Clinical utility of diffusion MRI-derived measures of cortical microstructure in a real-world memory clinic setting.

OBJECTIVE: To investigate cortical microstructural measures from diffusion MRI as "neurodegeneration" markers that could improve prognostic accuracy in mild cognitive impairment (MCI). METHODS: The prognostic power of Amyloid/Tau/Neurodegeneration (ATN) biomarkers to predict progression from MCI to AD or non-AD dementia was investigated. Ninety patients underwent clinical evaluation (follow-up interval 32 ± 18 months), lumbar puncture, and MRI. Participants were grouped by clinical stage and cerebrospinal fluid Amyloid and Tau status. T1-structural and diffusion MRI scans were analyzed to calculate diffusion metrics related to cortical columnar structure (AngleR, ParlPD, PerpPD+), cortical mean diffusivity, and fractional anisotropy. Statistical tests were corrected for multiple comparisons. Prognostic power was assessed using receiver operating characteristic (ROC) analysis and related indices. RESULTS: A progressive increase of whole-brain cortical diffusion values was observed along the AD continuum, with all A+ groups showing significantly higher AngleR than A-T-. Investigating clinical progression to dementia, the AT biomarkers together showed good positive predictive value (with 90.91% of MCI A+T+ converting to dementia) but poor negative predictive value (with 40% of MCI A-T- progressing to a mix of AD and non-AD dementias). Adding whole-brain AngleR as an N marker, produced good differentiation between stable and converting MCI A-T- patients (0.8 area under ROC curve) and substantially improved negative predictive value (+21.25%). INTERPRETATION: Results support the clinical utility of cortical microstructure to aid prognosis, especially in A-T- patients. Further work will investigate other complexities of the real-world clinical setting, including A-T+ groups. Diffusion MRI measures of neurodegeneration may complement fluid AT markers to support clinical decision-making.

In vivo cortical diffusion imaging relates to Alzheimer's disease neuropathology.

BACKGROUND: There has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology. This study aimed to characterise the associations between the main Alzheimer's disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated. METHODS: Forty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD+, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC-the "ABC score" from NIA-AA recommendations). Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated. Finally, the effect of coexistent pathologies-Lewy body disease and TAR DNA-binding protein 43 (TDP-43)-on cortical microstructure was assessed. RESULTS: Cortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD+ in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD+. LCh was associated with PerpPD+, ParlPD, and MD. Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology. CONCLUSIONS: Cortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain. Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making. Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy.

Delay in the induction of labour process: a retrospective cohort study and computer simulation of maternity unit workload.

OBJECTIVES: Delay in the induction of labour (IOL) process is associated with poor patient experience and adverse perinatal outcome. Our objective was to identify factors associated with delay in the IOL process and develop interventions to reduce delay. DESIGN AND SETTINGS: We performed a retrospective cohort study of maternity unit workload in a large UK district general hospital. Electronic hospital records were used to quantify delay in the IOL process and linear regression analysis was performed to assess significant associations between delay and potential causative factors. A novel computer maternity unit simulation model, MUMSIM (Maternity Unit Management SIMulation), was developed using real-world data and interventions were tested to identify those associated with a reduction in delay. PARTICIPANTS: All women giving birth at Stoke Mandeville Hospital, Buckinghamshire National Health Service (NHS) Trust in 2018 (n=4932). PRIMARY OUTCOME MEASURE: Delay in the IOL process of more than 12 hours. RESULTS: The retrospective analysis of real-world maternity unit workload showed 30% of women had IOL and of these, 33% were delayed >12 hours with 20% delayed >24 hours, 10% delayed >48 hours and 1.3% delayed >72 hours. Delay was significantly associated with the total number of labouring women (p=0.008) and the number of booked IOL (p=0.009) but not emergency IOL, spontaneously labouring women or staffing shortfall. The MUMSIM computer simulation predicted that changing from slow release 24-hour prostaglandin to 6-hour prostaglandin for primiparous women would reduce delay by 4% (p<0.0001) and that additional staffing interventions could significantly reduce delay up to 17.9% (p<0.0001). CONCLUSIONS: Planned obstetric workload of booked IOL is associated with delay rather than the unpredictable workload of women in spontaneous labour or emergency IOL. We present a novel maternity unit computer simulation model, MUMSIM, which allows prediction of the impact of interventions to reduce delay.