Interactions between age, sex and visceral adipose tissue on brain ageing.

AIM: To examine the associations between visceral adipose tissue (VAT) and brain structural measures at midlife and explore how these associations may be affected by age, sex and cardiometabolic factors. METHODS: We used abdominal and brain magnetic resonance imaging data from a population-based cohort of people at midlife in the UK Biobank. Regression modelling was applied to study associations of VAT volume with total brain volume (TBV), grey matter volume (GMV), white matter volume, white matter hyperintensity volume (WMHV) and total hippocampal volume (THV), and whether these associations were altered by age, sex or cardiometabolic factors. RESULTS: Complete data were available for 17 377 participants (mean age 63 years, standard deviation = 12, 53% female). Greater VAT was associated with lower TBV, GMV and THV (P < .001). We found an interaction between VAT and sex on TBV (P < .001), such that the negative association of VAT with TBV was greater in men (ß = -2.89, 95% confidence interval [CI] -2.32 to -10.15) than in women (ß = -1.32, 95% CI -0.49 to -3.14), with similar findings for GMV. We also found an interaction between VAT and age (but not sex) on WMHV (P < .001). The addition of other cardiometabolic factors or measures of physical activity resulted in little change to the models. CONCLUSIONS: VAT volume is associated with poorer brain health in midlife and this relationship is greatest in men and those at younger ages.

The implementation of a perioperative medicine for older people undergoing surgery service: a qualitative case study.

BACKGROUND: The international scale and spread of evidence-based perioperative medicine for older people undergoing surgery (POPS) services has not yet been fully realised. Implementation science provides a structured approach to understanding factors that act as barriers and facilitators to the implementation of POPS services. In this study, we aimed to identify factors that influence the implementation of POPS services in the UK. METHODS: A qualitative case study at three UK health services was undertaken. The health services differed across contextual factors (population, workforce, size) and stages of POPS service implementation maturity. Semi-structured interviews with purposively sampled clinicians (perioperative medical, nursing, allied health, and pharmacy) and managers (n = 56) were conducted. Data were inductively coded, then thematically analysed using the Consolidated Framework for Implementation Research (CFIR). RESULTS: Fourteen factors across all five CFIR domains were relevant to the implementation of POPS services. Key shared facilitators included stakeholders understanding the rationale of the POPS service, with support from their networks, POPS champions, and POPS clinical leads. We found substantial variation and flexibility in the way that health services responded to these shared facilitators and this was relevant to the implementation of POPS services. CONCLUSIONS: Health services planning to implement a POPS service should use health service-specific strategies to respond flexibly to local factors that are acting as barriers or facilitators to implementation. To support implementation of a POPS service, we recommend health services prioritise understanding local networks, identifying POPS champions, and ensuring that stakeholders understand the rationale for the POPS service. Our study also provides a structure for future research to understand the factors associated with 'unsuccessful' implementation of a POPS service, which can inform ongoing efforts to implement evidence-based perioperative models of care for older people.

HbA1c variability associated with dementia risk in people with type 2 diabetes.

INTRODUCTION: Although poor glycemic control is associated with dementia, it is unknown if variability in glycemic control, even in those with optimal glycosylated hemoglobin A1c (HbA1c) levels, increases dementia risk. METHODS: Among 171,964 people with type 2 diabetes, we evaluated the hazard of dementia association with long-term HbA1c variability using five operationalizations, including standard deviation (SD), adjusting for demographics and comorbidities. RESULTS: The mean baseline age was 61 years (48% women). Greater HbA1c SD was associated with greater dementia hazard (adjusted hazard ratio = 1.15 [95% confidence interval: 1.12, 1.17]). In stratified analyses, higher HbA1c SD quintiles were associated with greater dementia hazard among those with a mean HbA1c < 6% (P = 0.0004) or 6% to 8% (P < 0.0001) but not among those with mean HbA1c ≥ 8% (P = 0.42). DISCUSSION: Greater HbA1c variability is associated with greater dementia risk, even among those with HbA1c concentrations at ideal clinical targets. These findings add to the importance and clinical impact of recommendations to minimize glycemic variability. HIGHLIGHTS: We observed a cohort of 171,964 people with type 2 diabetes (mean age 61 years). This cohort was based in Northern California between 1996 and 2018. We examined the association between glycosylated hemoglobin A1c (HbA1c) variability and dementia risk. Greater HbA1c variability was associated with greater dementia hazard. This was most evident among those with normal-low mean HbA1c concentrations.

Lower brain glucose metabolism in normal ageing is predominantly frontal and temporal: A systematic review and pooled effect size and activation likelihood estimates meta-analyses.

This review provides a qualitative and quantitative analysis of cerebral glucose metabolism in ageing. We undertook a systematic literature review followed by pooled effect size and activation likelihood estimates (ALE) meta-analyses. Studies were retrieved from PubMed following the PRISMA guidelines. After reviewing 635 records, 21 studies with 22 independent samples (n = 911 participants) were included in the pooled effect size analyses. Eight studies with eleven separate samples (n = 713 participants) were included in the ALE analyses. Pooled effect sizes showed significantly lower cerebral metabolic rates of glucose for older versus younger adults for the whole brain, as well as for the frontal, temporal, parietal, and occipital lobes. Among the sub-cortical structures, the caudate showed a lower metabolic rate among older adults. In sub-group analyses controlling for changes in brain volume or partial volume effects, the lower glucose metabolism among older adults in the frontal lobe remained significant, whereas confidence intervals crossed zero for the other lobes and structures. The ALE identified nine clusters of lower glucose metabolism among older adults, ranging from 200 to 2640 mm3 . The two largest clusters were in the left and right inferior frontal and superior temporal gyri and the insula. Clusters were also found in the inferior temporal junction, the anterior cingulate and caudate. Taken together, the results are consistent with research showing less efficient glucose metabolism in the ageing brain. The findings are discussed in the context of theories of cognitive ageing and are compared to those found in neurodegenerative disease.

The older adult brain is less modular, more integrated, and less efficient at rest: A systematic review of large-scale resting-state functional brain networks in aging.

The literature on large-scale resting-state functional brain networks across the adult lifespan was systematically reviewed. Studies published between 1986 and July 2021 were retrieved from PubMed. After reviewing 2938 records, 144 studies were included. Results on 11 network measures were summarized and assessed for certainty of the evidence using a modified GRADE method. The evidence provides high certainty that older adults display reduced within-network and increased between-network functional connectivity. Older adults also show lower segregation, modularity, efficiency and hub function, and decreased lateralization and a posterior to anterior shift at rest. Higher-order functional networks reliably showed age differences, whereas primary sensory and motor networks showed more variable results. The inflection point for network changes is often the third or fourth decade of life. Age effects were found with moderate certainty for within- and between-network altered patterns and speed of dynamic connectivity. Research on within-subject bold variability and connectivity using glucose uptake provides low certainty of age differences but warrants further study. Taken together, these age-related changes may contribute to the cognitive decline often seen in older adults.

Emergency Department Resuscitative Endovascular Balloon Occlusion of the Aorta in Trauma Patients With Exsanguinating Hemorrhage: The UK-REBOA Randomized Clinical Trial.

Importance: Bleeding is the most common cause of preventable death after trauma. Objective: To determine the effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) when used in the emergency department along with standard care vs standard care alone on mortality in trauma patients with exsanguinating hemorrhage. Design, Setting, and Participants: Pragmatic, bayesian, randomized clinical trial conducted at 16 major trauma centers in the UK. Patients aged 16 years or older with exsanguinating hemorrhage were enrolled between October 2017 and March 2022 and followed up for 90 days. Intervention: Patients were randomly assigned (1:1 allocation) to a strategy that included REBOA and standard care (n = 46) or standard care alone (n = 44). Main Outcomes and Measures: The primary outcome was all-cause mortality at 90 days. Ten secondary outcomes included mortality at 6 months, while in the hospital, and within 24 hours, 6 hours, or 3 hours; the need for definitive hemorrhage control procedures; time to commencement of definitive hemorrhage control procedures; complications; length of stay; blood product use; and cause of death. Results: Of the 90 patients (median age, 41 years [IQR, 31-59 years]; 62 [69%] were male; and the median Injury Severity Score was 41 [IQR, 29-50]) randomized, 89 were included in the primary outcome analysis because 1 patient in the standard care alone group declined to provide consent for continued participation and data collection 4 days after enrollment. At 90 days, 25 of 46 patients (54%) had experienced all-cause mortality in the REBOA and standard care group vs 18 of 43 patients (42%) in the standard care alone group (odds ratio [OR], 1.58 [95% credible interval, 0.72-3.52]; posterior probability of an OR >1 [indicating increased odds of death with REBOA], 86.9%). Among the 10 secondary outcomes, the ORs for mortality and the posterior probabilities of an OR greater than 1 for 6-month, in-hospital, and 24-, 6-, or 3-hour mortality were all increased in the REBOA and standard care group, and the ORs were increased with earlier mortality end points. There were more deaths due to bleeding in the REBOA and standard care group (8 of 25 patients [32%]) than in standard care alone group (3 of 18 patients [17%]), and most occurred within 24 hours. Conclusions and Relevance: In trauma patients with exsanguinating hemorrhage, a strategy of REBOA and standard care in the emergency department does not reduce, and may increase, mortality compared with standard care alone. Trial Registration: isrctn.org Identifier: ISRCTN16184981.

Patient-reported outcome measures to evaluate postoperative quality of life in patients undergoing elective abdominal surgery: a systematic review.

PURPOSE: To appraise the measurement properties of generic patient-reported outcome measures (PROMs) measuring postoperative quality of life in adults undergoing elective abdominal surgery. METHODS: We conducted a systematic review of PROMs administered after elective abdominal surgery. We systematically searched Ovid MEDLINE, Embase, the Cumulative Index to Nursing & Allied Health Literature database, and the Cochrane Library from earliest available dates to July 24, 2021, using relevant search terms. Articles were included if they reported assessment of measurement properties of a generic PROM/s measuring postoperative quality of life in adults who had undergone elective abdominal surgery. We used the Consensus-based Standards for the selection of health status Measurement Instruments (COSMIN) Risk of Bias checklist to assess methodological quality. We synthesized the data and used the COSMIN criteria for good measurement properties and the Grading of Recommendations, Assessment, Development and Evaluations criteria to rate the certainty of evidence. RESULTS: Of 12,121 identified articles, nine articles assessing five PROMs (SF-6D, EQ-5D, SF-36, SF-12, PROMIS-10) met inclusion criteria. Measurement properties assessed included internal consistency (n = 2), construct validity (n = 5), and responsiveness (n = 8). Two PROMs had high quality evidence for a single measurement property each. The SF-6D demonstrated high quality evidence for responsiveness and the EQ-5D had high quality evidence for construct validity. CONCLUSION: There is insufficient evidence to support the choice of a specific generic PROM to evaluate quality of life following elective abdominal surgery. Clinicians and researchers should be aware of the current limitations in knowledge of the measurement properties of available PROMs.

New NHS Prehospital Major Incident Triage Tool: from MIMMS to MITT.

Triage is a key principle in the effective management of major incidents and is the process by which patients are prioritised on the basis of their clinical acuity. However, work published over the last decade has demonstrated that existing methods of triage perform poorly when trying to identify patients in need of life-saving interventions. As a result, a review of major incident triage was initiated by NHS England with the remit to determine the optimum way in which to triage patients of all ages in a major incident for the UK. This article describes the output from this review, the changes being undertaken to UK major incident triage and the introduction of the new NHS Major Incident Triage Tool from the Spring of 2023.

Redundancy within hospital-related harm prediction tools.

The predictive ability and efficiency of inpatient harm screening tools is unclear. We performed a retrospective analysis of approximately 25 000 people admitted to our hospital in 2019. We found that the discriminatory ability of the harm screening tools was at best moderate and could be attributed to one or two questions that overlapped with each other in the harm they predicted.

Adherence to the Australian Dietary Guidelines Is Not Associated with Brain Structure or Cognitive Function in Older Adults.

BACKGROUND: Cognitive dysfunction is common in older adults, particularly in those with type 2 diabetes (T2D). Higher adherence to the Dietary Guidelines for Americans is associated with better brain health. However, it is unclear if adherence to the Australian Dietary Guidelines (ADG) is associated with cognition or brain structure in older adults. OBJECTIVE: The aims of this study were to 1) examine the relation between adherence to the ADG, cognition, and brain MRI and 2) determine whether T2D modifies any associations. METHODS: The Cognition and Diabetes in Older Tasmanians Study is a cross-sectional study in 688 people (n = 343 with T2D) aged 55-90 y. A validated 80-item food-frequency questionnaire was used to assess dietary intake. Adherence to the 2013 ADG was estimated using the Dietary Guidelines Index (DGI). Cognitive function in multiple domains was assessed with a comprehensive battery of neuropsychological tests and brain structure with MRI. Multivariable linear models were used to assess the associations between DGI, cognitive z scores, and brain structure. Effect modification for T2D was examined with a DGI × T2D product term. RESULTS: The mean age of the sample was 69.9 y (SD: 7.4 y), with 57.1% men. The mean DGI was 54.8 (SD: 10.7; range: 24.1-84.6). No associations were observed between the Australian DGI and cognition or brain MRI measures. T2D did not modify any associations (P > 0.05). CONCLUSIONS: This is the first study to investigate associations between adherence to the ADG and brain health in the older adults with and without T2D. Future prospective studies are required to clarify if there are long-term associations.

Type 2 diabetes mellitus, brain atrophy and cognitive decline in older people: a longitudinal study.

AIMS/HYPOTHESIS: The aims of the study were to examine whether type 2 diabetes mellitus is associated with greater brain atrophy and cognitive decline, and whether brain atrophy mediates associations between type 2 diabetes and cognitive decline. METHODS: Participants without dementia aged 55-90 years from the Cognition and Diabetes in Older Tasmanians (CDOT) study underwent brain MRI (ventricular and total brain volume) and neuropsychological measures (global function and seven cognitive domains) at three time points over 4.6 years. Mixed models were used to examine longitudinal associations of type 2 diabetes with cognitive and MRI measures, adjusting for covariates. A test of mediation was used to determine whether brain atrophy explained associations between type 2 diabetes and cognitive decline. RESULTS: A total of 705 participants (diabetes: n = 348, mean age 68.2 years [SD 7.0]; no diabetes: n = 357, mean age 72.5 years [SD 7.1]) were available at baseline. Adjusting for age, sex, education and vascular risk factors, there were significant diabetes × time interactions for verbal memory (ß -0.06; 95% CI -0.09, -0.02) and verbal fluency (ß -0.03; 95% CI -0.06, -0.00). Although people with diabetes had lower brain (ß -14.273; 95% CI -21.197, -6.580) and greater ventricular (ß 2.672; 95% CI 0.152, 5.193) volumes at baseline, there were no significant diabetes × time interactions (p > 0.05) or evidence of mediation of the diabetes-cognition relationship by brain atrophy. CONCLUSIONS/INTERPRETATION: In older community-dwelling people, type 2 diabetes is associated with decline in verbal memory and fluency over ~5 years. The effect of diabetes on brain atrophy may begin earlier (midlife).

Dietary Patterns Are Not Associated with Brain Atrophy or Cerebral Small Vessel Disease in Older Adults with and without Type 2 Diabetes.

BACKGROUND: Unhealthy dietary patterns (DPs) are associated with poorer cognition, but few studies have investigated the underlying brain structural mechanisms. OBJECTIVE: We aimed to examine the relations between DPs, brain structure, and cognition in older people with and without type 2 diabetes. METHODS: This cross-sectional study consisted of a sample of people with (n = 343) and without type 2 diabetes (n = 346) aged 55-90 y. The 80-item Cancer Council of Victoria FFQ was used to assess dietary intake. Two DPs (prudent and traditional) for people with type 2 diabetes and 3 DPs (prudent, traditional, and Western) for those without type 2 diabetes were derived using principal component analysis. Neuropsychological tests assessed 6 cognitive domains. Brain MRI was performed to obtain gray, white matter, and hippocampal volumes and markers of small vessel disease (microbleeds, infarcts, and white matter hyperintensities). Multivariable linear regression was used to assess the cross-sectional associations between DPs, brain MRI, and cognitive variables. RESULTS: For those without type 2 diabetes, higher adherence to the Western DP was associated with lower gray matter volume (ß = -3.03 95% CI: -5.67, -0.38; P = 0.03). The addition of a cardiovascular risk score, mood, and physical activity weakened associations such that they were no longer significant (ß = -1.97 (95% CI: -4.68, 0.74) P = 0.15) for the Western DP. There were no significant associations for the other DPs in people with and without type 2 diabetes. CONCLUSIONS: In this cross-sectional study, DPs were not independently associated with brain structure in people with or without type 2 diabetes. Future prospective studies are needed to clarify the role of vascular risk factors on associations between DPs and brain health.

Determination of glyoxal and methylglyoxal in serum by UHPLC coupled with fluorescence detection.

Glyoxal (GO) and methylglyoxal (MGO) are two important biomarkers in diabetes. Analytical methods for determination of GO and MGO in serum samples are either HPLC with UV-Vis (low sensitivity) or MS/MS (expensive) detection. These disadvantages have hampered the introduction of these biomarkers as a routine analyte for diabetes diagnostics into the clinical laboratory. In this study, we introduce a UHPLC method with fluorescence detection for the measurement of GO and MGO in serum samples by pre-column derivatization at neutral pH with 5, 6-diamino-2,4-dihydroxypyrimidine sulfate (DDP) to form lumazines. The method was validated as per FDA guidelines. Using this method, we have determined GO and MGO in a variety of animal serum samples, and for example, determined the GO and MGO concentration in adult bovine serum to be 852 ±â€¯27 and 192 ±â€¯10 nmol/L, respectively. In human serum, GO and MGO levels in non-diabetic subjects (n = 14) were determined to be 154 ±â€¯88 and 98 ±â€¯27 nmol/L, and in serum samples from subjects with diabetes (n = 14) 244 ±â€¯137 and 190 ±â€¯68 nmol/L, respectively. In addition, interference studies showed that physiological serum components did not lead to an artificial increase in the levels of GO and MGO.

Diabetes Therapies for Dementia.

PURPOSE OF REVIEW: Type 2 diabetes (T2D) is a well-established risk factor for the development of dementia. Dementia and T2D share some underlying pathophysiology that has led to interest in the potential to repurpose drugs used in the management of T2D to benefit brain health. This review describes the scientific data available on the use of T2D medications for the risk reduction or management of dementia, in people with and without T2D. RECENT FINDINGS: Results from basic laboratory research support the potential for commonly-used medications for T2D, including those with direct glucose-lowering properties, to have a beneficial effect on brain health. However, human studies have been mostly observational in nature and report conflicting results. Preliminary data suggest that intranasal insulin, metformin, and GLP-1 agonists show promise for dementia, but confirmatory evidence for their benefit in dementia is still lacking. Current evidence does not support the repurposing of T2D medications for dementia risk reduction or management. Research in the field of T2D and dementia is active, and further data are required before definitive conclusions can be drawn.

Examination of risk scores to better predict hospital-related harms.

BACKGROUND: Many hospitals use predictive scores to identify a person's risk of inpatient falls, pressure injury and malnutrition despite evidence of limited predictive accuracy. AIM: To examine whether we could improve predictive accuracy by generating a score combining all components of currently used tools. METHODS: We performed a retrospective, cross-validation study in a single sub-acute (geriatrics and rehabilitation) hospital, extracting data regarding hospital risk scores, and incidence of falls, pressure injury and malnutrition from January 2014 to June 2016. The sample was randomly halved into training and testing data sets. For each harm outcome, model fit was examined using area under receiver operating characteristic curves (AUC) and proportions of people reclassified based on a combined score were calculated. Secondary analyses explored the predictive performance of individual question-responses. RESULTS: Data were available for 4487 admissions (median age 83.0 years). A total of 667 (15%) people had at least one fall, 499 (11%) had at least one pressure injury and 20 (0.4%) malnutrition. The currently used tools had, at best, moderate ability to predict risk of harm outcomes (AUC 0.56-0.73). Testing of the combined score models resulted in minimal change in AUC (<5.1%) and did not add value to risk category reclassification. Most of the predictive ability of the currently used tools relied on the performance of two individual question-responses. CONCLUSION: Combining scores or reducing to two-item question-responses did little to change predictive accuracy. This study highlights the limitations of hospital harm predictive scores and emphasises the importance of rigorous testing of predictive scores.

Stroke Severity and Comorbidity Index for Prediction of Mortality after Ischemic Stroke from the Virtual International Stroke Trials Archive-Acute Collaboration.

BACKGROUND: There is increasing interest in the use of administrative data (incorporating comorbidity index) and stroke severity score to predict ischemic stroke mortality. The aim of this study was to determine the optimal timing for the collection of stroke severity data and the minimum clinical dataset to be included in models of stroke mortality. To address these issues, we chose the Virtual International Stroke Trials Archive (VISTA), which contains National Institutes of Health Stroke Scale (NIHSS) on admission and at 24 hours, as well as outcome at 90 days. METHODS: VISTA was searched for patients who had baseline and 24-hour NIHSS. Improvement in regression models was performed by the net reclassification improvement (NRI) method. RESULTS: The clinical data among 5206 patients were mean age, 69 ± 13; comorbidity index, 3.3 ± .9; median NIHSS at baseline, 12 (interquartile range [IQR] 8-17); NIHSS at 24 hours, 9 (IQR 8-15); and death at 90 days in 15%. The baseline model consists of age, gender, and comorbidity index. Adding the baseline NIHSS to model 1 improved the NRI by 0.671 (95% confidence interval [CI] 0.595-0.747) [or 67.1% correct reclassification between model 1 and model 2]. Adding the 24 hour NIHSS term to model 1 (model 3) improved the NRI by 0.929 (95% CI 0.857-1.000) for model 3 versus model 1. Adding the variable thrombolysis to model 3 (model 4) improve NRI by 0.1 (95% CI 0.023-0.178) [model 4 versus model 3]. CONCLUSION: The optimal model for the prediction of mortality was achieved by adding the 24-hour NIHSS and thrombolysis to the baseline model.

Patient characteristics and outcomes of a hip fracture and concomitant fracture compared with hip fracture alone: results from a United Kingdom teaching hospital.

INTRODUCTION: A proportion of patients sustaining hip fractures present with a concomitant fracture. We aimed to evaluate the relationship between patient characteristics and clinical outcomes, in those with a hip and concomitant fracture compared with those sustaining a hip fracture alone from a clinical service registry. METHOD: Cross-sectional study using data obtained from a clinical service registry (Nottingham Hip Fracture Database) on patients aged 50 and above who suffered a hip fracture between 1/1/2003 and 31/12/2012. Data was collected on patient demographics, fracture information and healthcare outcomes. RESULTS: 7338 patients of which 75 % were female (mean age 82 (SD 9.4), had a hip fracture with 334 (4.6 %) patients having a concomitant fracture. The majority (58 %) were distal radius or proximal humeral fractures. Only females (p = 0.002), those taking three or fewer medications (p = 0.018) and those on long term steroids (p = 0.048) were more likely to suffer a concomitant fracture. There was no difference in mortality, rates of postoperative complication, intensive care unit or care home admission between both groups. Patients with a concomitant fracture have a 16 % longer average length of stay in hospital (mean difference 1.16; 95 % CI 1.07-1.25, p < 0.001). CONCLUSIONS: Patients with concomitant fractures have similar patient characteristics, except gender, polypharmacy and long term steroid use; and outcomes to those presenting with hip fracture alone, except a longer average inpatient stay.

White Matter Lesion Progression: Genome-Wide Search for Genetic Influences.

BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

Type 2 Diabetes and Biomarkers of Brain Structure, Perfusion, Metabolism, and Function in Late Mid-Life: A Multimodal Discordant Twin Study.

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of dementia and early features may become evident even in mid-life. Characterizing these early features comprehensively requires multiple measurement modalities and careful selection of participants with and without T2D. OBJECTIVE: We conducted a cross-sectional multimodal imaging study of T2D-discordant twins in late mid-life to provide insights into underlying mechanisms. METHODS: Measurements included computerized cognitive battery, brain MRI (including arterial spin labelling, diffusion tensor, resting state functional), fluorodeoxyglucose (FDG)-PET, and retinal optical coherence tomography. RESULTS: There were 23 pairs, mean age 63.7 (±6.1) years. In global analyses, T2D was associated with poorer attention (ß= -0.45, p <0.001) and with reduced FDG uptake (ß= -5.04, p = 0.02), but not with cortical thickness (p = 0.71), total brain volume (p = 0.51), fractional anisotropy (p = 0.15), mean diffusivity (p = 0.34), or resting state activity (p = 0.4). Higher FDG uptake was associated with better attention (ß= 3.19, p = 0.01) but not with other cognitive domains. In regional analyses, T2D was associated with lower accumbens volume (ß= -44, p = 0.0004) which was in turn associated with poorer attention. CONCLUSION: T2D-related brain dysfunction in mid-life manifests as attentional loss accompanied by evidence of subtle neurodegeneration and global reduction in cerebral metabolism, in the absence of overt cerebrovascular disease.

The association of regional cerebral blood flow and glucose metabolism in normative ageing and insulin resistance.

Rising rates of insulin resistance and an ageing population are set to exact an increasing toll on individuals and society. Here we examine the contribution of age and insulin resistance to the association of cerebral blood flow and glucose metabolism; both critical process in the supply of energy for the brain. Thirty-four younger (20-42 years) and 41 older (66-86 years) healthy adults underwent a simultaneous resting state MR/PET scan, including arterial spin labelling. Rates of cerebral blood flow and glucose metabolism were derived using a functional atlas of 100 brain regions. Older adults had lower cerebral blood flow than younger adults in 95 regions, reducing to 36 regions after controlling for cortical atrophy and blood pressure. Lower cerebral blood flow was also associated with worse working memory and slower reaction time in tasks requiring cognitive flexibility and response inhibition. Younger and older insulin sensitive adults showed small, negative correlations between relatively high rates of regional cerebral blood flow and glucose metabolism. This pattern was inverted in insulin resistant older adults, who showed hypoperfusion and hypometabolism across the cortex, and a positive correlation. In insulin resistant younger adults, the association showed inversion to positive correlations, although not to the extent seen in older adults. Our findings suggest that the normal course of ageing and insulin resistance alter the rates of and associations between cerebral blood flow and glucose metabolism. They underscore the criticality of insulin sensitivity to brain health across the adult lifespan.