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Abstract Background The gut-derived metabolite Trimethylamine N-oxide (TMAO) and its precursors - betaine, carnitine, choline, and deoxycarnitine – have been associated with an increased risk of cardiovascular disease, but their relation to cognition, neuroimaging markers, and dementia remains uncertain. Methods In the population-based Rotterdam Study, we used multivariable regression models to study the associations between plasma TMAO, its precursors, and cognition in 3,143 participants. Subsequently, we examined their link to structural brain MRI markers in 2,047 participants, with a partial validation in the Leiden Longevity Study (n = 318). Among 2,517 participants, we assessed the risk of incident dementia using multivariable Cox proportional hazard models. Following this, we stratified the longitudinal associations by medication use and sex, after which we conducted a sensitivity analysis for individuals with impaired renal function. Results Overall, plasma TMAO was not associated with cognition, neuroimaging markers or incident dementia. Instead, higher plasma choline was significantly associated with poor cognition (adjusted mean difference: -0.170 [95% confidence interval (CI) -0.297;-0.043]), brain atrophy and more markers of cerebral small vessel disease, such as white matter hyperintensity volume (0.237 [95% CI: 0.076;0.397]). By contrast, higher carnitine concurred with lower white matter hyperintensity volume (-0.177 [95% CI: -0.343;-0.010]). Only among individuals with impaired renal function, TMAO appeared to increase risk of dementia (hazard ratio (HR): 1.73 [95% CI: 1.16;2.60]). No notable differences were observed in stratified analyses. Conclusions Plasma choline, as opposed to TMAO, was found to be associated with cognitive decline, brain atrophy, and markers of cerebral small vessel disease. These findings illustrate the complexity of relationships between TMAO and its precursors, and emphasize the need for concurrent study to elucidate gut-brain mechanisms.

Abstract Background Inflammation plays a key role in the development of dementia, but its link to early biomarkers, particularly those in plasma or neuroimaging, remains elusive. This study aimed to investigate the association between serum immunoglobulins and biomarkers of dementia. Methods Between 1997 and 2009, serum immunoglobulins (IgA, IgG and IgM) were measured in dementia-free participants of the population-based Rotterdam Study. A random subset of participants had assessment of biomarkers in plasma (total tau (t-tau), neurofilament light chain (NfL), amyloid-β40 (Aβ-40), amyloid-β42 (Aβ-42), while another subset of participants underwent neuroimaging to quantify brain volume, white matter structural integrity and markers of cerebral small vessel disease. Linear regression models were constructed to determine cross-sectional associations between IgA, IgG, IgM and biomarkers of dementia, with adjustment for potential confounders. Multiple testing correction was applied using the false discovery rate. As a sensitivity analysis, we re-ran the models for participants within the reference range of immunoglobulins, excluding those using immunomodulating drugs, and conducted a stratified analysis by APOE-ε4 carriership and sex. Results Of 8,768 participants with serum immunoglobulins, 3,455 participants (65.8 years [interquartile range (IQR): 61.5–72.0], 57.2% female) had plasma biomarkers available and 3,139 participants (57.4 years [IQR: 52.7–60.7], 54.4% female) had neuroimaging data. Overall, no associations between serum immunoglobulins and biomarkers of dementia remained significant after correction for multiple testing. However, several suggestive associations were noted: higher serum IgA levels concurred with lower plasma levels of Aβ-42 (standardized adjusted mean difference: -0.015 [95% confidence interval (CI): -0.029−-0.002], p = 2.8 × 10–2), and a lower total brain volume, mainly driven by less gray matter (-0.027 [-0.046−-0.008], p = 6.0 × 10–3) and more white matter hyperintensities (0.047 [0.016 – 0.077], p = 3.0 × 10–3). In sensitivity analyses, higher IgM was linked to lower t-tau, Aβ-40, and Aβ-42, but also a loss of white matter microstructural integrity. Stratified analyses indicate that these associations potentially differ between carriers and non-carriers of the APOE-ε4 allele and men and women. Conclusions While associations between serum immunoglobulins and early markers of dementia could not be established in this population-based sample, it may be valuable to consider factors such as APOE-ε4 allele carriership and sex in future investigations.

Abstract Background Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and ultimately fatal neurodegenerative condition caused by prions. The clinical symptoms of CJD vary with its subtype, and may include dementia, visual hallucinations, myoclonus, ataxia, (extra)pyramidal signs and akinetic mutism. In the early course of disease however, several clinical symptoms of CJD may mimic those of co-existing morbidities. Case presentation We report a male in his 60s with a history of situs inversus totalis and Churg Strauss syndrome, who presented with speech fluency disturbances, neuropsychiatric symptoms and allodynia, a few months after becoming a widower. Initially presumed a bereavement disorder along with a flare-up of Churg Strauss, his symptoms gradually worsened with apraxia, myoclonic jerks and eventually, akinetic mutism. MRI revealed hyperintensities at the caudate nucleus and thalami, while the cerebrospinal fluid was positive for the 14-3-3 protein and the real-time quick test, making the diagnosis of CJD highly probable. This case illustrates the complexities that may arise in diagnosing CJD when pre-existing multimorbidity may cloud the clinical presentation. We also discuss the potential mechanisms underlying the co-occurrence of three rare conditions (situs inversus totalis, Churg Strauss syndrome, CJD) in one patient, taking into consideration the possibility of coincidence as well as common underlying factors. Conclusions The diagnosis of CJD may be easily missed when its clinical symptoms are obscured by those of pre-existing (rare) multimorbidity. This case highlights that when the multimorbidity has neurological manifestations, an extensive evaluation remains crucial to establish the diagnosis, minimize the risk of prion-transmission and provide appropriate guidance to patients and their caregivers.

A meta-analysis of genome-wide association studies of circulating total-tau levels identifies loci specific to European or African American ancestries, providing further insight to the genetic etiology of neurological diseases.

Abstract Application of biological age as a measure of an individual´s health status offers new perspectives into extension of both lifespan and healthspan. While algorithms predicting mortality and most aging-related morbidities have been reported, the major shortcoming has been an inability to predict dementia. We present a community-based cohort study of 1930 participants with a mean age of 72 years and a follow-up period of over 7 years, using two variants of a phenotypic blood-based algorithm that either excludes (BioAge1) or includes (BioAge2) neurofilament light chain (NfL) as a neurodegenerative marker. BioAge1 and BioAge2 predict dementia equally well, as well as lifespan and healthspan. Each one-year increase in BioAge1/2 was associated with 11% elevated risk (HR 1.11; 95%CI 1.08–1.14) of mortality and 7% elevated risk (HR 1.07; 95%CI 1.05–1.09) of first morbidities. We additionally tested the association of microRNAs with age and identified 263 microRNAs significantly associated with biological and chronological age alike. Top differentially expressed microRNAs based on biological age had a higher significance level than those based on chronological age, suggesting that biological age captures aspects of aging signals at the epigenetic level. We conclude that accelerated biological age for a given age is a predictor of major age-related morbidity, including dementia, among healthy elderly.