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Background and ObjectivesWhile there is growing evidence that physical activity promotes neuronal health, studies examining the relation between physical activity and brain morphology remain inconclusive. We therefore examined whether objectively quantified physical activity is related to brain volume, cortical thickness, and gray matter density in a large cohort study. In addition, we assessed molecular pathways that may underlie the effects of physical activity on brain morphology.MethodsWe used cross-sectional baseline data from 2,550 eligible participants (57.6% women; mean age: 54.7 years, range: 30–94 years) of a prospective cohort study. Physical activity dose (metabolic equivalent hours and step counts) and intensity (sedentary and light-intensity and moderate-to-vigorous intensity activities) were recorded with accelerometers. Brain volumetric, gray matter density, and cortical thickness measures were obtained from 3T MRI scans using FreeSurfer and Statistical Parametric Mapping. The relation of physical activity (independent variable) and brain structure (outcome) was examined with polynomial multivariable regression, while adjusting for age, sex, intracranial volume, education, and smoking. Using gene expression profiles from the Allen Brain Atlas, we extracted molecular signatures associated with the effects of physical activity on brain morphology.ResultsPhysical activity dose and intensity were independently associated with larger brain volumes, gray matter density, and cortical thickness of several brain regions. The effects of physical activity on brain volume were most pronounced at low physical activity quantities and differed between men and women and across age. For example, more time spent in moderate-to-vigorous intensity activities was associated with greater total gray matter volume, but the relation leveled off with more activity (standardized β [95% CIs]: 1.37 [0.35–2.39] and −0.70 [−1.25 to −0.15] for the linear and quadratic terms, respectively). The strongest effects of physical activity were observed in motor regions and cortical regions enriched for genes involved in mitochondrial respiration.DiscussionOur findings suggest that physical activity benefits brain health, with the strongest effects in motor regions and regions with a high oxidative demand. While young adults may particularly profit from additional high-intensity activities, older adults may already benefit from light-intensity activities. Physical activity and reduced sedentary time may be critical in the prevention of age-associated brain atrophy and neurodegenerative diseases.

Objective Maintaining muscle function throughout life is critical for healthy ageing. Although in vitro studies consistently indicate beneficial effects of 25-hydroxyvitamin D (25-OHD) on muscle function, findings from population-based studies remain inconclusive. We therefore aimed to examine the association between 25-OHD concentration and handgrip strength across a wide age range and assess potential modifying effects of age, sex and season. Methods We analysed cross-sectional baseline data of 2576 eligible participants out of the first 3000 participants (recruited from March 2016 to March 2019) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Multivariate linear regression models were used to assess the relation between 25-OHD levels and grip strength while adjusting for age, sex, education, smoking, season, body mass index, physical activity levels, osteoporosis and vitamin D supplementation. Results Compared to participants with deficient 25-OHD levels (ßinadequate = 1.222, 95% CI: 0.377; 2.067, P = 0.005; ßadequate = 1.228, 95% CI: 0.437; 2.019, P = 0.002). Modelling on a continuous scale revealed grip strength to increase with higher 25-OHD levels up to ~100 nmol/L, after which the direction reversed (ßlinear = 0.505, 95% CI: 0.179; 0.830, P = 0.002; ßquadratic = –0.153, 95% CI: –0.269; -0.038, P = 0.009). Older adults showed weaker effects of 25-OHD levels on grip strength than younger adults (ß25OHDxAge = –0.309, 95% CI: –0.594; –0.024, P = 0.033). Conclusions Our findings highlight the importance of sufficient 25-OHD levels for optimal muscle function across the adult life span. However, vitamin D supplementation should be closely monitored to avoid detrimental effects.

Individuals with a similar chronological age can exhibit marked differences in cardiovascular risk profiles, but it is unknown whether this variation is related to different rates of biological aging. Therefore, we investigated the relation between nine domains of cardiovascular function and four epigenetic age acceleration estimators (i.e., AgeAccel.Horvath, AgeAccel.Hannum, AgeAccelPheno, and AgeAccelGrim), derived from DNA methylation profiles. Among 4194 participants (mean age 54.2 years (range 30.0–95.0)) from the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany, epigenetic age acceleration increased by 0.19–1.84 years per standard deviation (SD) increase in cardiovascular risk across multiple domains, including measures of kidney function, adiposity, and a composite cardiovascular risk score. Measures of inflammation and glucose homeostasis were associated with AgeAccel.Hannum, AgeAccelPheno, and AgeAccelGrim, but not with AgeAccel.Horvath. Moreover, effect sizes were larger for AgeAccelPheno and AgeAccelGrim than for AgeAccel.Horvath and AgeAccel.Hannum. Similarly, epigenetic age acceleration increased by 0.15–0.81 years per SD increase in markers of vascular function (blood pressure, arterial stiffness, and hemodynamic measures), whereas better endothelial function was only associated with lower AgeAccelGrim. Most effects on epigenetic age acceleration were independent, which suggests they independently contribute to different rates of biological aging.

Visual impairment and retinal neurodegeneration are intrinsically connected and both have been associated with cognitive impairment and brain atrophy, but the underlying mechanisms remain unclear. To investigate whether transneuronal degeneration is implicated, we systematically assessed the relation between visual function and retinal, visual pathway, hippocampal and brain degeneration. We analyzed baseline data from 3316 eligible Rhineland Study participants with visual acuity (VA), optical coherence tomography (OCT), and magnetic resonance imaging (MRI) data available. Regional volumes, cortical volume, and fractional anisotropy (FA) were derived from T1-weighted and diffusion-weighted 3 T MRI scans. Statistical analyses were performed using multivariable linear regression and structural equation modeling. VA and ganglion cell layer (GCL) thinning were both associated with global brain atrophy (SD effect size [95% CI] -0.090 [-0.118 to -0.062] and 0.066 [0.053-0.080], respectively), and hippocampal atrophy (-0.029 [-0.055 to -0.003] and 0.114 [0.087-0.141], respectively). The effect of VA on whole brain and hippocampal volume was partly mediated by retinal neurodegeneration. Similarly, the effect of retinal neurodegeneration on brain and hippocampal atrophy was mediated through intermediate visual tracts, accounting for 5.2%-23.9% of the effect. Visual impairment and retinal neurodegeneration were robustly associated with worse brain atrophy, FA, and hippocampal atrophy, partly mediated through disintegration of intermediate visual tracts. Our findings support the use of OCT-derived retinal measures as markers of neurodegeneration, and indicate that both general and transneuronal neurodegeneration along the visual pathway, partly reflecting visual impairment, account for the association between retinal neurodegeneration and brain atrophy.

Tandem cytosine-adenine-guanine (CAG) repeat sizes of 36 or more in the huntingtin gene (HTT) cause Huntington's disease (HD). Apart from neuropsychiatric complications, the disease is also accompanied by metabolic dysregulation and weight loss, which contribute to a progressive functional decline. Recent studies also reported an association between repeats below the pathogenic threshold (

BackgroundNeurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels and its genetic correlation with neurological traits could therefore provide new insights into shared molecular mechanisms underlying neurodegenerative disorders.MethodsTo identify the genetic variations underlying blood NfL levels, we conducted an ancestry-specific meta-analyses of genome-wide association studies (GWAS) based on 18,532 participants from 11 cohorts of European and 1142 participants (3 cohorts) of African-American ancestry. In the post-GWAS analyses, we performed expression quantitative trait loci (eQTL) analysis, LD-regression, and genetic risk score (GRS) association analysis with neurological traits.ResultsIn the European ancestry GWAS meta-analysis, we identified two genome-wide significant (P< 5x10−8) loci at 16p12 (UMOD), and 17q24 (SLC39A11). In the African-American ancestry GWAS meta-analysis, we identified three novel loci at 1q43 (FMN2), 12q14, and 12q21. Genetic correlation based on the European ancestry meta-analysis with neurological traits showed a strong genetic correlation of NfL with Alzheimer’s disease(AD) (rg= 0.32,P= 1.74x10−6), total-tau (rg= 2.01,P= 1.03x10−6), amyloid-beta (Aβ)-40 (rg= 0.80,P= 6.92x10−6), and Aβ-42 (rg= 1.03,P= 4.39x10−5). A higher genetic risk score based on NfL-associated genetic variants was also related to increased plasma levels of total-tau (P= 1.97x10−4), Aβ-40 (P= 2.24x10−5), Aβ-42 (P= 2.92x10−4) in the Rotterdam Study.ConclusionThis large-scale GWAS meta-analysis revealed multiple novel genetic loci of NFL levels in blood in participants from European and African-American ancestry. Significant genetic correlation of genes underlying NfL with AD, Aβ-42, and total-tau may indicate a common underlying pathway of neurodegeneration.

Metabolic syndrome (MetS) is a major public health burden worldwide and associated with brain abnormalities. Although insulin resistance is considered a pivotal feature of MetS, its role in the pathogenesis of MetS‐related brain alterations in the general population is unclear. Therefore, in 973 participants (mean age 52.5 years) of the population‐based Rhineland Study, we assessed brain morphology in relation to MetS and insulin resistance, and evaluated to what extent the pattern of structural brain changes seen in MetS overlap with those associated with insulin resistance. Cortical reconstruction and volumetric segmentation were obtained from high‐resolution brain images at 3 Tesla using FreeSurfer. The relations between metabolic measures and brain structure were assessed through (generalized) linear models. Both MetS and insulin resistance were associated with smaller cortical gray matter volume and thickness, but not with white matter or subcortical gray matter volume. Age‐ and sex‐adjusted vertex‐based brain morphometry demonstrated that MetS and insulin resistance were related to cortical thinning in a similar spatial pattern. Importantly, no independent effect of MetS on cortical gray matter was observed beyond the effect of insulin resistance. Our findings suggest that addressing insulin resistance is critical in the prevention of MetS‐related brain changes in later life., Both MetS and insulin resistance were associated with smaller cortical gray matter volume and thickness, and related to cortical thinning in a similar spatial pattern. Importantly, no independent effect of MetS on cortical gray matter was observed beyond the effect of insulin resistance. Our findings suggest that addressing insulin resistance is critical in the prevention of MetS‐related brain changes in later life.

Background: Heart failure and chronic obstructive pulmonary disease (COPD) are leading causes of disability and lead to substantial healthcare costs. The aim of this study was to evaluate the effectiveness of home telemonitoring in reducing healthcare usage and costs in patients with heart failure or COPD. Methods: The study was a retrospective observational study with a follow-up duration of up to 3 years in which for all participants data before and after enrollment in the telemonitoring program was compared. Hundred seventy-seven patients with heart failure (NYHA functional class 3 or 4) and 83 patients with COPD (GOLD stage 3 or 4) enrolled in a home telemonitoring program in addition to receiving usual hospital care. The primary outcome was the number of hospitalizations; the secondary outcomes were total number of hospitalization days and healthcare costs during the follow-up period. Generalized Estimating Equations were applied to account for repeated measurements, adjusting for sex, age and length of follow-up. Results: In heart failure patients, after initiation of home telemonitoring both the number of hospitalizations and the total number of hospitalization days significantly decreased (incidence rate ratio of 0.35 (95% CI: 0.26–0.48) and 0.35 (95% CI: 0.24–0.51), respectively), as did the total healthcare costs (exp(B) = 0.11 (95% CI: 0.08–0.17)), all p

To identify cognitive measures that may be particularly sensitive to early cognitive decline in preclinical Alzheimer’s disease (AD), we investigated the relation between genetic risk for AD and cognitive task performance in a large population-based cohort study. We measured performance on memory, processing speed, executive function, crystallized intelligence and eye movement tasks in 5182 participants of the Rhineland Study, aged 30 to 95 years. We quantified genetic risk for AD by creating three weighted polygenic risk scores (PRS) based on the genome-wide significant single-nucleotide polymorphisms coming from three different genetic association studies. We assessed the relation of AD PRS with cognitive performance using generalized linear models. Three PRS were associated with lower performance on the Corsi forward task, and two PRS were associated with a lower probability of correcting antisaccade errors, but none of these associations remained significant after correction for multiple testing. Associations between age and trail-making test A (TMT-A) performance were modified by AD genetic risk, with individuals at high genetic risk showing the strongest association. We conclude that no single measure of our cognitive test battery robustly captures genetic liability for AD as quantified by current PRS. However, Corsi forward performance and the probability of correcting antisaccade errors may represent promising candidates whose ability to capture genetic liability for AD should be investigated further. Additionally, our finding on TMT-A performance suggests that processing speed represents a sensitive marker of AD genetic risk in old age and supports the processing speed theory of age-related cognitive decline.

ObjectiveTo assess whether severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with changes in plasma levels of neurofilament light chain (NfL), an extremely sensitive marker of neuroaxonal damage, in community-dwelling individuals.SettingThis study was embedded within the Rhineland Study, an ongoing community-based cohort study in Bonn, GermanyDesignCross-sectional nested case-control study.ParticipantsParticipants were selected based on results from a previously conducted seroprevalence survey within the framework of the Rhineland Study. Cases were defined as those individuals who had had two positive confirmatory test results, including a recombinant spike-based immunofluorescence assay and a plaque reduction neutralization test (N=21). As controls, a random sample of individuals with a negative ELISA test result (Controls I, N=1117), and those with a borderline or positive ELISA test result who failed confirmatory testing (Controls II, N=68), were selected.Outcome measuresPlasma levels of NfL at the time of measurement, as well as change in plasma NfL levels compared to previously measured pre-pandemic levelsResultsAfter adjustment for age, sex and batch effects, serologically confirmed SARS-CoV-2 infection was neither associated with cross-sectional NfL levels, nor with the magnitude of change from pre-pandemic levels, compared to either of the two control groups. Similarly, after adjustment for age, sex and batch effects, self-reported neurological symptoms – including altered sense of smell or taste, headache, myalgia and fever – were not associated with changes in NfL levels in participants with a serologically confirmed SARS-CoV-2 infection (all p ≥ 0.56).ConclusionsOur findings indicate that mild-to-moderate coronavirus disease-19 is unlikely to be associated with a clinically relevant degree of neuroaxonal damage, even in those cases associated with neurological symptoms.

Importance Olfactory dysfunction is a prodromal manifestation of many neurodegenerative disorders, including Alzheimer and Parkinson disease. However, its neuroanatomical basis is largely unknown. Objective To assess the association between olfactory brain structures and olfactory function in adults 30 years or older and to examine the extent to which olfactory bulb volume (OBV) mediates the association between central olfactory structures and olfactory function. Design, setting, and participants This cross-sectional study analyzed baseline data from the first 639 participants with brain magnetic resonance imaging (MRI) in the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany. Participants were enrolled between March 7, 2016, and October 31, 2017, and underwent brain MRI and olfactory assessment. Data were analyzed from March 1, 2018, to June 30, 2021. Exposure Volumetric measures were derived from 3-T MRI T1-weighted brain scans, and OBV was manually segmented on T2-weighted images. The mean volumetric brain measures from the right and left sides were calculated, adjusted by head size, and normalized to all participants. Main outcomes and measures Performance on the 12-item smell identification test (SIT-12) was used as a proxy for olfactory function. Results A total of 541 participants with complete data on MRI-derived measures and SIT-12 scores were included. This population had a mean (SD) age of 53.6 (13.1) years and comprised 306 women (56.6%). Increasing age (difference in SIT-12 score, -0.04; 95% CI, -0.05 to -0.03), male sex (-0.26; 95% CI, -0.54 to 0.02), and nasal congestion (-0.28; 95% CI, -0.66 to 0.09) were associated with worse olfactory function (SIT-12 scores). Conversely, larger OBV was associated with better olfactory function (difference in SIT-12 score, 0.46; 95% CI, 0.29-0.64). Larger volumes of amygdala (difference in OBV, 0.12; 95% CI, 0.01-0.24), hippocampus (0.16; 95% CI, 0.04-0.28), insular cortex (0.12; 95% CI, 0.01-0.24), and medial orbitofrontal cortex (0.10; 95% CI, 0.00-0.20) were associated with larger OBV. Larger volumes of amygdala (volume × age interaction effect, 0.17; 95% CI, 0.03-0.30), parahippocampal cortex (0.17; 95% CI, 0.03-0.31), and hippocampus (0.21; 95% CI, 0.08-0.35) were associated with better olfactory function only in older age groups. The age-modified association between volumes of central olfactory structures and olfactory function was largely mediated through OBV. Conclusions and relevance This cross-sectional study found that olfactory bulb volume was independently associated with odor identification function and was a robust mediator of the age-dependent association between volumes of central olfactory structures and olfactory function. Thus, neurodegeneration-associated olfactory dysfunction may primarily originate from the pathology of peripheral olfactory structures, suggesting that OBV may serve as a preclinical marker for the identification of individuals who are at an increased risk of neurodegenerative diseases.

BackgroundSchizophrenia is a heterogeneous disorder with substantial heritability. The use of endophenotypes may help clarify its aetiology. Measures from the smooth pursuit and antisaccade eye movement tasks have been identified as endophenotypes for schizophrenia in twin and family studies. However, the genetic basis of the overlap between schizophrenia and these oculomotor markers is largely unknown. Here, we tested whether schizophrenia polygenic risk scores (PRS) were associated with oculomotor performance in the general population.MethodsAnalyses were based on the data of 2956 participants (aged 30–95) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Genotyping was performed on Omni-2.5 exome arrays. Using summary statistics from a recent meta-analysis based on the two largest schizophrenia genome-wide association studies to date, we quantified genetic risk for schizophrenia by creating PRS at different p value thresholds for genetic markers. We examined associations between PRS and oculomotor performance using multivariable regression models.ResultsHigher PRS were associated with higher antisaccade error rate and latency, and lower antisaccade amplitude gain. PRS showed inconsistent patterns of association with smooth pursuit velocity gain and were not associated with saccade rate during smooth pursuit or performance on a prosaccade control task.ConclusionsThere is an overlap between genetic determinants of schizophrenia and oculomotor endophenotypes. Our findings suggest that the mechanisms that underlie schizophrenia also affect oculomotor function in the general population.

Huntington's disease (HD), an autosomal dominant hereditary disorder associated with the accumulation of mutant huntingtin, is classically associated with cognitive decline and motor symptoms, notably chorea. However, growing evidence suggests that nonmotor symptoms are equally prevalent and debilitating. Some of these symptoms may be linked to hypothalamic pathology, demonstrated by findings in HD animal models and HD patients showing specific changes in hypothalamic neuropeptidergic populations and their associated functions. At least some of these alterations are likely due to local mutant huntingtin expression and toxicity, while others are likely caused by disturbed hypothalamic circuitry. Common problems include circadian rhythm disorders, including desynchronization of daily hormone excretion patterns, which could be targeted by novel therapeutic interventions, such as timed circadian interventions with light therapy or melatonin. However, translation of these findings from bench-to-bedside is hampered by differences in murine HD models and HD patients, including mutant huntingtin trinucleotide repeat length, which is highly heterogeneous across the various models. In this chapter, we summarize the current knowledge regarding hypothalamic alterations in HD patients and animal models, and the potential for these findings to be translated into clinical practice and management.

Huntington's disease (HD), an autosomal dominant hereditary disorder associated with the accumulation of mutant huntingtin, is classically associated with cognitive decline and motor symptoms, notably chorea. However, growing evidence suggests that nonmotor symptoms are equally prevalent and debilitating. Some of these symptoms may be linked to hypothalamic pathology, demonstrated by findings in HD animal models and HD patients showing specific changes in hypothalamic neuropeptidergic populations and their associated functions. At least some of these alterations are likely due to local mutant huntingtin expression and toxicity, while others are likely caused by disturbed hypothalamic circuitry. Common problems include circadian rhythm disorders, including desynchronization of daily hormone excretion patterns, which could be targeted by novel therapeutic interventions, such as timed circadian interventions with light therapy or melatonin. However, translation of these findings from bench-to-bedside is hampered by differences in murine HD models and HD patients, including mutant huntingtin trinucleotide repeat length, which is highly heterogeneous across the various models. In this chapter, we summarize the current knowledge regarding hypothalamic alterations in HD patients and animal models, and the potential for these findings to be translated into clinical practice and management.

To estimate the seroprevalence and temporal course of SARS-CoV-2 neutralizing antibodies, we embedded a multi-tiered seroprevalence survey within an ongoing community-based cohort study in Bonn, Germany. We first assessed anti-SARS-CoV-2 immunoglobulin G levels with an immunoassay, followed by confirmatory testing of borderline and positive test results with a recombinant spike-based immunofluorescence assay and a plaque reduction neutralization test (PRNT). Those with a borderline or positive immunoassay result were retested after 4 to 5 months. At baseline, 4771 persons participated (88% response rate). Between April 24th and June 30th, 2020, seroprevalence was 0.97% (95% CI: 0.72−1.30) by immunoassay and 0.36% (95% CI: 0.21−0.61) when considering only those with two additional positive confirmatory tests. Importantly, about 20% of PRNT+ individuals lost their neutralizing antibodies within five months. Here, we show that neutralizing antibodies are detectable in only one third of those with a positive immunoassay result, and wane relatively quickly., Population-based studies of SARS-CoV-2 seroprevalence are needed to understand levels of immunity and antibody dynamics. Here, the authors show that the seroprevalence in Bonn, Germany was low (

BackgroundAccurate estimates of SARS-CoV-2 seroprevalence are crucial for the implementation of effective public health measures, but are currently largely lacking in regions with low infection rates. This is further complicated by inadequate test performance of many widely used serological assays. We therefore aimed to assess SARS-CoV-2 seroprevalence in a region with low COVID-19 burden, especially focusing on neutralizing antibodies that presumably constitute a major component of acquired immunity.MethodsWe invited all individuals who were enrolled in the Rhineland Study, an ongoing community-based prospective cohort study in people aged 30 years and above in the city of Bonn, Germany (N=5427). Between April 24th and June 30th, 2020, 4771 (88%) of these individuals participated in the serosurvey. Anti-SARS-CoV-2 IgG levels were measured using an ELISA assay, and all positive or borderline results were subsequently examined through both a recombinant immunofluorescent assay and a plaque reduction neutralisation test (PRNT).FindingsSeroprevalence was 0·97% (95% CI: 0·72–1·30) by ELISA and 0·36% (95% CI: 0·21–0·61) by PRNT, and did not vary with either age or sex. All PRNT+ individuals reported having experienced at least one symptom (odds ratio (OR) of PRNT+ for each additional symptom: 1·12 (95% CI: 1·04–1·21)). Apart from living in a household with a SARS-CoV-2 confirmed or suspected person, a recent history of reduced taste or smell, fever, chills/hot flashes, pain while breathing, pain in arms/legs, as well as muscle pain and weakness were significantly associated with the presence of neutralizing antibodies in those with mild to moderate infection (ORs 3·44 to 9·97, all pInterpretationOur findings indicate a relatively low SARS-CoV-2 seroprevalence in Bonn, Germany (until June 30th, 2020), with neutralizing antibodies detectable in only one third of those with a positive immunoassay result, implying that almost the entire population in this region remains susceptible to SARS-CoV-2 infection.FundingThe Rhineland Study is predominantly funded through the German Center for Neurodegenerative Diseases (DZNE) by the Federal Ministry of Education and Research (BMBF) and the Ministry of Culture and Science of the German State of North Rhine-Westphalia. The National Consultant Laboratory for Coronaviruses is funded by the Federal Ministry of Health (BMG). No additional funding was received for this seroprevalence study.

SUMMARYThe SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases calls for a better characterization and understanding of the changes in the immune system. Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 11 COVID-19 patients. Comparison of COVID-19 blood transcriptomes with those of a collection of over 2,800 samples derived from 11 different viral infections, inflammatory diseases and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host.

A recent clinical trial found that exenatide, an antidiabeticdrug, could slow down the rate of decline in motor perfor-mance in patients with Parkinson’s disease (PD).1A higherprevalence of diabetes mellitus (DM) has been reported in PDpatients,2whereas an increased incidence of PD was found inpatients with DM.3–5Although these ndings suggest thatperipheral insulin resistance might be involved in PDpathogenesis,6systemic substrate metabolism and its respon-siveness to insulin stimulation have not been rigorouslyassessed before in de novo, medication-free PD patients. There-fore, using the hyperinsulinemic-euglycemic clamp technique,the most accurate and precise method available for quantifyinginsulin sensitivity, we aimed to assess whether insulin resistanceis an inherent feature of PD.

Identification of patients with life-threatening diseases including leukemias or infections such as tuberculosis and COVID-19 is an important goal of precision medicine. We recently illustrated that leukemia patients are identified by machine learning (ML) based on their blood transcriptomes. However, there is an increasing divide between what is technically possible and what is allowed because of privacy legislation. To facilitate integration of any omics data from any data owner world-wide without violating privacy laws, we here introduce Swarm Learning (SL), a decentralized machine learning approach uniting edge computing, blockchain-based peer-to-peer networking and coordination as well as privacy protection without the need for a central coordinator thereby going beyond federated learning. Using more than 14,000 blood transcriptomes derived from over 100 individual studies with non-uniform distribution of cases and controls and significant study biases, we illustrate the feasibility of SL to develop disease classifiers based on distributed data for COVID-19, tuberculosis or leukemias that outperform those developed at individual sites. Still, SL completely protects local privacy regulations by design. We propose this approach to noticeably accelerate the introduction of precision medicine.

Although the heritability of cognitive function in old age is substantial, genome-wide association studies have had limited success in elucidating its genetic basis, leaving a considerable amount of “missing heritability.” Aside from single nucleotide polymorphisms, genome-wide association studies are unable to assess other large sources of genetic variation, such as tandem repeat polymorphisms. Therefore, here, we studied the association of cytosine-adenine-guanine (CAG) repeat variations in polyglutamine disease–associated genes (PDAGs) with cognitive function in older adults. In a large cohort consisting of 5786 participants, we found that the CAG repeat number in 3 PDAGs (TBP, HTT, and AR) were significantly associated with the decline in cognitive function, which together accounted for 0.49% of the variation. Furthermore, in an magnetic resonance imaging substudy, we found that CAG repeat polymorphisms in 4 PDAGs (ATXN2, CACNA1A, ATXN7, and AR) were associated with different imaging characteristics, including brain stem, putamen, globus pallidus, thalamus, and amygdala volumes. Our findings indicate that tandem repeat polymorphisms are associated with cognitive function in older adults and highlight the importance of PDAGs in elucidating its missing heritability.

ObjectiveA fundamental but still unresolved issue regarding Huntington disease (HD) pathogenesis is whether the factors that determine age at onset are the same as those that govern disease progression. Because elucidation of this issue is crucial for the development as well as optimal timing of administration of novel disease-modifying therapies, we aimed to assess the extent of overlap between age-at-onset and disease-progression determinants in HD.MethodsUsing observational data from Enroll-HD, the largest cohort of patients with HD worldwide, in this study we present, validate, and apply an intuitive method based on linear mixed-effect models to quantify the variability in the rate of disease progression in HD.ResultsA total of 3,411 patients with HD met inclusion criteria. We found that (1) about two-thirds of the rate of functional, motor, and cognitive progression in HD is determined by the same factors that also determine age at onset, with CAG repeat–dependent mechanisms having by far the largest effect; (2) although expanded HTT CAG repeat size had a large influence on average body weight, the rate of weight loss was largely independent of factors that determine age at onset in HD; and (3) about one-third of the factors that determine the rate of functional, motor, and cognitive progression are different from those that govern age at onset and need further elucidation.ConclusionOur findings imply that targeting of CAG repeat–dependent mechanisms, for example through gene-silencing approaches, is likely to affect the rate of functional, motor, and cognitive impairment, but not weight loss, in manifest HD mutation carriers.

ObjectiveWeight loss is associated with clinical progression in Huntington disease (HD), but whether body weight causally affects disease onset or progression is unknown. Therefore, we aimed to assess whether genetically determined variations in body weight are causally related to age at onset in HD.MethodsUsing data from different recent genome-wide association studies, we performed a 2-sample mendelian randomization (MR) analysis to assess whether genetic markers of body mass index (BMI) are causally related to residual age at onset in HD, i.e., the difference between observed and expected age at onset based on mutation size. Our study had a statistical power of 90% to detect a causal effect of ≥3.8 months per BMI unit change at a type I error rate of 0.05.ResultsInverse-variance weighted MR estimates showed that a higher genetically determined BMI was not causally related to residual age at onset in HD (β = −0.44 years per unit increase in BMI, confidence interval: −1.33 to 0.46, p = 0.34). All other complementary (nonparametric) MR regression methods yielded similar results.ConclusionsAlthough maintaining a healthy and stable body weight remains important in patients with HD, promoting weight gain with the aim of delaying disease onset or slowing down disease progression should be discouraged. Our findings point toward the existence of underlying pathologic processes that dictate both the rate of clinical progression and weight loss in HD, which need further elucidation as targeting these pathways, rather than body weight per se, could be of therapeutic value.

Unintended weight loss is a hallmark of Huntington disease (HD), but it is unknown to what extent weight loss impacts the rate of disease progression. Therefore, using longitudinal data from the Enroll-HD study, we assessed the association between baseline body mass index (BMI) and the rate of clinical progression in 5,821 HD mutation carriers. We found that high baseline BMI was associated with a significantly slower rate of functional, motor, and cognitive deterioration (all p < 0.001), independent of mutant HTT CAG repeat size. Our findings provide strong rationale for exploration of systemic metabolism as a therapeutic target in HD. Ann Neurol 2017;82:479-483.

Huntington disease (HD) is an autosomal dominant, neurodegenerative disease caused by a CAG repeat expansion within the coding sequence of the HTT gene, resulting in a highly toxic protein with an expanded polyglutamine stretch that forms typical protein aggregates throughout the brain. We generated human induced pluripotent stem cells (hiPSCs) from two HD patients using non-integrating Sendai virus (SeV). The hiPSCs display a normal karyotype, express all pluripotency markers, have the same CAG repeat expansion as the original fibroblasts and are able to differentiate into the three germ layers in vitro.

I read with interest the article by Schultz et al.,1 which addressed a key issue faced by many clinicians treating patients with Huntington disease (HD)—the conundrum of whether or not to start tetrabenazine (TBZ) for treating chorea in those with a history of depression, given its black box warning of increased depression and suicidality risk. Nevertheless, I was puzzled by the study's finding that among the total group of patients with HD, especially the subgroup with a history of depression, TBZ use was associated with lower odds of both depression and suicidality.1 The most likely explanation for this finding is the phenomenon known as confounding by indication—a form of selection bias introduced by the fact that clinicians are simply less likely to prescribe TBZ to those with severe depressive symptoms due to the perceived detrimental effects of this drug on mood.2–4 Although the multiple logistic regression analysis was adjusted for a range of potential confounders,1 conditional regression estimates generally do not provide an unbiased estimate of true marginal effect in contexts where treatment selection is partially based on the outcome of interest (i.e., depression and suicidality).3 This issue can, at least partly, be addressed by applying inverse probability of treatment weighing using propensity scores.2,4 Therefore, it is important to know whether application of this method would result in similar findings or, conversely, support the notion of confounding by indication.4

Genomewide association studies (GWASs) have contributed greatly to unraveling the genetic basis of Alzheimer's disease (AD). However, a large amount of “missing heritability” remains. In this exploratory study, we investigated the effect of cytosine-adenine-guanine (CAG) repeats in polyglutamine disease–associated genes (PDAGs) on the risk of AD and its expression. In a cohort of 959 patients diagnosed with AD (Amsterdam Dementia cohort) and 4106 cognitively healthy participants (Leiden 85-plus Study and the Prospective Study of Pravastatin in the Elderly at Risk), we determined the CAG repeat sequences in ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR. We did not find a significant association between the risk of AD and variations in CAG repeat numbers of PDAGs. However, we found that differences in CAG repeat numbers in ATXN1, ATXN2, and AR were significantly associated with several clinical and imaging features in AD patients. Specifically, the association between memory performance in patients with AD and the CAG repeat size in the longer ATXN1 allele, and the association between atrophy in the medial temporal lobes and the CAG repeat number in the longer AR allele remained significant after correction for multiple testing. Our findings suggest that repeat polymorphisms in ATXN1 and AR can act as important genetic modifiers of AD, warranting further scrutiny of their role in its missing heritability and pathogenesis.

BACKGROUND: Huntington's disease like 2 (HDL2) is the most common Huntington's disease (HD) phenocopy in many countries and described as the phenocopy with the greatest resemblance to HD. The current clinical description of HDL2 is based on retrospective data. It is unknown whether HDL2 has clinical features that distinguish it from HD. OBJECTIVE: To describe the HDL2 phenotype and compare it to HD systematically. METHODS: A blinded cross‐sectional design was used to compare the HDL2 (n = 15) and HD (n = 13) phenotypes. African ancestry participants underwent assessments, including the Unified Huntington's Disease Rating Scale (UHDRS). The UHDRS motor component was video recorded and evaluated by blinded experts and the inter‐rater reliability calculated. RESULTS: Both groups were homogeneous in terms of demographics and disease characteristics. However, HDL2 patients presented three years earlier with more prominent dysarthria and dystonia. Raters could not distinguish between the two diseases with a high level of agreement. No significant differences in the TMS between HDL2 and HD were found. In both disorders, disease duration correlated with motor scores, with the exception of chorea. Psychiatric and cognitive scores were not significantly different between the groups. CONCLUSIONS: The HDL2 phenotype is similar to HD and is initially characterized by dementia, chorea, and oculomotor abnormalities, progressing to a rigid and bradykinetic state, suggesting the UHDRS is useful to monitor disease progression in HDL2. Although HDL2 patients scored higher on some UHDRS domains, this did not differentiate between the two diseases; it may however be emerging evidence of HDL2 having a more severe clinical phenotype.

Introduction Disrupted gating of motor control through striatal pathways is thought to drive the development of motor symptoms in Huntington’s disease (HD). The range of motor symptoms, from chorea to bradykinesia, is thought to be driven by disruption in different striatal pathways. Aside from motor control, striatal pathways are also thought to play a key role in the expression of motivated behaviour. On this basis we asked whether the association between apathy and specific motor symptoms is in keeping with the hypothesis that apathy in HD is another manifestation of dysfunctional striatal gating. Methods Clinical data on 2608 patients with manifest HD disease was retrieved from the ENROLL-HD database. A linear mixed model was built to assess the relationship between motor symptoms and apathy (measured using the PBA and square root transformed) controlling for cognitive impairment, depression, medication use, disease duration, CAG repeat size and age. In a separate analysis the bradykinesia item was replaced by voluntary finger tapping performance. Results Although both bradykinesia and chorea were significantly associated with apathy, their effects were in opposite directions. Bradykinesia was associated with greater apathy (β=0.14, p Conclusion This analysis suggests that the processes driving distinct motor symptoms in HD may also underlie hard-to-treat psychiatric symptoms such as apathy. A common substrate and likely target for this shared mechanism is the disruption of specific striatal pathways that gate actions, decisions and motivated behaviour.