Measures of fragmentation of rest activity patterns: mathematical properties and interpretability based on accelerometer real life data.

Accelerometers, devices that measure body movements, have become valuable tools for studying the fragmentation of rest-activity patterns, a core circadian rhythm dimension, using metrics such as inter-daily stability (IS), intradaily variability (IV), transition probability (TP), and self-similarity parameter (named α ). However, their use remains mainly empirical. Therefore, we investigated the mathematical properties and interpretability of rest-activity fragmentation metrics by providing mathematical proofs for the ranges of IS and IV, proposing maximum likelihood and Bayesian estimators for TP, introducing the activity balance index (ABI) metric, a transformation of α , and describing distributions of these metrics in real-life setting. Analysis of accelerometer data from 2,859 individuals (age=60-83 years, 21.1% women) from the Whitehall II cohort (UK) shows modest correlations between the metrics, except for ABI and α . Sociodemographic (age, sex, education, employment status) and clinical (body mass index (BMI), and number of morbidities) factors were associated with these metrics, with differences observed according to metrics. For example, a difference of 5 units in BMI was associated with all metrics (differences ranging between -0.261 (95% CI -0.302, -0.220) to 0.228 (0.18, 0.268) for standardised TP rest to activity during the awake period and TP activity to rest during the awake period, respectively). These results reinforce the value of these rest-activity fragmentation metrics in epidemiological and clinical studies to examine their role for health. This paper expands on a set of methods that have previously demonstrated empirical value, improves the theoretical foundation for these methods, and evaluates their empirical use in a large dataset.

Associations of inner retinal layers with risk of incident dementia: An individual participant data analysis of four prospective cohort studies.

INTRODUCTION: Our main objective was to investigate whether retinal neurodegeneration, estimated from lower thickness of inner retinal layers, was associated with incident all-cause dementia and Alzheimer's disease (AD). METHODS: We performed an individual participant data meta-analysis using unpublished data from four prospective cohort studies with a total of 69,955 participants (n = 1087 cases of incident all-cause dementia; n = 520 cases incident AD; follow-up time median [interquartile range] 11.3 [8.8-11.5] years). RESULTS: General baseline characteristics of the study population were mean (standard deviation) age, 58.1 (8.8) years; 47% women. After adjustment, lower baseline macular retinal nerve fiber layer thickness was significantly associated with a 10% and 11% higher incidence of all-cause dementia and AD, respectively. Lower baseline macular ganglion cell-inner plexiform layer thickness was not significantly associated with these outcomes. DISCUSSION: These findings suggest that retinal neurodegeneration precedes the onset of clinical dementia. Retinal imaging tools may be informative biomarkers for the study of the early pathophysiology of dementia.

Thinner inner retinal layers are associated with lower cognitive performance, lower brain volume, and altered white matter network structure-The Maastricht Study.

INTRODUCTION: The retina may provide non-invasive, scalable biomarkers for monitoring cerebral neurodegeneration. METHODS: We used cross-sectional data from The Maastricht study (n = 3436; mean age 59.3 years; 48% men; and 21% with type 2 diabetes [the latter oversampled by design]). We evaluated associations of retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses with cognitive performance and magnetic resonance imaging indices (global grey and white matter volume, hippocampal volume, whole brain node degree, global efficiency, clustering coefficient, and local efficiency). RESULTS: After adjustment, lower thicknesses of most inner retinal layers were significantly associated with worse cognitive performance, lower grey and white matter volume, lower hippocampal volume, and worse brain white matter network structure assessed from lower whole brain node degree, lower global efficiency, higher clustering coefficient, and higher local efficiency. DISCUSSION: The retina may provide biomarkers that are informative of cerebral neurodegenerative changes in the pathobiology of dementia.

(Pre)diabetes and a higher level of glycaemic measures are continuously associated with corneal neurodegeneration assessed by corneal confocal microscopy: the Maastricht Study.

AIMS/HYPOTHESIS: To assess the associations between glucose metabolism status and a range of continuous measures of glycaemia with corneal nerve fibre measures, as assessed using corneal confocal microscopy. METHODS: We used population-based observational cross-sectional data from the Maastricht Study of N=3471 participants (mean age 59.4 years, 48.4% men, 14.7% with prediabetes, 21.0% with type 2 diabetes) to study the associations, after adjustment for demographic, cardiovascular risk and lifestyle factors, between glucose metabolism status (prediabetes and type 2 diabetes vs normal glucose metabolism) plus measures of glycaemia (fasting plasma glucose, 2 h post-load glucose, HbA1c, skin autofluorescence [SAF] and duration of diabetes) and composite Z-scores of corneal nerve fibre measures or individual corneal nerve fibre measures (corneal nerve bifurcation density, corneal nerve density, corneal nerve length and fractal dimension). We used linear regression analysis, and, for glucose metabolism status, performed a linear trend analysis. RESULTS: After full adjustment, a more adverse glucose metabolism status was associated with a lower composite Z-score for corneal nerve fibre measures (ß coefficients [95% CI], prediabetes vs normal glucose metabolism -0.08 [-0.17, 0.03], type 2 diabetes vs normal glucose metabolism -0.14 [-0.25, -0.04]; linear trend analysis showed a p value of 0.001), and higher levels of measures of glycaemia (fasting plasma glucose, 2 h post-load glucose, HbA1c, SAF and duration of diabetes) were all significantly associated with a lower composite Z-score for corneal nerve fibre measures (per SD: -0.09 [-0.13, -0.05], -0.07 [-0.11, -0.03], -0.08 [-0.11, -0.04], -0.05 [-0.08, -0.01], -0.09 [-0.17, -0.001], respectively). In general, directionally similar associations were observed for individual corneal nerve fibre measures. CONCLUSIONS/INTERPRETATION: To our knowledge, this is the first population-based study to show that a more adverse glucose metabolism status and higher levels of glycaemic measures were all linearly associated with corneal neurodegeneration after adjustment for an extensive set of potential confounders. Our results indicate that glycaemia-associated corneal neurodegeneration is a continuous process that starts before the onset of type 2 diabetes. Further research is needed to investigate whether early reduction of hyperglycaemia can prevent corneal neurodegeneration.

Alcohol consumption and microvascular dysfunction: a J-shaped association: The Maastricht Study.

BACKGROUND: Microvascular dysfunction (MVD) is an important contributor to major clinical disease such as stroke, dementia, depression, retinopathy, and chronic kidney disease. Alcohol consumption may be a determinant of MVD. OBJECTIVE: Main objectives were (1) to study whether alcohol consumption was associated with MVD as assessed in the brain, retina, skin, kidney and in the blood; and (2) to investigate whether associations differed by history of cardiovascular disease or sex. DESIGN: We used cross-sectional data from The Maastricht Study (N = 3,120 participants, 50.9% men, mean age 60 years, and 27.5% with type 2 diabetes [the latter oversampled by design]). We used regression analyses to study the association between total alcohol (per unit and in the categories, i.e. none, light, moderate, high) and MVD, where all measures of MVD were combined into a total MVD composite score (expressed in SD). We adjusted all associations for potential confounders; and tested for interaction by sex, and history of cardiovascular disease. Additionally we tested for interaction with glucose metabolism status. RESULTS: The association between total alcohol consumption and MVD was non-linear, i.e. J-shaped. Moderate versus light total alcohol consumption was significantly associated with less MVD, after full adjustment (beta [95% confidence interval], -0.10 [-0.19; -0.01]). The shape of the curve differed with sex (Pinteraction = 0.03), history of cardiovascular disease (Pinteraction < 0.001), and glucose metabolism status (Pinteraction = 0.02). CONCLUSIONS: The present cross-sectional, population-based study found evidence that alcohol consumption may have an effect on MVD. Hence, although increasing alcohol consumption cannot be recommended as a policy, this study suggests that prevention of MVD may be possible through dietary interventions.

Carotid stiffness is associated with retinal microvascular dysfunction-The Maastricht study.

OBJECTIVE: This study investigated whether arterial stiffening is a determinant of subtle retinal microvascular changes that precede diabetic retinopathy. RESEARCH DESIGN AND METHODS: This study used cross-sectional data from the Maastricht Study, a type 2 diabetes-enriched population-based cohort study. We used multivariable linear regression analysis to investigate, in individuals without and with type 2 diabetes, the associations of carotid distensibility coefficient and carotid-femoral pulse wave velocity with retinal microvascular diameters and flicker light-induced dilation and adjusted for cardiovascular and lifestyle risk factors. RESULTS: The retinal microvascular diameter study population consisted of N = 2434 participants (51.4% men, mean ± SD age 59.8 ± 8.1 years, and 28.1% type 2 diabetes). No measures of arterial stiffness were significantly associated with microvascular diameters. Greater carotid distensibility coefficient (i.e., lower carotid stiffness) was significantly associated with greater retinal arteriolar flicker light-induced dilation (per standard deviation, standardized beta [95% CI] 0.06 [0.00; 0.12]) and non-significantly, but directionally similarly, associated with greater retinal venular flicker light-induced dilation (0.04 [-0.02; 0.10]). Carotid-femoral pulse wave velocity (i.e., aortic stiffness) was not associated with retinal microvascular flicker light-induced dilation. The associations between carotid distensibility coefficient and retinal arteriolar and venular flicker light-induced dilation were two- to threefold stronger in individuals with type 2 diabetes than in those without. CONCLUSION: In this population-based study greater carotid, but not aortic, stiffness was associated with worse retinal flicker light-induced dilation and this association was stronger in individuals with type 2 diabetes. Hence, carotid stiffness may be a determinant of retinal microvascular dysfunction.

Higher levels of daily physical activity are associated with better skin microvascular function in type 2 diabetes-The Maastricht Study.

OBJECTIVE: Physical activity may provide a means for the prevention of cardiovascular disease via improving microvascular function. Therefore, this study investigated whether physical activity is associated with skin and retinal microvascular function. METHODS: In The Maastricht Study, a population-based cohort study enriched with type 2 diabetes (n = 1298, 47.3% women, aged 60.2 ± 8.1 years, 29.5% type 2 diabetes), we studied whether accelerometer-assessed physical activity and sedentary time associate with skin and retinal microvascular function. Associations were studied by linear regression and adjusted for major cardiovascular risk factors. In addition, we investigated whether associations were stronger in type 2 diabetes. RESULTS: In individuals with type 2 diabetes, total physical activity and higher-intensity physical activity were independently associated with greater heat-induced skin hyperemia (regression coefficients per hour), respectively, 10 (95% CI: 1; 18) and 36 perfusion units (14; 58). In individuals without type 2 diabetes, total physical activity and higher-intensity physical activity were not associated with heat-induced skin hyperemia. No associations with retinal arteriolar %-dilation were identified. CONCLUSION: Higher levels of total and higher-intensity physical activity were associated with greater skin microvascular vasodilation in individuals with, but not in those without, type 2 diabetes.

Role of cardiovascular health factors in mediating social inequalities in the incidence of dementia in the UK: two prospective, population-based cohort studies.

Background: The contribution of modifiable risk factors to social inequalities in dementia, observed in longitudinal studies, remains unclear. We aimed to quantify the role of cardiovascular health factors, assessed using Life's Essential 8 (LE8) score, in mediating social inequalities in incidence of dementia and, for comparison, in incidence of stroke, coronary heart disease, and mortality. Methods: In this prospective, population-based cohort study, we collected data from the UK Whitehall II Study and UK Biobank databases. Participants were included if data were available on SEP, outcomes and LE8 (smoking, physical activity, diet, body mass index, blood pressure, fasting blood glucose, lipid levels, sleep duration). The primary outcome was incident dementia and secondary outcomes were stroke, coronary heart disease, and mortality. Outcomes were derived from electronic healthcare records. Socioeconomic position (SEP) was measured by occupation in Whitehall II and education in UK Biobank. Counterfactual mediation analysis was used to quantify the extent to which LE8 score explained the associations of SEP with all outcomes. Analyses involved Cox regression, accelerated failure time models, and linear regression; and were adjusted for age, sex, and ethnicity. Findings: Between 10.09.1985 and 29.03.1988, a total of 9688 participants (mean age ± SD 44.9 ± 6.0; 67% men) from the Whitehall II study, and between 19.12.2006 and 01.10.2010, 278,215 participants (mean age ± SD 56.0 ± 8.1; 47% men) from the UK Biobank were included. There were 606 and 4649 incident dementia cases over a median (interquartile range) follow-up of 31.7 (31.1-32.7) and 13.5 (12.7-14.1) years respectively in Whitehall II and UK Biobank. In Whitehall II, the hazard ratio was 1.85 [95% CI 1.42, 2.32] for the total effect of SEP on dementia and 1.20 [1.12, 1.28] for the indirect effect via the LE8, the proportion mediated being 36%. In UK Biobank, the total effect of SEP on dementia was 1.65 [1.54, 1.78]; the indirect effect was 1.11 [1.09, 1.12], and the proportion mediated was 24%. The proportions mediated for stroke, coronary heart disease, and mortality were higher, ranging between 34% and 63% in Whitehall II and between 36% and 50% in UK Biobank. Interpretation: In two well-characterised cohort studies, up to one third of the social inequalities in incidence of dementia was attributable to cardiovascular health factors. Promotion of cardiovascular health in midlife may contribute to reducing social inequalities in risk of dementia, in addition to cardiovascular diseases and all-cause mortality. This study used adult measures of SEP, further research is warranted using lifecourse measures of SEP. Funding: NIH (RF1AG062553).

Retinal Vascular Changes in Heart Failure with Preserved Ejection Fraction Using Optical Coherence Tomography Angiography.

Background: Systemic microvascular regression and dysfunction are considered important underlying mechanisms in heart failure with preserved ejection fraction (HFpEF), but retinal changes are unknown. Methods: This prospective study aimed to investigate whether retinal microvascular and structural parameters assessed using optical coherence tomography angiography (OCT-A) differ between patients with HFpEF and control individuals (i.e., capillary vessel density, thickness of retina layers). We also aimed to assess the associations of retinal parameters with clinical and echocardiographic parameters in HFpEF. HFpEF patients, but not controls, underwent echocardiography. Macula-centered 6 × 6 mm volume scans were computed of both eyes. Results: Twenty-two HFpEF patients and 24 controls without known HFpEF were evaluated, with an age of 74 [68-80] vs. 68 [58-77] years (p = 0.027), and 73% vs. 42% females (p = 0.034), respectively. HFpEF patients showed vascular degeneration compared to controls, depicted by lower macular vessel density (p < 0.001) and macular ganglion cell-inner plexiform layer thickness (p = 0.025), and a trend towards lower total retinal volume (p = 0.050) on OCT-A. In HFpEF, a lower total retinal volume was associated with markers of diastolic dysfunction (septal e', septal and average E/e': R2 = 0.38, 0.36, 0.25, respectively; all p < 0.05), even after adjustment for age, sex, diabetes mellitus, or atrial fibrillation. Conclusions: Patients with HFpEF showed clear levels of retinal vascular changes compared to control individuals, and retinal alterations appeared to be associated with markers of more severe diastolic dysfunction in HFpEF. OCT-A may therefore be a promising technique for monitoring systemic microvascular regression and cardiac diastolic dysfunction.

Retinal Functional and Structural Neural Indices: Potential Biomarkers for the Monitoring of Cerebral Neurodegeneration: The Maastricht Study.

BACKGROUND: If retinal indices of neurodegeneration are to be biomarkers for the monitoring of cerebral neurodegeneration, it is important to establish whether potentially modifiable risk factors for dementia are associated with retinal neurodegenerative changes. OBJECTIVE: To study associations of dementia risk factors with retinal sensitivity, an index of retinal neural function, and retinal nerve fiber layer (RNFL) thickness, an index of retinal neural structure. METHODS: We used cross-sectional data from The Maastricht Study (up to 5,666 participants, 50.5% men, mean age 59.7), and investigated associations with regression analyses (adjusted for potential confounders). RESULTS: Most risk factors under study (i.e., hyperglycemia, unhealthy diet, lower cardiorespiratory fitness, smoking, alcohol consumption, and hypertension) were significantly associated with lower retinal sensitivity and lower RNFL thickness. CONCLUSION: Findings of this population-based study support the concept that retinal neural indices may be biomarkers for the monitoring of therapeutic strategies that aim to prevent early-stage cerebral neurodegeneration and, ultimately, dementia.

Neurovascular coupling unit dysfunction and dementia: Retinal measurements as tools to move towards population-based evidence.

Dysfunction of the neurovascular coupling unit may be an important contributor to dementia. The neurovascular coupling unit comprises neuronal structures (e.g. astrocytes) and vascular structures (e.g. endothelial cells) that functionally interact both at the level of the arterioles as well as at the capillary level (blood-brain barrier) to regulate optimal metabolic conditions in the brain. However, it remains unclear how and to what extent dysfunction of the neurovascular coupling unit contributes to the early-stage pathobiology of dementia. Currently, limited data are available on the association between neurovascular coupling unit dysfunction, as quantified by cerebral imaging techniques, and cognitive performance. In particular, there is a lack of population-based human data (defined as studies with a sample size ~n>500). This is an important limitation because population-based studies, in comparison with smaller clinical studies, provide data which is better representative of the general population; are less susceptible to selection bias; and have a larger statistical power to detect small associations. To acquire population-based data, however, alternative imaging techniques than cerebral imaging techniques may be required. Disadvantages of cerebral imaging techniques, which limit use in population-based studies, are that these techniques are relatively expensive, time-consuming, and/or invasive. In this review, we propose that retinal imaging techniques can be used for population-based studies: on the one hand the retina and brain have many anatomical and physiological similarities; and on the other hand retinal imaging techniques are non-invasive, highly accurate, relatively inexpensive, and require relatively short measurement time. To provide support for this concept, we provide an overview on the human (population-based) evidence on the associations of retinal indices of neurodegeneration, microvascular dysfunction, and dysfunction of the neurovascular coupling unit with magnetic resonance imaging (MRI) features of structural brain abnormalities and cognitive performance.

(Pre)diabetes, glycemia, and daily glucose variability are associated with retinal nerve fiber layer thickness in The Maastricht Study.

Retinopathy and neuropathy in type 2 diabetes are preceded by retinal nerve fibre layer (RNFL) thinning, an index of neurodegeneration. We investigated whether glucose metabolism status (GMS), measures of glycaemia, and daily glucose variability (GV) are associated with RNFL thickness over the entire range of glucose tolerance. We used cross-sectional data from The Maastricht Study (up to 5455 participants, 48.9% men, mean age 59.5 years and 22.7% with type 2 diabetes) to investigate the associations of GMS, measures of glycaemia (fasting plasma glucose [FPG], 2-h post-load glucose [2-h PG], HbA1c, advanced glycation endproducts [AGEs] assessed as skin autofluorescence [SAF]) and indices of daily GV (incremental glucose peak [IGP] and continuous glucose monitoring [CGM]-assessed standard deviation [SD]) with mean RNFL thickness. We used linear regression analyses and, for GMS, P for trend analyses. We adjusted associations for demographic, cardiovascular risk and lifestyle factors, and, only for measures of GV, for indices of mean glycaemia. After full adjustment, type 2 diabetes and prediabetes (versus normal glucose metabolism) were associated with lower RNFL thickness (standardized beta [95% CI], respectively - 0.16 [- 0.25; - 0.08]; - 0.05 [- 0.13; 0.03]; Ptrend = 0.001). Greater FPG, 2-h PG, HbA1c, SAF, IGP, but not CGM-assessed SD, were also associated with lower RNFL thickness (per SD, respectively - 0.05 [- 0.08; - 0.01]; - 0.06 [- 0.09; - 0.02]; - 0.05 [- 0.08; - 0.02]; - 0.04 [- 0.07; - 0.01]; - 0.06 [- 0.12; - 0.01]; and - 0.07 [- 0.21; 0.07]). In this population-based study, a more adverse GMS and, over the entire range of glucose tolerance, greater glycaemia and daily GV were associated with lower RNFL thickness. Hence, early identification of individuals with hyperglycaemia, early glucose-lowering treatment, and early monitoring of daily GV may contribute to the prevention of RNFL thinning, an index of neurodegeneration and precursor of retinopathy and neuropathy.

Association of Retinal Nerve Fiber Layer Thickness, an Index of Neurodegeneration, With Depressive Symptoms Over Time.

Importance: Whether neurodegeneration contributes to the early pathobiology of late-life depression remains incompletely understood. Objective: To investigate whether lower retinal nerve fiber layer (RNFL) thickness, a marker of neurodegeneration, is associated with the incidence of clinically relevant depressive symptoms and depressive symptoms over time. Design, Setting, and Participants: This is a population-based cohort study from the Netherlands (The Maastricht Study) with baseline examination between 2010 and 2020 and median (IQR) follow-up of 5.0 (3.0-6.0) years. Participants were recruited from the general population. Individuals with type 2 diabetes were oversampled by design. Data analysis was performed from September 2020 to January 2021. Exposures: RNFL, an index of neurodegeneration, assessed with optical coherence tomography. Main Outcomes and Measures: Depressive symptoms were assessed with the Patient Health Questionnaire (PHQ)-9 (continuous score, 0-27) at baseline and over time via annual assessments. The presence of clinically relevant depressive symptoms was defined as a PHQ-9 score of 10 or higher. Results: We used data from 4934 participants with depressive symptoms over time (mean [SD] age, 59.7 [8.4] years; 2159 women [50.8%]; 870 had type 2 diabetes [20.5%]). Lower RNFL thickness was associated with higher incidence of clinically relevant depressive symptoms (per 1 SD, hazard ratio 1.11; 95% CI, 1.01-1.23) and more depressive symptoms over time (per 1 SD, rate ratio, 1.04; 95% CI, 1.01-1.06), after adjustment for demographic, cardiovascular, and lifestyle factors. Conclusions and Relevance: The findings of this study suggest that lower RNFL thickness is associated with higher incidence of clinically relevant depressive symptoms and more depressive symptoms over time. Hence, neurodegeneration may be associated with the early pathobiology of late-life depression.

Blood pressure variability and microvascular dysfunction: the Maastricht Study.

BACKGROUND: Microvascular dysfunction (MVD) contributes to stroke, dementia, depression, retinopathy and chronic kidney disease. However, the determinants of MVD are incompletely understood. Greater blood pressure variability (BPV) may be one such determinant. METHODS AND RESULTS: We used cross-sectional data of The Maastricht Study (n = 2773, age 59.9 years; 51.9% men) to investigate whether greater very short- to mid-term BPV is associated with various MVD measures. We standardized and averaged within-visit, 24-h and 7-day BPV into a systolic and a diastolic BPV composite score. MVD measures included a composite score of MRI cerebral small vessel disease (CSVD) features (total brain parenchymal volume, white matter hyperintensity volume, lacunar infarcts and cerebral microbleeds), a composite score of flicker light-induced retinal arteriolar and venular dilation response, albuminuria, heat-induced skin hyperemia and a composite score of plasma biomarkers of MVD (sICAM-1, sVCAM-1, sE-selectin and von Willebrand Factor). We used linear regression adjusted for age, sex, glucose metabolism status, mean 24-h systolic or DBP, cardiovascular risk factors and antihypertensive medication. We found that higher systolic and diastolic BPV composite scores (per SD) were associated with higher albuminuria [higher ratio, 1.04 (95% CI 1.00-1.08) and 1.07 (1.03-1.11), respectively], but not with other measures of MVD tested. CONCLUSION: Greater systolic and diastolic BPV was associated with higher albuminuria, but not with CSVD features, flicker light-induced retinal arteriolar and venular dilation response, heat-induced skin hyperemia and plasma biomarkers of MVD. This suggests that the microvasculature of the kidneys is most vulnerable to the detrimental effects of greater BPV.