymptomatic individuals (CDR=0) to have 80 % power (5 % statistical significance) to detect a 25 % reduction in absolute levels of pathology, allowing 40 % dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50 % reduction in rate of change. Sample sizes ranged from 250 to 900 (examples hippocampal volume: 338[131,2096], cognitive composite: 326[157,1074]). MRI, FDG and cognitive outcomes had lower sample sizes when including indivduals with mild impairment (CDR=0.5 and 1) as well as presymptomatic individuals (CDR=0). Discussion: Despite the rarity of ADAD, presymptomatic clinical trials with feasible sample sizes given the number of cases appear possible.

Background Effective treatments are now available, which have demonstrated reductions in amyloid plaque burden while slowing cognitive decline in early symptomatic Alzheimer’s disease (AD). Intervening before onset of cognitive impairment could provide greater benefit, particularly for individuals who carry an autosomal dominant mutation known to cause AD. To better guide the design of upcoming prevention trials, reliable sample size estimates for detecting relevant reductions in pathology are needed. Method Longitudinal PIB PET and CSF biomarker data were obtained from the Dominantly Inherited Alzheimer Network Observation study (datafreeze 14, see Table). Participants were included in the analysis based on eligibility criteria from DIAN‐TU‐001: estimated years to expected onset (EYO) between ‐15 to +10 and global Clinical Dementia Rating (CDR) score between 0 and 1, inclusive. Sample size estimates were also obtained for trials with individuals having CDR = 0 only. Linear mixed‐effects models were used to estimate baseline values and rates of change in outcome measures for mutation carriers and non‐carriers. Outcomes included CSF biomarkers of amyloid and p‐tau 181 using three assays (INNOTEST, XMAP and Lumipulse) and Standardized Uptake Value Ratio (SUVR, cerebellar grey matter reference region) of PIB PET from six regions. We then used these estimates to compute sample size estimates to detect a 25% reduction in pathology by four years, assuming 5% significance, 80% power, and 40% dropout. Uncertainty in sample size estimates was quantified through bootstrapping. Result There were large differences between carriers and non‐carriers at baseline and the end of a four‐year study (Figure 1). Sample size estimates were consistently higher in scenarios involving only CDR = 0 carriers (Figure 2). For PIB PET cortical mean, 40[95%CI: 26,66] pariticpants per arm would be needed to detect a 25% reduction and (63[40,115] for the CDR = 0 subsample. Similar estimates were observed for individual brain regions. XMAP Aβ42 (CDR 0‐1: 21, [11,65], CDR 0: 51 [21,333]) and Lumipulse Aβ42‐40 ratio (CDR 0‐1: 22 [13,46], CDR 0: 47[25,104]) were the most promising CSF outcome measures. Conclusion Sample size estimates needed to detect a 25% reduction in pathology levels in prevention studies are in the range of 30‐40 participants per arm.

Objective: Visual processing deficits arising in dementia are associated with particular functional disability. This study aimed to investigate the effects of the built environment on mobility and navigation in people with dementia-related visual loss. Methods: Participants with posterior cortical atrophy (PCA; “visual-variant Alzheimer’s”; n = 11), typical Alzheimer’s disease (tAD; N = 10), and controls (n = 13) repeatedly walked down routes within a simplified real-world setting. Participant groups were of comparable age and gender. Routes were of different complexity (straight, U-shaped, and S-shaped), overhead lighting levels (low and high) and with or without a dynamic LED (light-emitting diode) cue (trial n = 24). Ratios of walking times for each experimental condition (each complex route vs the straight route, high lighting vs low, and LED cue vs no cue) were compared between participant groups. Kinematic measures were produced from a total of 10,813 steps using wearable inertial measurement units (IMUs). Results: The walking time ratios relating to route complexity were higher in the PCA group than in controls: 30.3% (95% CI [13.5%, 49.5%] higher for U-shaped vs straight and 31.9% [21.1%, 55.3%] for S-shaped vs straight, averaged over other conditions). The analogous results relating to route complexity for the tAD group were intermediate between those for the PCA and control groups. There was no evidence that walking time ratios differed according to lighting level or the presence of the LED cue. Conclusions: Findings contribute to evidence-based design for dementia-friendly environments, emphasizing consequences of environmental complexity for functional independence and mobility in people with dementia-related visual loss. Findings inform recommendations for environmental design to support the independence of individuals with dementia.

INTRODUCTION: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals. METHODS: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. RESULTS: Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 22[95%CI 13,46], cortical PIB 32[20,57], CSF p-tau181 58[40,112]) for a four-year trial to have 80% power (5% statistical significance) to detect a 25% reduction in absolute levels of pathology, allowing 40% dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50% reduction in rate of change. Sample sizes ranged from 75-250 (examples precuneus volume: 137[80,284], cortical FDG: 256[100,1208], CDR-SB: 161[102,291]). DISCUSSION: Despite the rarity of ADAD, clinical trials with feasible sample sizes given the number of cases appear possible.

Background Since 2005, maternal and newborn deaths have declined in India. Nonetheless, if the current mortality trends continue, India may not achieve the Sustainable Development Goal targets without enhancing the quality of care across the continuum from pregnancy to delivery, particularly in poorly performing states. This study aimed to help the development of an evidence-based contextualised CHAMPION2 trial package of maternal and child health (being implemented in rural villages of Satna district, India) by assessing the quality of, and the factors associated with antenatal care (ANC) provision across four aspects of care and exploring reasons if uptake of care was inadequate. Methods We conducted a cross-sectional study in 50 of 196 villages in the CHAMPION2 cluster randomized trial in Satna district, Madhya Pradesh, India before randomization. We interviewed 792 women, who were eligible for the trial and had given birth in the previous two years from the interview date. We assessed the quality of ANC provision across four aspects of care (i.e., skilled care, timeliness (ANC in first trimester), number of ANC visits (at least four), and content of care) and explored reasons given by women if the uptake of care was inadequate. The quality of ANC provision was considered ‘adequate’ if all the four aspects of care were judged sufficient. We conducted logistic regression analyses to determine the socio-demographic factors associated with the adequate quality of ANC provision. Results Only 21.2% of women received ANC provision of 'adequate' quality (skilled care:98.9%, timeliness: 75.3%, minimum four ANCs: 73.5%, and appropriate content of care: 28.3%). The inadequate quality was primarily due to inappropriate content of care particularly, poor compliance with iron-folate intake for at least 100 days and no counselling by healthcare providers on key ANC issues. The odds of receiving adequate quality ANC were increased when either the woman or husband was educated to at least high school level. Conclusions The quality of ANC provision in the study setting was inadequate. The quality of care was emphasised in refresher training for nurses in the CHAMPION2 trial and health promotion, demand generation, and community mobilisation activities were locally contextualised.

Introduction There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. Methods and analysis MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0–6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years. Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate. The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression. Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. Ethics and dissemination The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. Trial registration numbers NCT03387670; ISRCTN82598726.

Background Deep grey matter pathology is a key driver of disability worsening in people with multiple sclerosis. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique which quantifies local magnetic susceptibility from variations in phase produced by changes in the local magnetic field. In the deep grey matter, susceptibility has previously been validated against tissue iron concentration. However, it currently remains unknown whether susceptibility is abnormal in older progressive MS cohorts, and whether it correlates with disability. Objectives To investigate differences in mean regional susceptibility in deep grey matter between people with secondary progressive multiple sclerosis (SPMS) and healthy controls; to examine in patients the relationships between deep grey matter susceptibility and clinical and imaging measures of disease severity. Methods Baseline data from a subgroup of the MS-STAT2 trial (simvastatin vs. placebo in SPMS, NCT03387670) were included. The subgroup underwent clinical assessments and an advanced MRI protocol at 3T. A cohort of age-matched healthy controls underwent the same MRI protocol. Susceptibility maps were reconstructed using a robust QSM pipeline from multi-echo 3D gradient-echo sequence. Regions of interest (ROIs) in the thalamus, globus pallidus and putamen were segmented from 3D T1-weighted images, and lesions segmented from 3D fluid-attenuated inversion recovery images. Linear regression was used to compare susceptibility from ROIs between patients and controls, adjusting for age and sex. Where significant differences were found, we further examined the associations between ROI susceptibility and clinical and imaging measures of MS severity. Results 149 SPMS (77% female; mean age: 53 yrs; median Expanded Disability Status Scale (EDSS): 6.0 [interquartile range 4.5–6.0]) and 33 controls (52% female, mean age: 57) were included. Thalamic susceptibility was significantly lower in SPMS compared to controls: mean (SD) 28.6 (12.8) parts per billion (ppb) in SPMS vs. 39.2 (12.7) ppb in controls; regression coefficient: −12.0 [95% confidence interval: −17.0 to −7.1], p < 0.001. In contrast, globus pallidus and putamen susceptibility were similar between both groups. In SPMS, a 10 ppb lower thalamic susceptibility was associated with a +0.13 [+0.01 to +0.24] point higher EDSS (p < 0.05), a −2.4 [−3.8 to −1.0] point lower symbol digit modality test (SDMT, p = 0.001), and a −2.4 [−3.7 to −1.1] point lower Sloan low contrast acuity, 2.5% (p < 0.01). Lower thalamic susceptibility was also strongly associated with a higher T2 lesion volume (T2LV, p < 0.001) and lower normalised whole brain, deep grey matter and thalamic volumes (all p < 0.001). Conclusions The reduced thalamic susceptibility found in SPMS compared to controls suggests that thalamic iron concentrations are lower at this advanced stage of the disease. The observed relationships between lower thalamic susceptibility and more severe physical, cognitive and visual disability suggests that reductions in thalamic iron may correlate with important mechanisms of clinical disease progression. Such mechanisms appear to intimately link reductions in thalamic iron with higher T2LV and the development of thalamic atrophy, encouraging further research into QSM-derived thalamic susceptibility as a biomarker of disease severity in SPMS.

Background Older people admitted to hospital in an emergency often have prolonged inpatient stays that worsen their outcomes, increase health-care costs, and reduce bed availability. Growing evidence suggests that the biopsychosocial complexity of their problems, which include cognitive impairment, depression, anxiety, multiple medical illnesses, and care needs resulting from functional dependency, prolongs hospital stays by making medical treatment less efficient and the planning of post-discharge care more difficult. We aimed to assess the effects of enhancing older inpatients’ care with Proactive Integrated Consultation-Liaison Psychiatry (PICLP) in The HOME Study. We have previously described the benefits of PICLP reported by patients and clinicians. In this Article, we report the effectiveness and cost-effectiveness of PICLP-enhanced care, compared with usual care alone, in reducing time in hospital. Methods We did a parallel-group, multicentre, randomised controlled trial in 24 medical wards of three English acute general hospitals. Patients were eligible to take part if they were 65 years or older, had been admitted in an emergency, and were expected to remain in hospital for at least 2 days from the time of enrolment. Participants were randomly allocated to PICLP or usual care in a 1:1 ratio by a database software algorithm that used stratification by hospital, sex, and age, and randomly selected block sizes to ensure allocation concealment. PICLP clinicians (consultation-liaison psychiatrists supported by assisting clinicians) made proactive biopsychosocial assessments of patients’ problems, then delivered discharge-focused care as integrated members of ward teams. The primary outcome was time spent as an inpatient (during the index admission and any emergency readmissions) in the 30 days post-randomisation. Secondary outcomes were the rate of discharge from hospital for the total length of the index admission; discharge destination; the length of the index admission after random allocation truncated at 30 days; the number of emergency readmissions to hospital, the number of days spent as an inpatient in an acute general hospital, and the rate of death in the year after random allocation; the patient's experience of the hospital stay; their view on the length of the hospital stay; anxiety (Generalized Anxiety Disorder-2); depression (Patient Health Questionnaire-2); cognitive function (Montreal Cognitive Assessment-Telephone version); independent functioning (Barthel Index of Activities of Daily Living); health-related quality of life (five-level EuroQol five-dimension questionnaire); and overall quality of life. Statisticians and data collectors were masked to treatment allocation; participants and ward staff could not be. Analyses were intention-to-treat. The trial had a patient and public involvement panel and was registered with ISRTCN (ISRCTN86120296). Findings 2744 participants (1399 [51·0%] male and 1345 [49·0%] female) were enrolled between May 2, 2018, and March 5, 2020; 1373 were allocated to PICLP and 1371 to usual care. Participants’ mean age was 82·3 years (SD 8·2) and 2565 (93·5%) participants were White. The mean time spent in hospital in the 30 days post-randomisation (analysed for 2710 [98·8%] participants) was 11·37 days (SD 8·74) with PICLP and 11·85 days (SD 9·00) with usual care; adjusted mean difference –0·45 (95% CI –1·11 to 0·21; p=0·18). The only statistically and clinically significant difference in secondary outcomes was the rate of discharge, which was 8.5% higher (rate ratio 1·09 [95% CI 1·00 to 1·17]; p=0·042) with PICLP—a difference most apparent in patients who stayed for more than 2 weeks. Compared with usual care, PICLP was estimated to be modestly cost-saving and cost-effective over 1 and 3, but not 12, months. No intervention-related serious adverse events occurred. Interpretation This is the first randomised controlled trial of PICLP. PICLP is experienced by older medical inpatients and ward staff as enhancing medical care. It is also likely to be cost-saving in the short-term. Although the trial does not provide strong evidence that PICLP reduces time in hospital, it does support and inform its future development and evaluation. Funding UK National Institute for Health and Care Research.