Association of hippocampal subfield volumes with prevalence, course and incidence of depressive symptoms: The Maastricht Study.

BACKGROUND: Late-life depression has been associated with volume changes of the hippocampus. However, little is known about its association with specific hippocampal subfields over time. AIMS: We investigated whether hippocampal subfield volumes were associated with prevalence, course and incidence of depressive symptoms. METHOD: We extracted 12 hippocampal subfield volumes per hemisphere with FreeSurfer v6.0 using T1-weighted and fluid-attenuated inversion recovery 3T magnetic resonance images. Depressive symptoms were assessed at baseline and annually over 7 years of follow-up (9-item Patient Health Questionnaire). We used negative binominal, logistic, and Cox regression analyses, corrected for multiple comparisons, and adjusted for demographic, cardiovascular and lifestyle factors. RESULTS: A total of n = 4174 participants were included (mean age 60.0 years, s.d. = 8.6, 51.8% female). Larger right hippocampal fissure volume was associated with prevalent depressive symptoms (odds ratio (OR) = 1.26, 95% CI 1.08-1.48). Larger bilateral hippocampal fissure (OR = 1.37-1.40, 95% CI 1.14-1.71), larger right molecular layer (OR = 1.51, 95% CI 1.14-2.00) and smaller right cornu ammonis (CA)3 volumes (OR = 0.61, 95% CI 0.48-0.79) were associated with prevalent depressive symptoms with a chronic course. No associations of hippocampal subfield volumes with incident depressive symptoms were found. Yet, lower left hippocampal amygdala transition area (HATA) volume was associated with incident depressive symptoms with chronic course (hazard ratio = 0.70, 95% CI 0.55-0.89). CONCLUSIONS: Differences in hippocampal fissure, molecular layer and CA volumes might co-occur or follow the onset of depressive symptoms, in particular with a chronic course. Smaller HATA was associated with an increased risk of incident (chronic) depression. Our results could capture a biological foundation for the development of chronic depressive symptoms, and stresses the need to discriminate subtypes of depression to unravel its biological underpinnings.

Associations of an individual's need for cognition with structural brain damage and cognitive functioning/impairment: cross-sectional population-based study.

BACKGROUND: High cognitive activity possibly reduces the risk of cognitive decline and dementia. AIMS: To investigate associations between an individual's need to engage in cognitively stimulating activities (need for cognition, NFC) and structural brain damage and cognitive functioning in the Dutch general population with and without existing cognitive impairment. METHOD: Cross-sectional data were used from the population-based cohort of the Maastricht Study. NFC was measured using the Need For Cognition Scale. Cognitive functioning was tested in three domains: verbal memory, information processing speed, and executive functioning and attention. Values 1.5 s.d. below the mean were defined as cognitive impairment. Standardised volumes of white matter hyperintensities (WMH), cerebrospinal fluid (CSF) and presence of cerebral small vessel disease (CSVD) were derived from 3T magnetic resonance imaging. Multiple linear and binary logistic regression analyses were used adjusted for demographic, somatic and lifestyle factors. RESULTS: Participants (n = 4209; mean age 59.06 years, s.d. = 8.58; 50.1% women) with higher NFC scores had higher overall cognition scores (B = 0.21, 95% CI 0.17-0.26, P < 0.001) and lower odds for CSVD (OR = 0.74, 95% CI 0.60-0.91, P = 0.005) and cognitive impairment (OR = 0.60, 95% CI 0.48-0.76, P < 0.001) after adjustment for demographic, somatic and lifestyle factors. The association between NFC score and cognitive functioning was similar for individuals with and without prevalent cognitive impairment. We found no significant association between NFC and WMH or CSF volumes. CONCLUSIONS: A high need to engage in cognitively stimulating activities is associated with better cognitive functioning and less presence of CSVD and cognitive impairment. This suggests that, in middle-aged individuals, motivation to engage in cognitively stimulating activities may be an opportunity to improve brain health.

Social relationship factors, depressive symptoms, and incident dementia: a prospective cohort study into their interrelatedness.

BACKGROUND: Different aspects of social relationships (e.g., social network size or loneliness) have been associated with dementia risk, while their overlap and potentially underlying pathways remain largely unexplored. This study therefore aimed to (1) discriminate between different facets of social relationships by means of factor analysis, (2) examine their associations with dementia risk, and (3) assess mediation by depressive symptoms. METHODS: Thirty-six items from questionnaires on social relationships administered in Wave 2 (2004/2005) of the English Longitudinal Study of Ageing (n = 7536) were used for exploratory and confirmatory factor analysis. Factors were then used as predictors in Cox proportional hazard models with dementia until Wave 9 as outcome, adjusted for demographics and cardiovascular risk factors. Structural equation modeling tested mediation by depressive symptoms through effect decomposition. RESULTS: Factor analyses identified six social factors. Across a median follow-up time of 11.8 years (IQR = 5.9-13.9 years), 501 people developed dementia. Higher factor scores for frequency and quality of contact with children (HR = 0.88; p = 0.021) and more frequent social activity engagement (HR = 0.84; p < 0.001) were associated with lower dementia risk. Likewise, higher factor scores for loneliness (HR = 1.13; p = 0.011) and negative experiences of social support (HR = 1.10; p = 0.047) were associated with higher dementia risk. Mediation analyses showed a significant partial effect mediation by depressive symptoms for all four factors. Additional analyses provided little evidence for reverse causation. CONCLUSIONS: Frequency and quality of social contacts, social activity engagement, and feelings of loneliness are associated with dementia risk and might be suitable targets for dementia prevention programs, partly by lowering depressive symptoms.

Retinal microvascular function and incidence and trajectories of clinically relevant depressive symptoms: the Maastricht Study.

BACKGROUND: Cerebral microvascular dysfunction may contribute to depression via disruption of brain structures involved in mood regulation, but evidence is limited. We investigated the association of retinal microvascular function, a proxy for microvascular function in the brain, with incidence and trajectories of clinically relevant depressive symptoms. METHODS: Longitudinal data are from The Maastricht Study of 5952 participants (59.9 ± 8.5 years/49.7% women) without clinically relevant depressive symptoms at baseline (2010-2017). Central retinal arteriolar equivalent and central retinal venular equivalent (CRAE and CRVE) and a composite score of flicker light-induced retinal arteriolar and venular dilation were assessed at baseline. We assessed incidence and trajectories of clinically relevant depressive symptoms (9-item Patient Health Questionnaire score ⩾10). Trajectories included continuously low prevalence (low, n = 5225 [87.8%]); early increasing, then chronic high prevalence (early-chronic, n = 157 [2.6%]); low, then increasing prevalence (late-increasing, n = 247 [4.2%]); and remitting prevalence (remitting, n = 323 [5.4%]). RESULTS: After a median follow-up of 7.0 years (range 1.0-11.0), 806 (13.5%) individuals had incident clinically relevant depressive symptoms. After full adjustment, a larger CRAE and CRVE were each associated with a lower risk of clinically relevant depressive symptoms (hazard ratios [HRs] per standard deviation [s.d.]: 0.89 [95% confidence interval (CI) 0.83-0.96] and 0.93 [0.86-0.99], respectively), while a lower flicker light-induced retinal dilation was associated with a higher risk of clinically relevant depressive symptoms (HR per s.d.: 1.10 [1.01-1.20]). Compared to the low trajectory, a larger CRAE was associated with lower odds of belonging to the early-chronic trajectory (OR: 0.83 [0.69-0.99]) and a lower flicker light-induced retinal dilation was associated with higher odds of belonging to the remitting trajectory (OR: 1.23 [1.07-1.43]). CONCLUSIONS: These findings support the hypothesis that cerebral microvascular dysfunction contributes to the development of depressive symptoms.

Increasing awareness for dementia risk reduction through a public awareness campaign in Denmark: A pre-post study.

OBJECTIVE: It is estimated that about 40% of all dementia cases are potentially attributable to modifiable risk factors, but awareness of this is relatively lacking. METHODS: An 18-months nation-wide public awareness campaign on dementia risk reduction was rolled out in Denmark that combined a mass-media approach with an online risk assessment tool and knowledge bank targeting all inhabitants aged between 40 and 75 years. Campaign effects (increase in awareness and knowledge of modifiable dementia risk and protective factors) were assessed via online surveys in two independent random samples before (n = 1003) and after the campaign (n = 1076). RESULTS: After adjusting for differences in educational level between the two samples, there was no significant difference in awareness of dementia risk reduction between the pre-campaign (66.5% aware) and post-campaign (63.4% aware) sample (probit z = -0.08, p = 0.151). The number of correctly identified risk/protective factors was significantly higher in the post-campaign sample. After adjusting for potential confounding factors, self-reported exposure to the campaign was associated with more awareness, better recognition of risk/protective factors, more motivation for and actual implementation of lifestyle changes. CONCLUSIONS: This mass-media campaign did not increase overall awareness that dementia risk is partly modifiable. However, exposure to the campaign was associated with more awareness and willingness to take action to improve brain health. Future campaigns should tailor messages to specific subgroups to broaden the reach (e.g., males), co-create materials with the target group, and give special attention to the contribution of metabolic/cardiovascular risk factors to dementia risk.

Conformational control of antimicrobial peptide amphiphilicity: consequences for boosting membrane interactions and antimicrobial effects of photocatalytic TiO2 nanoparticles.

This study reports on the effects of conformationally controlled amphiphilicity of antimicrobial peptides (AMPs) on their ability to coat TiO2 nanoparticles (NPs) and boost the photocatalytic antimicrobial effects of such NPs. For this, TiO2 NPs were combined with AMP EFK17 (EFKRIVQRIKDFLRNLV), displaying a disordered conformation in aqueous solution but helix formation on interaction with bacterial membranes. The membrane-bound helix is amphiphilic, with all polar and charged amino acid residues located at one side and all non-polar and hydrophobic residues on the other. In contrast, the d-enantiomer variant EFK17-d (E(dF)KR(dI)VQR(dI)KD(dF)LRNLV) is unable to form the amphiphilic helix on bacterial membrane interaction, whereas the W-residues in EFK17-W (EWKRWVQRWKDFLRNLV) boost hydrophobic interactions of the amphiphilic helix. Circular dichroism results showed the effects displayed for the free peptide, to also be present for peptide-coated TiO2 NPs, causing peptide binding to decrease in the order EFK17-W > EFK17 > EFK17-d. Notably, the formation of reactive oxygen species (ROS) by the TiO2 NPs was essentially unaffected by the presence of peptide coating, for all the peptides investigated, and the coatings stabilized over hours of UV exposure. Photocatalytic membrane degradation from TiO2 NPs coated with EFK17-W and EFK17 was promoted for bacteria-like model bilayers containing anionic phosphatidylglycerol but suppressed in mammalian-like bilayers formed by zwitterionic phosphatidylcholine and cholesterol. Structural aspects of these effects were further investigated by neutron reflectometry with clear variations observed between the bacteria- and mammalian-like model bilayers for the three peptides. Mirroring these results in bacteria-like model membranes, combining TiO2 NPs with EFK17-W and EFK17, but not with non-adsorbing EFK17-d, resulted in boosted antimicrobial effects of the resulting cationic composite NPs already in darkness, effects enhanced further on UV illumination.

Do poor psychosocial resources mediate health inequalities in type 2 diabetes mellitus? Findings from the Maastricht study.

Low socioeconomic position (SEP) has been identified as a risk factor for type 2 diabetes mellitus (T2DM), and psychosocial resources might be on the pathway in this association. We examined two poor psychosocial resources, low control beliefs and inferiority beliefs, that might link low SEP with T2DM. 8292 participants aged 40-75 living in Southern Netherlands participated in The Maastricht Study starting from September 2010 to October 2020 and were followed up to 10 years with annual questionnaires. SEP (education, income, occupation), low control beliefs, inferiority beliefs, and (pre)diabetes by oral glucose tolerance test were measured at baseline. Incident T2DM was self-reported per annum. We analysed the mediating roles of poor psychosocial resources by using counterfactual mediation analysis. People with low SEP had more often prevalent and incident T2DM (e.g. low education: HR = 2.13, 95%CI: 1.53-2.97). Low control beliefs and high inferiority beliefs were more common among people with low SEP. Moreover, low control beliefs and high inferiority beliefs were risk factors for T2DM (e.g. low control beliefs: HR = 1.50, 95%CI: 1.08-2.09). The relationship between SEP and T2DM was partially mediated by control beliefs (8.0-13.6%) and inferiority beliefs (2.2-4.5%). We conclude that poor psychosocial resources are important in socioeconomic inequalities in diabetes. Researchers and practitioners should consider the psychosocial profile of people with lower SEP, as such a profile might interfere with the development, treatment, and prevention of T2DM. Further research should explore how poor psychosocial resources interact with chronic stress in relation to socioeconomic health inequalities.

Network analysis of neuropsychiatric, cognitive, and functional complications of stroke: implications for novel treatment targets.

AIM: Recovery from stroke is adversely affected by neuropsychiatric complications, cognitive impairment, and functional disability. Better knowledge of their mutual relationships is required to inform effective interventions. Network theory enables the conceptualization of symptoms and impairments as dynamic and mutually interacting systems. We aimed to identify interactions of poststroke complications using network analysis in diverse stroke samples. METHODS: Data from 2185 patients were sourced from member studies of STROKOG (Stroke and Cognition Consortium), an international collaboration of stroke studies. Networks were generated for each cohort, whereby nodes represented neuropsychiatric symptoms, cognitive deficits, and disabilities on activities of daily living. Edges characterized associations between them. Centrality measures were used to identify hub items. RESULTS: Across cohorts, a single network of interrelated poststroke complications emerged. Networks exhibited dissociable depression, apathy, fatigue, cognitive impairment, and functional disability modules. Worry was the most central symptom across cohorts, irrespective of the depression scale used. Items relating to activities of daily living were also highly central nodes. Follow-up analysis in two studies revealed that individuals who worried had more densely connected networks than those free of worry (CASPER [Cognition and Affect after Stroke: Prospective Evaluation of Risks] study: S = 9.72, P = 0.038; SSS [Sydney Stroke Study]: S = 13.56, P = 0.069). CONCLUSION: Neuropsychiatric symptoms are highly interconnected with cognitive deficits and functional disabilities resulting from stroke. Given their central position and high level of connectedness, worry and activities of daily living have the potential to drive multimorbidity and mutual reinforcement between domains of poststroke complications. Targeting these factors early after stroke may have benefits that extend to other complications, leading to better stroke outcomes.

Cognitive change in prevalent and incident hearing loss: The Maastricht Aging Study.

INTRODUCTION: Hearing loss (HL) has been associated with cognitive decline and dementia. We examined the temporal association between prevalent and incident HL and cognitive change. METHODS: A total of 1823 participants (24-82 years) from the Maastricht Aging Study (MAAS) were assessed at baseline, 6 and 12 years, including pure-tone audiometry. Linear-mixed models were used to test the association between HL and cognition, adjusted for demographics and other dementia risk factors. RESULTS: Participants with prevalent and incident HL showed a faster decline in verbal memory, information processing speed, and executive function than participants without HL. Decline was steady from baseline to 6 and 12 years for prevalent HL, but time-delayed from 6 to 12 years for incident HL. Having a hearing aid did not change associations. DISCUSSION: Findings support the notion that HL is a risk factor for cognitive decline independent of other dementia risk factors. Onset of HL preceded onset of cognitive decline. HIGHLIGHTS: We examined cognitive change in prevalent and incident hearing loss. Prevalent and incident hearing loss were associated with faster cognitive decline. For prevalent hearing loss, decline was steady from baseline to 6 and 12 years. Onset of hearing loss preceded the onset of cognitive decline. Having a hearing aid did not change the observed associations.

Umbrella review and Delphi study on modifiable factors for dementia risk reduction.

A 2013 systematic review and Delphi consensus study identified 12 modifiable risk and protective factors for dementia, which were subsequently merged into the "LIfestyle for BRAin health" (LIBRA) score. We systematically evaluated whether LIBRA requires revision based on new evidence. To identify modifiable risk and protective factors suitable for dementia risk reduction, we combined an umbrella review of systematic reviews and meta-analyses with a two-round Delphi consensus study. The review of 608 unique primary studies and opinions of 18 experts prioritized six modifiable factors: hearing impairment, social contact, sleep, life course inequalities, atrial fibrillation, and psychological stress. Based on expert ranking, hearing impairment, social contact, and sleep were considered the most suitable candidates for inclusion in updated dementia risk scores. As such, the current study shows that dementia risk scores need systematic updates based on emerging evidence. Future studies will validate the updated LIBRA score in different cohorts. HIGHLIGHTS: An umbrella review was combined with opinions of 18 dementia experts. Various candidate targets for dementia risk reduction were identified. Experts prioritized hearing impairment, social contact, and sleep. Re-assessment of dementia risk scores is encouraged. Future work should evaluate the predictive validity of updated risk scores.

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.

Lifestyle and incident dementia: A COSMIC individual participant data meta­analysis.

INTRODUCTION: The LIfestyle for BRAin Health (LIBRA) index yields a dementia risk score based on modifiable lifestyle factors and is validated in Western samples. We investigated whether the association between LIBRA scores and incident dementia is moderated by geographical location or sociodemographic characteristics. METHODS: We combined data from 21 prospective cohorts across six continents (N = 31,680) and conducted cohort-specific Cox proportional hazard regression analyses in a two-step individual participant data meta-analysis. RESULTS: A one-standard-deviation increase in LIBRA score was associated with a 21% higher risk for dementia. The association was stronger for Asian cohorts compared to European cohorts, and for individuals aged ≤75 years (vs older), though only within the first 5 years of follow-up. No interactions with sex, education, or socioeconomic position were observed. DISCUSSION: Modifiable risk and protective factors appear relevant for dementia risk reduction across diverse geographical and sociodemographic groups. HIGHLIGHTS: A two-step individual participant data meta-analysis was conducted. This was done at a global scale using data from 21 ethno-regionally diverse cohorts. The association between a modifiable dementia risk score and dementia was examined. The association was modified by geographical region and age at baseline. Yet, modifiable dementia risk and protective factors appear relevant in all investigated groups and regions.

Blood-based multivariate methylation risk score for cognitive impairment and dementia.

INTRODUCTION: The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood-derived DNA methylation as a promising tool for early dementia risk detection. METHODS: In conjunction with an extensive array of machine learning techniques, we employed whole blood genome-wide DNA methylation data as a surrogate for 14 modifiable and non-modifiable factors in the assessment of dementia risk in independent dementia cohorts. RESULTS: We established a multivariate methylation risk score (MMRS) for identifying mild cognitive impairment cross-sectionally, independent of age and sex (P = 2.0 × 10-3). This score significantly predicted the prospective development of cognitive impairments in independent studies of Alzheimer's disease (hazard ratio for Rey's Auditory Verbal Learning Test (RAVLT)-Learning = 2.47) and Parkinson's disease (hazard ratio for MCI/dementia = 2.59). DISCUSSION: Our work shows the potential of employing blood-derived DNA methylation data in the assessment of dementia risk. HIGHLIGHTS: We used whole blood DNA methylation as a surrogate for 14 dementia risk factors. Created a multivariate methylation risk score for predicting cognitive impairment. Emphasized the role of machine learning and omics data in predicting dementia. The score predicts cognitive impairment development at the population level.

White Matter Hyperintensity Volume and Poststroke Cognition: An Individual Patient Data Pooled Analysis of 9 Ischemic Stroke Cohort Studies.

BACKGROUND: White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patients with ischemic stroke from different cohorts. METHODS: We pooled and harmonized individual patient data (n=1568) from 9 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Included cohorts comprised patients with available magnetic resonance imaging and multidomain cognitive assessment <15 months poststroke. In this individual patient data meta-analysis, linear mixed models were used to determine the association between WMH volume and domain-specific cognitive functioning (Z scores; attention and executive functioning, processing speed, language and verbal memory) for the total sample and stratified by infarct type. Preexisting brain injury was accounted for in the multivariable models and all analyses were corrected for the study site as a random effect. RESULTS: In the total sample (67 years [SD, 11.5], 40% female), we found a dose-dependent inverse relationship between WMH volume and poststroke cognitive functioning across all 4 cognitive domains (coefficients ranging from -0.09 [SE, 0.04, P=0.01] for verbal memory to -0.19 [SE, 0.03, P<0.001] for attention and executive functioning). This relation was independent of acute infarct volume and the presence of lacunes and old infarcts. In stratified analyses, the relation between WMH volume and domain-specific functioning was also largely independent of infarct type. CONCLUSIONS: In patients with ischemic stroke, increasing WMH volume is independently associated with worse cognitive functioning across all major domains, regardless of old ischemic lesions and infarct type.

Sex Differences in Poststroke Cognitive Impairment: A Multicenter Study in 2343 Patients With Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women. METHODS: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278). RESULTS: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61-0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45-0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17-1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P=0.02), with a lower specificity for women (0.80) than men (0.96; P=0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P=0.62 and 0.29 versus 0.28; P=0.86, respectively). CONCLUSIONS: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

Interpretable Clinical Genomics with a Likelihood Ratio Paradigm.

Human Phenotype Ontology (HPO)-based analysis has become standard for genomic diagnostics of rare diseases. Current algorithms use a variety of semantic and statistical approaches to prioritize the typically long lists of genes with candidate pathogenic variants. These algorithms do not provide robust estimates of the strength of the predictions beyond the placement in a ranked list, nor do they provide measures of how much any individual phenotypic observation has contributed to the prioritization result. However, given that the overall success rate of genomic diagnostics is only around 25%-50% or less in many cohorts, a good ranking cannot be taken to imply that the gene or disease at rank one is necessarily a good candidate. Here, we present an approach to genomic diagnostics that exploits the likelihood ratio (LR) framework to provide an estimate of (1) the posttest probability of candidate diagnoses, (2) the LR for each observed HPO phenotype, and (3) the predicted pathogenicity of observed genotypes. LIkelihood Ratio Interpretation of Clinical AbnormaLities (LIRICAL) placed the correct diagnosis within the first three ranks in 92.9% of 384 case reports comprising 262 Mendelian diseases, and the correct diagnosis had a mean posttest probability of 67.3%. Simulations show that LIRICAL is robust to many typically encountered forms of genomic and phenomic noise. In summary, LIRICAL provides accurate, clinically interpretable results for phenotype-driven genomic diagnostics.

The association of white matter connectivity with prevalence, incidence and course of depressive symptoms: The Maastricht Study.

BACKGROUND: Altered white matter brain connectivity has been linked to depression. The aim of this study was to investigate the association of markers of white matter connectivity with prevalence, incidence and course of depressive symptoms. METHODS: Markers of white matter connectivity (node degree, clustering coefficient, local efficiency, characteristic path length, and global efficiency) were assessed at baseline by 3 T MRI in the population-based Maastricht Study (n = 4866; mean ± standard deviation age 59.6 ± 8.5 years, 49.0% women; 17 406 person-years of follow-up). Depressive symptoms (9-item Patient Health Questionnaire; PHQ-9) were assessed at baseline and annually over seven years of follow-up. Major depressive disorder (MDD) was assessed with the Mini-International Neuropsychiatric Interview at baseline only. We used negative binominal, logistic and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle risk factors. RESULTS: A lower global average node degree at baseline was associated with the prevalence and persistence of clinically relevant depressive symptoms [PHQ-9 ⩾ 10; OR (95% confidence interval) per standard deviation = 1.21 (1.05-1.39) and OR = 1.21 (1.02-1.44), respectively], after full adjustment. On the contrary, no associations were found of global average node degree with the MDD at baseline [OR 1.12 (0.94-1.32) nor incidence or remission of clinically relevant depressive symptoms [HR = 1.05 (0.95-1.17) and OR 1.08 (0.83-1.41), respectively]. Other connectivity measures of white matter organization were not associated with depression. CONCLUSIONS: Our findings suggest that fewer white matter connections may contribute to prevalent depressive symptoms and its persistence but not to incident depression. Future studies are needed to replicate our findings.

Correlations between kynurenines in plasma and CSF, and their relation to markers of Alzheimer's disease pathology.

INTRODUCTION: Altered levels of kynurenines in blood and cerebrospinal fluid (CSF) have been reported in Alzheimer's disease (AD). However, it is still largely unknown whether peripheral kynurenine concentrations resemble those found in CSF and how they relate to AD pathology. We therefore studied correlations between kynurenines in plasma and CSF and their associations with CSF amyloid-beta (Aß1-42) and tau levels in patients from the memory clinic spanning the whole cognitive spectrum. METHODS: The Biobank Alzheimer Center Limburg study is a prospective cohort study of consecutive patients referred to the memory clinic of the Alzheimer Center Limburg. Plasma and CSF concentrations of tryptophan (TRP), eight kynurenines and neopterin from 138 patients were determined by means of LC-MS/MS. Additionally, CSF Aß1-42, total-tau (t-tau) and phosphorylated tau (p-tau) concentrations were determined using commercially available single-parameter ELISA methods. Partial correlations were used to analyze cross-sectional associations between kynurenines in plasma and CSF and their relation to AD related CSF-biomarkers adjusted for age, sex, educational level, and kidney function. RESULTS: Moderate to strong correlations were observed between plasma and CSF levels for quinolinic acid (QA; r = 0.63), TRP (r = 0.47), anthranilic acid (r = 0.59), picolinic acid (r = 0.55), and the kynurenine (KYN)/TRP ratio (KTR; r = 0.55; all p < 0.0001), while other kynurenines correlated only weakly with their corresponding CSF values. No correlations were found between plasma and CSF levels of KA/QA. Several kynurenines were also weakly correlated with Aß1-42, t-tau or p-tau. Plasma levels of KA/QA were negatively correlated with Aß1-42 (r = -0.21, p < 0.05). Plasma levels of TRP were negatively correlated with t-tau (r = -0.19) and levels of KYN with p-tau (r = -0.18; both p < 0.05). CSF levels of KYN (r = 0.20, p < 0.05), KA (r = 0.23, p < 0.01), and KTR (r = 0.18, p < 0.05) were positively correlated with Aß1-42. Finally, TRP and KYN were negatively (r = -0.22 and r = -0.18, respectively), and neopterin positively (r = 0.19) correlated with p-tau (all p < 0.05). CONCLUSIONS: Plasma concentrations of TRP, KP metabolites, KTR, and neopterin all significantly correlated positively with their corresponding CSF concentrations, but many correlations were weak. Additionally, our results suggest a relation between higher kynurenine levels and lower AD pathology load. These results need verification in future studies and require more research into (shared) underlying mechanisms.

Sex comparisons in the association of prediabetes and type 2 diabetes with cognitive function, depression, and quality of life: The Maastricht study.

AIMS: There are sex differences in the excess risk of diabetes-associated cardiovascular disease. However, it is not clear whether these sex differences exist with regard to other complications like mental health aspects. Therefore, we investigated sex differences in the association of prediabetes and type 2 diabetes (T2D) with cognitive function, depression, and quality of life (QoL). MATERIALS AND METHODS: In a population-based cross-sectional cohort study (n = 7639; age 40-75 years, 50% women, 25% T2D), we estimated sex-specific associations, and differences therein, of prediabetes and T2D (reference: normal glucose metabolism) with measures of cognitive function, depression, and physical and mental QoL. Sex differences were analysed using multiple regression models with interaction terms. RESULTS: In general, T2D, but not prediabetes, was associated with higher odds of cognitive impairment, major depressive disorder, and poorer QoL. The odds ratio (OR) of cognitive impairment associated with T2D was 1.29 (95% CI: 0.96-1.72) for women and 1.39 (1.10-1.75) for men. The OR of major depressive disorder associated with T2D was 1.19 (0.69-2.04) for women and 1.68 (1.02-2.75) for men. The mean difference of the physical QoL score (ranging from 0 to 100, with 100 indicating the best possible QoL) associated with T2D was -2.09 (-2.92 to -1.25) for women and -1.81 (-2.48 to -1.13) for men. The mean difference of the mental QoL score associated with T2D was -0.90 (-1.79 to -0.02) for women and -0.52 (-1.23 to 0.20) for men. There was no clear pattern of sex differences in the associations of either prediabetes or T2D with measures of cognitive function, depression, or QoL. CONCLUSIONS: In general, T2D was associated with worse cognitive function, depression, and poorer QoL. The strength of these associations was similar among women and men.

Selection bias in follow-up studies of stem cell transplantation survivors: an experience within the Maastricht Observational study of late effects after Stem cell trAnsplantation (MOSA).

Hematopoietic stem cell transplantation is an important treatment for many malignant hematological and non-hematological diseases. Survivors of hematopoietic stem cell transplantation (HCT) are at risk of long-term health problems and reduced quality of life related to previous treatments. Many studies about these long-term effects have been conducted over the last decades. However, selection bias is a concern in long-term follow-up studies and little is known about the non-participating group. As part of the Maastricht Observational study of late effects after Stem cell trAnsplantation (MOSA), investigating long-term health effects by extensively phenotyping HCT survivors, we conducted a survey to characterise the non-participating group. This survey mostly focused on quality of life and physical complaints. The survey responders were generally older than the MOSA group, had more history of relapsed disease, and described their general health as bad or mediocre significantly more often than the MOSA group. Also, more deaths occurred in the group of non-participants between the start of study inclusion in 2015 and analysis of the survey results in 2021. This study suggests that a selection of higher functioning HCT survivors with a relatively better quality of life participated in this long-term follow-up study of stem cell transplantation survivors. These results could also impact the results of other long-term follow-up studies in cancer survivors, knowing that possibly an unhealthier population is missed in these studies and some long-term negative effects of treatments might be underestimated.Trial registration number: NL-48599.