Association Between Accelerometer-Derived Physical Activity Measurements and Brain Structure: A Population-Based Cohort Study.

BACKGROUND AND OBJECTIVES: While 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. METHODS: We 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. RESULTS: Physical 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 ß [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. DISCUSSION: Our 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.

Neurofilament light chain and retinal layers' determinants and association: A population-based study.

Both retinal atrophy measured through optical coherence tomography and plasma neurofilament light chain (NfL) levels are markers of neurodegeneration, but their relationship is unknown. Therefore, we assessed their determinants and association in 4369 participants of a population-based study. Both plasma NfL levels and inner retinal atrophy increased exponentially with age. In the presence of risk factors for neurodegeneration (including age, smoking, and a history of neurological disorders), plasma NfL levels were associated with inner retinal atrophy and outer retinal thickening. Our findings indicate that inner retinal atrophy can reflect neuroaxonal damage as mirrored by rising plasma NfL levels.

Evaluation of the Neuroanatomical Basis of Olfactory Dysfunction in the General Population.

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.

Swarm Learning for decentralized and confidential clinical machine learning.

Fast and reliable detection of patients with severe and heterogeneous illnesses is a major goal of precision medicine1,2. Patients with leukaemia can be identified using machine learning on the basis of their blood transcriptomes3. However, there is an increasing divide between what is technically possible and what is allowed, because of privacy legislation4,5. Here, to facilitate the integration of any medical data from any data owner worldwide without violating privacy laws, we introduce Swarm Learning-a decentralized machine-learning approach that unites edge computing, blockchain-based peer-to-peer networking and coordination while maintaining confidentiality without the need for a central coordinator, thereby going beyond federated learning. To illustrate the feasibility of using Swarm Learning to develop disease classifiers using distributed data, we chose four use cases of heterogeneous diseases (COVID-19, tuberculosis, leukaemia and lung pathologies). With more than 16,400 blood transcriptomes derived from 127 clinical studies with non-uniform distributions of cases and controls and substantial study biases, as well as more than 95,000 chest X-ray images, we show that Swarm Learning classifiers outperform those developed at individual sites. In addition, Swarm Learning completely fulfils local confidentiality regulations by design. We believe that this approach will notably accelerate the introduction of precision medicine.

Repeat variations in polyglutamine disease-associated genes and cognitive function in old age.

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.

Prevalence of Carriers of Intermediate and Pathological Polyglutamine Disease-Associated Alleles Among Large Population-Based Cohorts.

Importance: Nine hereditary neurodegenerative diseases are known as polyglutamine diseases, including Huntington disease, 6 spinocerebellar ataxias (SCAs) (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17), dentatorubral-pallidoluysion atrophy, and spinal bulbar muscular atrophy. Objective: To determine the prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among the general population. Design, Setting, and Participants: This observational cross-sectional study included data from 5 large European population-based cohorts that were compiled between 1997 and 2012, and the analyses were conducted in 2018. In total, 16 547 DNA samples were obtained from participants of the 5 cohorts. Individuals with a lifetime diagnosis of major depression were excluded (n = 2351). In the remaining 14 196 participants without an established polyglutamine disease diagnosis, the CAG repeat size in both alleles of all 9 polyglutamine disease-associated genes (PDAGs) (ie, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR) was determined. Exposure: The number of CAG repeats in the alleles of the 9 PDAGs. Main Outcomes and Measures: The number of individuals with alleles within the intermediate or pathological range per PDAG, as well as differences in sex, age, and body mass index between individuals carrying alleles within the normal or intermediate range and individuals carrying alleles within the pathological range of PDAGs. Results: In the 14 196 analyzed participants (age range, 18-99 years; 56.3% female), 10.7% had a CAG repeat number within the intermediate range of at least 1 PDAG. Moreover, up to 1.3% of the participants had a CAG repeat number within the disease-causing range, predominantly in the lower pathological range associated with elderly onset. No differences in sex, age, or body mass index were found between individuals with CAG repeat numbers within the pathological range and individuals with CAG repeat numbers within the normal or intermediate range. Conclusions and Relevance: These results indicate a high prevalence of individuals carrying intermediate and pathological ranges of polyglutamine disease-associated alleles among the general population. Therefore, a substantially larger proportion of individuals than previously estimated may be at risk of developing a polyglutamine disease later in life or bearing children with a de novo mutation.

Repeat length variations in polyglutamine disease-associated genes affect body mass index.

BACKGROUND: The worldwide prevalence of obesity, a major risk factor for numerous debilitating chronic disorders, is increasing rapidly. Although a substantial amount of the variation in body mass index (BMI) is estimated to be heritable, the largest meta-analysis of genome-wide association studies (GWAS) to date explained only ~2.7% of the variation. To tackle this 'missing heritability' problem of obesity, here we focused on the contribution of DNA repeat length polymorphisms which are not detectable by GWAS. SUBJECTS AND METHODS: We determined the cytosine-adenine-guanine (CAG) repeat length in the nine known polyglutamine disease-associated genes (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1 and AR) in two large cohorts consisting of 12,457 individuals and analyzed their association with BMI, using generalized linear mixed-effect models. RESULTS: We found a significant association between BMI and the length of CAG repeats in seven polyglutamine disease-associated genes (including ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP and AR). Importantly, these repeat variations could account for 0.75% of the total BMI variation. CONCLUSIONS: Our findings incriminate repeat polymorphisms as an important novel class of genetic risk factors of obesity and highlight the role of the brain in its pathophysiology.

Suprachiasmatic nucleus neuropeptide expression in patients with Huntington's Disease.

STUDY OBJECTIVE: To study whether sleep and circadian rhythm disturbances in patients with Huntington's disease (HD) arise from dysfunction of the body's master clock, the hypothalamic suprachiasmatic nucleus. DESIGN: Postmortem cohort study. PATIENTS: Eight patients with HD and eight control subjects matched for sex, age, clock time and month of death, postmortem delay, and fixation time of paraffin-embedded hypothalamic tissue. MEASUREMENTS AND RESULTS: Using postmortem paraffin-embedded tissue, we assessed the functional integrity of the suprachiasmatic nucleus in patients with HD and control subjects by determining the expression of two major regulatory neuropeptides, vasoactive intestinal polypeptide and arginine vasopressin. Additionally, we studied melatonin 1 and 2 receptor expression. Compared with control subjects, the suprachiasmatic nucleus contained 85% fewer neurons immunoreactive for vasoactive intestinal polypeptide and 33% fewer neurons for arginine vasopressin in patients with HD (P = 0.002 and P = 0.027). The total amount of vasoactive intestinal polypeptide and arginine vasopressin messenger RNA was unchanged. No change was observed in the number of melatonin 1 or 2 receptor immunoreactive neurons. CONCLUSIONS: These findings indicate posttranscriptional neuropeptide changes in the suprachiasmatic nucleus of patients with HD, and suggest that sleep and circadian rhythm disorders in these patients may at least partly arise from suprachiasmatic nucleus dysfunction.

Leptin secretion rate increases with higher CAG repeat number in Huntington's disease patients.

BACKGROUND: Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an increased number of CAG repeats in the huntingtin gene. A hallmark of HD is unintended weight loss, the cause of which is unknown. OBJECTIVE: To perform a detailed analysis of adipose tissue function in HD patients as abnormal fat tissue function could contribute to the weight loss. DESIGN, SETTING AND PARTICIPANTS: In a clinical research laboratory, 24-h plasma concentrations of leptin, adiponectin and resistin were studied in nine early-stage, medication-free HD patients and nine age-, gender- and body mass index (BMI)-matched controls. MEASUREMENTS: Leptin was measured every 20 min whereas adiponectin and resistin were measured hourly. Autodeconvolution and cosinor regression were applied to quantify secretion characteristics of leptin and diurnal variations in leptin, adiponectin and resistin levels. RESULTS: Plasma levels and diurnal rhythmicity of leptin, adiponectin and resistin were not significantly different between HD patients and controls. However, although leptin production increased with higher BMI and fat mass in controls, no such relation was present in HD patients. Moreover, when corrected for fat mass, mean plasma leptin concentration as well as basal, pulsatile and total secretion rates increased with the size of the CAG repeat mutation (r = +0.72 to r = +0.80; all P < 0.05). Both higher pulsatile leptin secretion and higher mean adiponectin levels were associated with a greater degree of motor and functional impairment in HD patients. CONCLUSIONS: CAG-repeat size-dependent interference of the HD mutation with adipose tissue function may contribute to weight loss in HD patients.